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Cancers, Volume 15, Issue 9 (May-1 2023) – 258 articles

Cover Story (view full-size image): Six platinum(IV) complexes (16) that are mono-substituted in the axial position with a non-steroidal anti-inflammatory drug, naproxen or acemetacin, were synthesised and characterised. The potency of the complexes was significantly better than cisplatin in multiple cell lines. The platinum(IV) derivatives containing acemetacin (5 and 6) were the most potent, eliciting GI50 values ranging between 0.22 and 250 nM. In the Du145 prostate cell line, 6 elicited a GI50 value of 0.22 nM which is 5,450-fold more potent than cisplatin. A progressive decrease in reactive oxygen species and mitochondrial activity was observed for 16 in the HT29 colon cell line. Inhibition of the cyclooxygenase-2 enzyme was also demonstrated by 16, indicating that these complexes may reduce COX-2-dependent inflammation. View this paper
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23 pages, 7585 KiB  
Article
Intraoperative Assessment of Breast Cancer Tissues after Breast-Conserving Surgery Based on Mapping the Attenuation Coefficients in 3D Cross-Polarization Optical Coherence Tomography
by Ekaterina Gubarkova, Elena Kiseleva, Alexander Moiseev, Dmitry Vorontsov, Sergey Kuznetsov, Anton Plekhanov, Maria Karabut, Marina Sirotkina, Grigory Gelikonov, Sergey Gamayunov, Alexey Vorontsov, Petr Krivorotko and Natalia Gladkova
Cancers 2023, 15(9), 2663; https://doi.org/10.3390/cancers15092663 - 08 May 2023
Cited by 1 | Viewed by 1804
Abstract
Intraoperative differentiation of tumorous from non-tumorous tissue can help in the assessment of resection margins in breast cancer and its response to therapy and, potentially, reduce the incidence of tumor recurrence. In this study, the calculation of the attenuation coefficient and its color-coded [...] Read more.
Intraoperative differentiation of tumorous from non-tumorous tissue can help in the assessment of resection margins in breast cancer and its response to therapy and, potentially, reduce the incidence of tumor recurrence. In this study, the calculation of the attenuation coefficient and its color-coded 2D distribution was performed for different breast cancer subtypes using spectral-domain CP OCT. A total of 68 freshly excised human breast specimens containing tumorous and surrounding non-tumorous tissues after BCS was studied. Immediately after obtaining structural 3D CP OCT images, en face color-coded attenuation coefficient maps were built in co-(Att(co)) and cross-(Att(cross)) polarization channels using a depth-resolved approach to calculating the values in each A-scan. We determined spatially localized signal attenuation in both channels and reported ranges of attenuation coefficients to five selected breast tissue regions (adipose tissue, non-tumorous fibrous connective tissue, hyalinized tumor stroma, low-density tumor cells in the fibrotic tumor stroma and high-density clusters of tumor cells). The Att(cross) coefficient exhibited a stronger gain contrast of studied tissues compared to the Att(co) coefficient (i.e., conventional attenuation coefficient) and, therefore, allowed improved differentiation of all breast tissue types. It has been shown that color-coded attenuation coefficient maps may be used to detect inter- and intra-tumor heterogeneity of various breast cancer subtypes as well as to assess the effectiveness of therapy. For the first time, the optimal threshold values of the attenuation coefficients to differentiate tumorous from non-tumorous breast tissues were determined. Diagnostic testing values for Att(cross) coefficient were higher for differentiation of tumor cell areas and tumor stroma from non-tumorous fibrous connective tissue: diagnostic accuracy was 91–99%, sensitivity—96–98%, and specificity—87–99%. Att(co) coefficient is more suitable for the differentiation of tumor cell areas from adipose tissue: diagnostic accuracy was 83%, sensitivity—84%, and specificity—84%. Therefore, the present study provides a new diagnostic approach to the differentiation of breast cancer tissue types based on the assessment of the attenuation coefficient from real-time CP OCT data and has the potential to be used for further rapid and accurate intraoperative assessment of the resection margins during BCS. Full article
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13 pages, 584 KiB  
Review
Roles of the PARP Inhibitor in BRCA1 and BRCA2 Pathogenic Mutated Metastatic Prostate Cancer: Direct Functions and Modification of the Tumor Microenvironment
by Takahiro Inoue, Sho Sekito, Takumi Kageyama, Yusuke Sugino and Takeshi Sasaki
Cancers 2023, 15(9), 2662; https://doi.org/10.3390/cancers15092662 - 08 May 2023
Cited by 2 | Viewed by 2197
Abstract
Cancer cells frequently exhibit defects in DNA damage repair (DDR), leading to genomic instability. Mutations in DDR genes or epigenetic alterations leading to the downregulation of DDR genes can result in increased dependency on other DDR pathways. Therefore, DDR pathways could be a [...] Read more.
Cancer cells frequently exhibit defects in DNA damage repair (DDR), leading to genomic instability. Mutations in DDR genes or epigenetic alterations leading to the downregulation of DDR genes can result in increased dependency on other DDR pathways. Therefore, DDR pathways could be a treatment target for various cancers. In fact, polyadenosine diphosphatase ribose polymerase (PARP) inhibitors, such as olaparib (Lynparza®), have shown remarkable therapeutic efficacy against BRCA1/2-mutant cancers through synthetic lethality. Recent genomic analytical advancements have revealed that BRCA1/BRCA2 pathogenic variants are the most frequent mutations among DDR genes in prostate cancer. Currently, the PROfound randomized controlled trial is investigating the efficacy of a PARP inhibitor, olaparib (Lynparza®), in patients with metastatic castration-resistant prostate cancer (mCRPC). The efficacy of the drug is promising, especially in patients with BRCA1/BRCA2 pathogenic variants, even if they are in the advanced stage of the disease. However, olaparib (Lynparza®) is not effective in all BRCA1/2 mutant prostate cancer patients and inactivation of DDR genes elicits genomic instability, leading to alterations in multiple genes, which eventually leads to drug resistance. In this review, we summarize PARP inhibitors’ basic and clinical mechanisms of action against prostate cancer cells and discuss their effects on the tumor microenvironment. Full article
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49 pages, 17207 KiB  
Review
Endorsement of TNBC Biomarkers in Precision Therapy by Nanotechnology
by Aiswarya Chaudhuri, Dulla Naveen Kumar, Deepa Dehari, Rohit Patil, Sanjay Singh, Dinesh Kumar and Ashish Kumar Agrawal
Cancers 2023, 15(9), 2661; https://doi.org/10.3390/cancers15092661 - 08 May 2023
Cited by 5 | Viewed by 3851
Abstract
Breast cancer is a heterogeneous disease which accounts globally for approximately 1 million new cases annually, wherein more than 200,000 of these cases turn out to be cases of triple-negative breast cancer (TNBC). TNBC is an aggressive and rare breast cancer subtype that [...] Read more.
Breast cancer is a heterogeneous disease which accounts globally for approximately 1 million new cases annually, wherein more than 200,000 of these cases turn out to be cases of triple-negative breast cancer (TNBC). TNBC is an aggressive and rare breast cancer subtype that accounts for 10–15% of all breast cancer cases. Chemotherapy remains the only therapy regimen against TNBC. However, the emergence of innate or acquired chemoresistance has hindered the chemotherapy used to treat TNBC. The data obtained from molecular technologies have recognized TNBC with various gene profiling and mutation settings that have helped establish and develop targeted therapies. New therapeutic strategies based on the targeted delivery of therapeutics have relied on the application of biomarkers derived from the molecular profiling of TNBC patients. Several biomarkers have been found that are targets for the precision therapy in TNBC, such as EGFR, VGFR, TP53, interleukins, insulin-like growth factor binding proteins, c-MET, androgen receptor, BRCA1, glucocorticoid, PTEN, ALDH1, etc. This review discusses the various candidate biomarkers identified in the treatment of TNBC along with the evidence supporting their use. It was established that nanoparticles had been considered a multifunctional system for delivering therapeutics to target sites with increased precision. Here, we also discuss the role of biomarkers in nanotechnology translation in TNBC therapy and management. Full article
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21 pages, 5028 KiB  
Article
Senolytic Flavonoids Enhance Type-I and Type-II Cell Death in Human Radioresistant Colon Cancer Cells through AMPK/MAPK Pathway
by Maria Russo, Stefania Moccia, Diomira Luongo and Gian Luigi Russo
Cancers 2023, 15(9), 2660; https://doi.org/10.3390/cancers15092660 - 08 May 2023
Cited by 8 | Viewed by 2435
Abstract
Resistance to cancer therapies remains a clinical challenge and an unsolved problem. In a previous study, we characterized a new colon cancer cell line, namely HT500, derived from human HT29 cells and resistant to clinically relevant levels of ionizing radiation (IR). Here, we [...] Read more.
Resistance to cancer therapies remains a clinical challenge and an unsolved problem. In a previous study, we characterized a new colon cancer cell line, namely HT500, derived from human HT29 cells and resistant to clinically relevant levels of ionizing radiation (IR). Here, we explored the effects of two natural flavonoids, quercetin (Q) and fisetin (F), well-known senolytic agents that inhibit genotoxic stress by selectively removing senescent cells. We hypothesized that the biochemical mechanisms responsible for the radiosensitising effects of these natural senolytics could intercept multiple biochemical pathways of signal transduction correlated to cell death resistance. Radioresistant HT500 cells modulate autophagic flux differently than HT29 cells and secrete pro-inflammatory cytokines (IL-8), commonly associated with senescence-related secretory phenotypes (SASP). Q and F inhibit PI3K/AKT and ERK pathways, which promote p16INK4 stability and resistance to apoptosis, but they also activate AMPK and ULK kinases in response to autophagic stress at an early stage. In summary, the combination of natural senolytics and IR activates two forms of cell death: apoptosis correlated to the inhibition of ERKs and lethal autophagy dependent on AMPK kinase. Our study confirms that senescence and autophagy partially overlap, share common modulatory pathways, and reveal how senolytic flavonoids can play an important role in these processes. Full article
(This article belongs to the Section Cancer Therapy)
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15 pages, 1899 KiB  
Article
Efficacy of Lymph Node Location-Number Hybrid Staging System on the Prognosis of Gastric Cancer Patients
by Junpeng Wu, Hao Wang, Xin Yin, Xibo Wang, Yufei Wang, Zhanfei Lu, Jiaqi Zhang, Yao Zhang and Yingwei Xue
Cancers 2023, 15(9), 2659; https://doi.org/10.3390/cancers15092659 - 08 May 2023
Cited by 1 | Viewed by 2225
Abstract
Background: Lymph node metastasis location and number significantly affects the prognosis of patients with gastric cancer (GC). This study was designed to examine a new lymph node hybrid staging (hN) system to increase the predictive ability for patients with GC. Methods: This study [...] Read more.
Background: Lymph node metastasis location and number significantly affects the prognosis of patients with gastric cancer (GC). This study was designed to examine a new lymph node hybrid staging (hN) system to increase the predictive ability for patients with GC. Methods: This study analyzed the gastrointestinal treatment of GC at the Harbin Medical University Cancer Hospital from January 2011 to December 2016, and selected 2598 patients from 2011 to 2015 as the training cohort (hN) and 756 patients from 2016 as the validation cohort (2016-hN). The study utilized the receiver operating characteristic curve (ROC), c-index, and decision curve analysis (DCA) to compare the prognostic performance of the hN with the 8th edition of AJCC pathological lymph node (pN) staging for GC patients. Results: The ROC verification of the training cohort and validation cohort based on each hN staging and pN staging showed that for each N staging, the hN staging had a training cohort with an AUC of 0.752 (0.733, 0.772) and a validation cohort with an AUC of 0.812 (0.780, 0.845). In the pN staging, the training cohort had an AUC of 0.728 (0.708, 0.749), and the validation cohort had an AUC of 0.784 (0.754, 0.824). c-Index and DCA also showed that hN staging had a higher prognostic ability than pN staging, which was confirmed in the training cohort and the verification cohort, respectively. Conclusion: Lymph node location-number hybrid staging can significantly improve the prognosis of patients with GC. Full article
(This article belongs to the Section Clinical Research of Cancer)
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24 pages, 735 KiB  
Review
Clinical Significance of microRNAs in Hematologic Malignancies and Hematopoietic Stem Cell Transplantation
by Aneta Sevcikova, Ivana Fridrichova, Nataliia Nikolaieva, Lenka Kalinkova, Radoslav Omelka, Monika Martiniakova and Sona Ciernikova
Cancers 2023, 15(9), 2658; https://doi.org/10.3390/cancers15092658 - 08 May 2023
Cited by 5 | Viewed by 2008
Abstract
Hematologic malignancies are a group of neoplastic conditions that can develop from any stage of the hematopoiesis cascade. Small non-coding microRNAs (miRNAs) play a crucial role in the post-transcriptional regulation of gene expression. Mounting evidence highlights the role of miRNAs in malignant hematopoiesis [...] Read more.
Hematologic malignancies are a group of neoplastic conditions that can develop from any stage of the hematopoiesis cascade. Small non-coding microRNAs (miRNAs) play a crucial role in the post-transcriptional regulation of gene expression. Mounting evidence highlights the role of miRNAs in malignant hematopoiesis via the regulation of oncogenes and tumor suppressors involved in proliferation, differentiation, and cell death. In this review, we provide current knowledge about dysregulated miRNA expression in the pathogenesis of hematological malignancies. We summarize data about the clinical utility of aberrant miRNA expression profiles in hematologic cancer patients and their associations with diagnosis, prognosis, and the monitoring of treatment response. Moreover, we will discuss the emerging role of miRNAs in hematopoietic stem cell transplantation (HSCT), and severe post-HSCT complications, such as graft-versus-host disease (GvHD). The therapeutical potential of the miRNA-based approach in hemato-oncology will be outlined, including studies with specific antagomiRs, mimetics, and circular RNAs (circRNAs). Since hematologic malignancies represent a full spectrum of disorders with different treatment paradigms and prognoses, the potential use of miRNAs as novel diagnostic and prognostic biomarkers might lead to improvements, resulting in a more accurate diagnosis and better patient outcomes. Full article
(This article belongs to the Collection miRNAs: New Insights in Tumor Biology)
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13 pages, 594 KiB  
Article
Preoperative Arterial Embolization of Musculoskeletal Tumors: A Tertiary Center Experience
by Alice Kedra, Anthony Dohan, David Biau, Anissa Belbachir, Raphael Dautry, Alexandre Lucas, Mathilde Aissaoui, Antoine Feydy, Philippe Soyer and Maxime Barat
Cancers 2023, 15(9), 2657; https://doi.org/10.3390/cancers15092657 - 08 May 2023
Viewed by 1364
Abstract
The purpose of this study was to report the effectiveness of preoperative transcatheter arterial embolization (TAE) of musculoskeletal tumors in terms of blood loss and functional outcomes. Patients who underwent preoperative TAE of hypervascular musculoskeletal tumors between January 2018 and December 2021 were [...] Read more.
The purpose of this study was to report the effectiveness of preoperative transcatheter arterial embolization (TAE) of musculoskeletal tumors in terms of blood loss and functional outcomes. Patients who underwent preoperative TAE of hypervascular musculoskeletal tumors between January 2018 and December 2021 were retrospectively included. The patients’ characteristics, TAE procedure details, degree of post-TAE devascularization, surgical outcomes in terms of red blood cell transfusion and functional results were collected. The degree of devascularization was compared between patients who had peri-operative transfusion and those who did not. Thirty-one patients were included. The 31 TAE procedures led to complete (58%) or near-complete (42%) tumor devascularization. Twenty-two patients (71%) had no blood transfusion during surgery. Nine patients (29%) had a blood transfusion, with a median number of red blood cell packs of three (q1, 2; q3, 4; range: 1–4). Eight patients (27%) had complete improvement of the initial musculoskeletal symptoms at the end of the follow-up, 15 (50%) had partially satisfying improvement, 4 (13%) had partially unsatisfying improvement and 3 (10%) had no improvement. Our study suggests that preoperative TAE of hypervascular musculoskeletal tumors allowed for bloodless surgery in 71% of patients and minimal transfusion needs for the remaining 29%. Full article
(This article belongs to the Collection Advances in Diagnostic and Interventional Radiology in Oncology)
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11 pages, 2252 KiB  
Article
Automated Deep Learning-Based Classification of Wilms Tumor Histopathology
by Ananda van der Kamp, Thomas de Bel, Ludo van Alst, Jikke Rutgers, Marry M. van den Heuvel-Eibrink, Annelies M. C. Mavinkurve-Groothuis, Jeroen van der Laak and Ronald R. de Krijger
Cancers 2023, 15(9), 2656; https://doi.org/10.3390/cancers15092656 - 08 May 2023
Viewed by 1537
Abstract
(1) Background: Histopathological assessment of Wilms tumors (WT) is crucial for risk group classification to guide postoperative stratification in chemotherapy pre-treated WT cases. However, due to the heterogeneous nature of the tumor, significant interobserver variation between pathologists in WT diagnosis has been observed, [...] Read more.
(1) Background: Histopathological assessment of Wilms tumors (WT) is crucial for risk group classification to guide postoperative stratification in chemotherapy pre-treated WT cases. However, due to the heterogeneous nature of the tumor, significant interobserver variation between pathologists in WT diagnosis has been observed, potentially leading to misclassification and suboptimal treatment. We investigated whether artificial intelligence (AI) can contribute to accurate and reproducible histopathological assessment of WT through recognition of individual histopathological tumor components. (2) Methods: We assessed the performance of a deep learning-based AI system in quantifying WT components in hematoxylin and eosin-stained slides by calculating the Sørensen–Dice coefficient for fifteen predefined renal tissue components, including six tumor-related components. We trained the AI system using multiclass annotations from 72 whole-slide images of patients diagnosed with WT. (3) Results: The overall Dice coefficient for all fifteen tissue components was 0.85 and for the six tumor-related components was 0.79. Tumor segmentation worked best to reliably identify necrosis (Dice coefficient 0.98) and blastema (Dice coefficient 0.82). (4) Conclusions: Accurate histopathological classification of WT may be feasible using a digital pathology-based AI system in a national cohort of WT patients. Full article
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17 pages, 2695 KiB  
Review
Interventional Treatment Strategies in Intrahepatic Cholangiocarcinoma and Perspectives for Combined Hepatocellular-Cholangiocarcinoma
by Timo Alexander Auer, Federico Collettini, Laura Segger, Uwe Pelzer, Raphael Mohr, Felix Krenzien, Bernhard Gebauer, Dominik Geisel, Clarissa Hosse, Wenzel Schöning and Uli Fehrenbach
Cancers 2023, 15(9), 2655; https://doi.org/10.3390/cancers15092655 - 08 May 2023
Cited by 2 | Viewed by 1749
Abstract
cHCC-CCA is an uncommon type of liver cancer that exhibits clinical and pathological characteristics of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), which are the two main forms of primary liver cancer. The similarity to HCC and CCA makes therapeutical strategies challenging. The [...] Read more.
cHCC-CCA is an uncommon type of liver cancer that exhibits clinical and pathological characteristics of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), which are the two main forms of primary liver cancer. The similarity to HCC and CCA makes therapeutical strategies challenging. The poor prognosis of CCA in general, as well as for cHCC-CCA, is mainly attributable to the fact that diagnosis is often at an advanced stage of disease. During the last decade, locoregional therapies usually performed by interventional radiologists and its established role in HCC treatment have gained an increasing role in CCA treatment as well. These comprise a wide range of options from tumor ablation procedures such as radiofrequency ablation (RFA), microwave ablation (MWA), computed tomography high-dose rate brachytherapy (CT-HDRBT), and cryoablation to transarterial chemoembolization (TACE), including the option of intra-arterial administration of radioactive spheres (transarterial radioembolization—TARE), and much attention has focused on the potential of individual concepts in recent years. The purpose of this review is to provide an overview of current radiologic interventions for CCA (excluding options for eCCA), to review and appraise the existing literature on the topic, and to provide an outlook on whether such interventions may have a role as treatment for cHCC-CCA in the future. Full article
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12 pages, 600 KiB  
Review
Prostate Cancer in Sexual Minorities: Epidemiology, Screening and Diagnosis, Treatment, and Quality of Life
by Omid Yazdanpanah, David J. Benjamin and Arash Rezazadeh Kalebasty
Cancers 2023, 15(9), 2654; https://doi.org/10.3390/cancers15092654 - 08 May 2023
Viewed by 1911
Abstract
Prostate cancer has the highest incidence among all cancers in men. Sexual minorities, including gay and bisexual men, as well as transgender, were previously a “hidden population” that experienced prostate cancer. Although there continues to remain a paucity of data in this population, [...] Read more.
Prostate cancer has the highest incidence among all cancers in men. Sexual minorities, including gay and bisexual men, as well as transgender, were previously a “hidden population” that experienced prostate cancer. Although there continues to remain a paucity of data in this population, analyses from studies do not reveal whether this population is more likely to endure prostate cancer. Nonetheless, several qualitative and quantitative studies have established worse quality-of-life outcomes for sexual minorities following prostate cancer treatment. Increased awareness of this previously “hidden population” among healthcare workers, as well as more research, is warranted to gain further understanding on potential disparities faced by this growing population. Full article
(This article belongs to the Collection Advances in Cancer Disparities)
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17 pages, 1262 KiB  
Review
Impact of the Cancer Cell Secretome in Driving Breast Cancer Progression
by Syazalina Zahari, Saiful Effendi Syafruddin and M. Aiman Mohtar
Cancers 2023, 15(9), 2653; https://doi.org/10.3390/cancers15092653 - 08 May 2023
Cited by 4 | Viewed by 2473
Abstract
Breast cancer is a complex and heterogeneous disease resulting from the accumulation of genetic and epigenetic alterations in breast epithelial cells. Despite remarkable progress in diagnosis and treatment, breast cancer continues to be the most prevalent cancer affecting women worldwide. Recent research has [...] Read more.
Breast cancer is a complex and heterogeneous disease resulting from the accumulation of genetic and epigenetic alterations in breast epithelial cells. Despite remarkable progress in diagnosis and treatment, breast cancer continues to be the most prevalent cancer affecting women worldwide. Recent research has uncovered a compelling link between breast cancer onset and the extracellular environment enveloping tumor cells. The complex network of proteins secreted by cancer cells and other cellular components within the tumor microenvironment has emerged as a critical player in driving the disease’s metastatic properties. Specifically, the proteins released by the tumor cells termed the secretome, can significantly influence the progression and metastasis of breast cancer. The breast cancer cell secretome promotes tumorigenesis through its ability to modulate growth-associated signaling pathways, reshaping the tumor microenvironment, supporting pre-metastatic niche formation, and facilitating immunosurveillance evasion. Additionally, the secretome has been shown to play a crucial role in drug resistance development, making it an attractive target for cancer therapy. Understanding the intricate role of the cancer cell secretome in breast cancer progression will provide new insights into the underlying mechanisms of this disease and aid in the development of more innovative therapeutic interventions. Hence, this review provides a nuanced analysis of the impact of the cancer cell secretome on breast cancer progression, elucidates the complex reciprocal interaction with the components of the tumor microenvironment and highlights emerging therapeutic opportunities for targeting the constituents of the secretome. Full article
(This article belongs to the Special Issue Updates on Breast Cancer)
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17 pages, 1477 KiB  
Article
Gene Expression Pattern of ESPL1, PTTG1 and PTTG1IP Can Potentially Predict Response to TKI First-Line Treatment of Patients with Newly Diagnosed CML
by Eva Christiani, Nicole Naumann, Christel Weiss, Birgit Spiess, Helga Kleiner, Alice Fabarius, Wolf-Karsten Hofmann, Susanne Saussele and Wolfgang Seifarth
Cancers 2023, 15(9), 2652; https://doi.org/10.3390/cancers15092652 - 08 May 2023
Cited by 1 | Viewed by 1446
Abstract
The achievement of major molecular response (MMR, BCR::ABL1 ≤ 0.1% IS) within the first year of treatment with tyrosine kinase inhibitors (TKI) is a milestone in the therapeutic management of patients with newly diagnosed chronic myeloid leukemia (CML). We analyzed the predictive value [...] Read more.
The achievement of major molecular response (MMR, BCR::ABL1 ≤ 0.1% IS) within the first year of treatment with tyrosine kinase inhibitors (TKI) is a milestone in the therapeutic management of patients with newly diagnosed chronic myeloid leukemia (CML). We analyzed the predictive value of gene expression levels of ESPL1/Separase, PTTG1/Securin and PTTG1IP/Securin interacting protein for MMR achievement within 12 months. Relative expression levels (normalized to GUSB) of ESPL1, PTTG1 and PTTG1IP in white blood cells of patients (responders n = 46, non-responders n = 51) at the time of diagnosis were comparatively analyzed by qRT-PCR. 3D scatter plot analysis combined with a distance analysis performed with respect to a commonly calculated centroid center resulted in a trend to larger distances for non-responders compared to the responder cohort (p = 0.0187). Logistic regression and analysis of maximum likelihood estimates revealed a positive correlation of distance (cut-off) with non-achieving MMR within 12 months (p = 0.0388, odds ratio 1.479, 95%CI: 1.020 to 2.143). Thus, 10% of the tested non-responders (cut-off ≥ 5.9) could have been predicted already at the time of diagnosis. Future scoring of ESPL1, PTTG1 and PTTG1IP transcript levels may be a helpful tool in risk stratification of CML patients before initiation of TKI first-line treatment. Full article
(This article belongs to the Section Cancer Biomarkers)
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16 pages, 3489 KiB  
Review
Role of PET/CT in Oropharyngeal Cancers
by Emily W. Avery, Kavita Joshi, Saral Mehra and Amit Mahajan
Cancers 2023, 15(9), 2651; https://doi.org/10.3390/cancers15092651 - 08 May 2023
Cited by 3 | Viewed by 1910
Abstract
Oropharyngeal squamous cell carcinoma (OPSCC) comprises cancers of the tonsils, tongue base, soft palate, and uvula. The staging of oropharyngeal cancers varies depending upon the presence or absence of human papillomavirus (HPV)-directed pathogenesis. The incidence of HPV-associated oropharyngeal cancer (HPV + OPSCC) is [...] Read more.
Oropharyngeal squamous cell carcinoma (OPSCC) comprises cancers of the tonsils, tongue base, soft palate, and uvula. The staging of oropharyngeal cancers varies depending upon the presence or absence of human papillomavirus (HPV)-directed pathogenesis. The incidence of HPV-associated oropharyngeal cancer (HPV + OPSCC) is expected to continue to rise over the coming decades. PET/CT is a useful modality for the diagnosis, staging, and follow up of patients with oropharyngeal cancers undergoing treatment and surveillance. Full article
(This article belongs to the Special Issue PET/CT in Head and Neck Cancer)
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12 pages, 1765 KiB  
Article
Genetic Polymorphisms of the Telomerase Reverse Transcriptase Gene in Relation to Prostate Tumorigenesis, Aggressiveness and Mortality: A Cross-Ancestry Analysis
by Yongle Zhan, Xiaohao Ruan, Jiacheng Liu, Da Huang, Jingyi Huang, Jinlun Huang, Tsun Tsun Stacia Chun, Ada Tsui-Lin Ng, Yishuo Wu, Gonghong Wei, Haowen Jiang, Danfeng Xu and Rong Na
Cancers 2023, 15(9), 2650; https://doi.org/10.3390/cancers15092650 - 08 May 2023
Cited by 1 | Viewed by 1301
Abstract
Background: Telomerase reverse transcriptase (TERT) has been consistently associated with prostate cancer (PCa) risk. However, few studies have explored the association between TERT variants and PCa aggressiveness. Methods: Individual and genetic data were obtained from UK Biobank and a Chinese PCa [...] Read more.
Background: Telomerase reverse transcriptase (TERT) has been consistently associated with prostate cancer (PCa) risk. However, few studies have explored the association between TERT variants and PCa aggressiveness. Methods: Individual and genetic data were obtained from UK Biobank and a Chinese PCa cohort (Chinese Consortium for Prostate Cancer Genetics). Results: A total of 209,694 Europeans (14,550 PCa cases/195,144 controls) and 8873 Chinese (4438 cases/4435 controls) were involved. Nineteen susceptibility loci with five novel ones (rs144704378, rs35311994, rs34194491, rs144020096, and rs7710703) were detected in Europeans, whereas seven loci with two novel ones (rs7710703 and rs11291391) were discovered in the Chinese cohort. The index SNP for the two ancestries was rs2242652 (odds ratio [OR] = 1.16, 95% confidence interval [CI]:1.12–1.20, p = 4.12 × 10−16) and rs11291391 (OR = 1.73, 95%CI:1.34–2.25, p = 3.04 × 10−5), respectively. SNPs rs2736100 (OR = 1.49, 95%CI:1.31–1.71, p = 2.91 × 10−9) and rs2853677 (OR = 1.74, 95%CI:1.52–1.98, p = 3.52 × 10−16) were found significantly associated with aggressive PCa, while rs35812074 was marginally related to PCa death (hazard ratio [HR] = 1.61, 95%CI:1.04–2.49, p = 0.034). Gene-based analysis showed a significant association of TERT with PCa (European: p = 3.66 × 10−15, Chinese: p = 0.043) and PCa severity (p = 0.006) but not with PCa death (p = 0.171). Conclusion: TERT polymorphisms were associated with prostate tumorigenesis and severity, and the genetic architectures of PCa susceptibility loci were heterogeneous among distinct ancestries. Full article
(This article belongs to the Special Issue The Dual Roles of Telomeres and Telomerase in Aging and Cancer)
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2 pages, 188 KiB  
Comment
Role of PSA Density and MRI in PSA Interpretation. Comment on Lumbreras et al. Variables Associated with False-Positive PSA Results: A Cohort Study with Real-World Data. Cancers 2023, 15, 261
by Joshua S. Jue and Mahmoud Alameddine
Cancers 2023, 15(9), 2649; https://doi.org/10.3390/cancers15092649 - 08 May 2023
Cited by 1 | Viewed by 714
Abstract
Prostate-specific antigen (PSA) has been utilized as a prostate cancer screening test for its high sensitivity for prostate cancer but is often criticized for its low specificity [...] Full article
12 pages, 1298 KiB  
Article
Performance of Ultra-Rapid Idylla™ EGFR Mutation Test in Non-Small-Cell Lung Cancer and Its Potential at Clinical Molecular Screening
by Kenichi Suda, Kazuko Sakai, Tatsuo Ohira, Takaaki Chikugo, Takao Satou, Jun Matsubayashi, Toshitaka Nagao, Norihiko Ikeda, Yasuhiro Tsutani, Tetsuya Mitsudomi and Kazuto Nishio
Cancers 2023, 15(9), 2648; https://doi.org/10.3390/cancers15092648 - 07 May 2023
Cited by 1 | Viewed by 1939
Abstract
Background: The Idylla™ EGFR Mutation Test is an ultra-rapid single-gene test that detects epidermal growth factor receptor (EGFR) mutations using formalin-fixed paraffin-embedded specimens. Here, we compared the performance of the Idylla EGFR Mutation Test with the Cobas® EGFR Mutation Test [...] Read more.
Background: The Idylla™ EGFR Mutation Test is an ultra-rapid single-gene test that detects epidermal growth factor receptor (EGFR) mutations using formalin-fixed paraffin-embedded specimens. Here, we compared the performance of the Idylla EGFR Mutation Test with the Cobas® EGFR Mutation Test v2. Methods: Surgically resected NSCLC specimens obtained at two Japanese institutions (N = 170) were examined. The Idylla EGFR Mutation Test and the Cobas EGFR Mutation Test v2 were performed independently and the results were compared. For discordant cases, the Ion AmpliSeq Colon and Lung Cancer Research Panel V2 was performed. Results: After the exclusion of five inadequate/invalid samples, 165 cases were evaluated. EGFR mutation analysis revealed 52 were positive and 107 were negative for EGFR mutation in both assays (overall concordance rate: 96.4%). Analyses of the six discordant cases revealed that the Idylla EGFR Mutation Test was correct in four and the Cobas EGFR Mutation Test v2 was correct in two. In a trial calculation, the combination of the Idylla EGFR Mutation Test followed by a multi-gene panel test will reduce molecular screening expenses if applied to a cohort with EGFR mutation frequency >17.9%. Conclusions: We demonstrated the accuracy and potential clinical utility of the Idylla EGFR Mutation Test as a molecular screening platform in terms of turnaround time and molecular testing cost if applied to a cohort with a high EGFR mutation incidence (>17.9%). Full article
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16 pages, 3315 KiB  
Article
Complement Activation and Up-Regulated Expression of Anaphylatoxin C3a/C3aR in Glioblastoma: Deciphering the Links with TGF-β and VEGF
by Franck Ah-Pine, Axelle Malaterre-Septembre, Yosra Bedoui, Mohamed Khettab, James W. Neal, Sébastien Freppel and Philippe Gasque
Cancers 2023, 15(9), 2647; https://doi.org/10.3390/cancers15092647 - 07 May 2023
Cited by 4 | Viewed by 2161
Abstract
The complement (C) innate immune system has been shown to be activated in the tumor microenvironment of various cancers. The C may support tumor growth by modulating the immune response and promoting angiogenesis through the actions of C anaphylatoxins (e.g., C5a, C3a). The [...] Read more.
The complement (C) innate immune system has been shown to be activated in the tumor microenvironment of various cancers. The C may support tumor growth by modulating the immune response and promoting angiogenesis through the actions of C anaphylatoxins (e.g., C5a, C3a). The C has important double-edged sword functions in the brain, but little is known about its role in brain tumors. Hence, we analyzed the distribution and the regulated expression of C3a and its receptor C3aR in various primary and secondary brain tumors. We found that C3aR was dramatically upregulated in Grade 4 diffuse gliomas, i.e., glioblastoma multiforme, IDH-wildtype (GBM) and astrocytoma, IDH-mutant, Grade 4, and was much less expressed in other brain tumors. C3aR was observed in tumor-associated macrophages (TAM) expressing CD68, CD18, CD163, and the proangiogenic VEGF. Robust levels of C3a were detected in the parenchyma of GBM as a possible result of Bb-dependent C activation of the alternative C pathway. Interestingly, in vitro models identified TGF-β1 as one of the most potent growth factors that upregulate VEGF, C3, and C3aR in TAM (PMA-differentiated THP1) cell lines. Further studies should help to delineate the functions of C3a/C3aR on TAMs that promote chemotaxis/angiogenesis in gliomas and to explore the therapeutic applications of C3aR antagonists for brain tumors. Full article
(This article belongs to the Special Issue Inflammation, Immunity, and Cancer Progression)
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11 pages, 1091 KiB  
Article
Diagnostic Value of FDG PET/CT in Surveillance after Curative Resection of Breast Cancer
by Hwanhee Lee, Joon Young Choi, Yeon Hee Park, Jeong Eon Lee, Seok Won Kim, Seok Jin Nam and Young Seok Cho
Cancers 2023, 15(9), 2646; https://doi.org/10.3390/cancers15092646 - 07 May 2023
Viewed by 1479
Abstract
With increasing incidence of breast cancer and improvement in treatment, the concern about surveillance management also has increased. This retrospective study was designed to evaluate the diagnostic value of routine surveillance FDG PET/CT in patients with breast cancer. The diagnostic performance of surveillance [...] Read more.
With increasing incidence of breast cancer and improvement in treatment, the concern about surveillance management also has increased. This retrospective study was designed to evaluate the diagnostic value of routine surveillance FDG PET/CT in patients with breast cancer. The diagnostic performance of surveillance PET/CT was analyzed regarding sensitivity, specificity, positive predictive value, negative predictive value and accuracy. The diagnostic accuracy was defined as the ability to differentiate recurrence and no-disease correctly and the proportion of true results, either true positive or true negative, in the population. Findings from pathologic examination; other imaging modalities such as CT, MRI and bone scan; or clinical follow-up were used as the reference standard. In this study of 1681 consecutive patients with breast cancer who underwent curative surgery, surveillance fluorodeoxyglucose PET/CT showed good diagnostic performance in the detection of clinically unexpected recurrent breast cancer or other malignancy, with a sensitivity of 100%, specificity of 98.5%, positive predictive value of 70.5%, negative predictive value of 100% and accuracy of 98.5%. In conclusion, surveillance fluorodeoxyglucose PET/CT showed good diagnostic performance in the detection of clinically unexpected recurrent breast cancer after curative surgery. Full article
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19 pages, 1126 KiB  
Review
Osteocytes: New Kids on the Block for Cancer in Bone Therapy
by Aric Anloague and Jesus Delgado-Calle
Cancers 2023, 15(9), 2645; https://doi.org/10.3390/cancers15092645 - 07 May 2023
Cited by 3 | Viewed by 2096
Abstract
The tumor microenvironment plays a central role in the onset and progression of cancer in the bone. Cancer cells, either from tumors originating in the bone or from metastatic cancer cells from other body systems, are located in specialized niches where they interact [...] Read more.
The tumor microenvironment plays a central role in the onset and progression of cancer in the bone. Cancer cells, either from tumors originating in the bone or from metastatic cancer cells from other body systems, are located in specialized niches where they interact with different cells of the bone marrow. These interactions transform the bone into an ideal niche for cancer cell migration, proliferation, and survival and cause an imbalance in bone homeostasis that severely affects the integrity of the skeleton. During the last decade, preclinical studies have identified new cellular mechanisms responsible for the dependency between cancer cells and bone cells. In this review, we focus on osteocytes, long-lived cells residing in the mineral matrix that have recently been identified as key players in the spread of cancer in bone. We highlight the most recent discoveries on how osteocytes support tumor growth and promote bone disease. Additionally, we discuss how the reciprocal crosstalk between osteocytes and cancer cells provides the opportunity to develop new therapeutic strategies to treat cancer in the bone. Full article
(This article belongs to the Collection Oncology: State-of-the-Art Research in the USA)
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12 pages, 4740 KiB  
Article
US Evaluation of Topical Hemostatic Agents in Post-Thyroidectomy
by Vincenzo Dolcetti, Eleonora Lori, Daniele Fresilli, Giovanni Del Gaudio, Chiara Di Bella, Patrizia Pacini, Vito D’Andrea, Fabrizio Maria Frattaroli, Giulia Giordana Vallone, Piero Liberatore, Daniele Pironi, Gian Luigi Canu, Pietro Giorgio Calò, Vito Cantisani and Salvatore Sorrenti
Cancers 2023, 15(9), 2644; https://doi.org/10.3390/cancers15092644 - 07 May 2023
Cited by 2 | Viewed by 1570
Abstract
Background: the aim of this study was to describe the ultrasound appearance of topical hemostatics after thyroidectomy. Methods: we enrolled 84 patients who were undergoing thyroid surgery and were treated with two types of topical hemostats, 49 with an absorbable hemostat of oxidized [...] Read more.
Background: the aim of this study was to describe the ultrasound appearance of topical hemostatics after thyroidectomy. Methods: we enrolled 84 patients who were undergoing thyroid surgery and were treated with two types of topical hemostats, 49 with an absorbable hemostat of oxidized regenerated cellulose (Oxitamp®) and 35 with a fibrin glue-based hemostat (Tisseel®). All patients were examined using B-mode ultrasound. Results: In 39 patients of the first group (approximately 80%), a hemostatic residue was detected and in some cases confused with a native gland residue, or with cancer recurrence in oncological patients. No residue was detected in patients in the second group. The main ultrasound characteristics of the tampon were analyzed and arranged according to predefined patterns, and suggestions to recognize it and avoid wrong diagnoses were provided. A part of the group of patients with tampon residue was re-evaluated after 6–12 months, ensuring that the swab remained for months after the maximum resorption time declared by the manufacturer. Conclusions: with equal hemostatic effectiveness, the fibrin glue pad is more favorable in the ultrasound follow-up because it creates reduced surgical outcomes. It is also important to know and recognize the ultrasound characteristics of oxidized cellulose-based hemostats in order to reduce the number of diagnostic errors and inappropriate diagnostic investigations. Full article
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11 pages, 1031 KiB  
Article
Rising Trend in the Prevalence of HPV-Driven Oropharyngeal Squamous Cell Carcinoma during 2000–2022 in Northeastern Italy: Implication for Using p16INK4a as a Surrogate Marker for HPV-Driven Carcinogenesis
by Paolo Boscolo-Rizzo, Jerry Polesel, Annarosa Del Mistro, Elisabetta Fratta, Chiara Lazzarin, Anna Menegaldo, Valentina Lupato, Giuseppe Fanetti, Fabrizio Zanconati, Maria Guido, Vittorio Giacomarra, Enzo Emanuelli, Margherita Tofanelli and Giancarlo Tirelli
Cancers 2023, 15(9), 2643; https://doi.org/10.3390/cancers15092643 - 07 May 2023
Cited by 5 | Viewed by 1583
Abstract
Background: The prevalence and incidence of oropharyngeal squamous cell carcinomas (OPSCCs) driven by human papillomavirus (HPV) infection are increasing worldwide, being higher in high-income countries. However, data from Italy are scanty. p16INK4a overexpression is the standard in determining HPV-driven carcinogenesis, but disease [...] Read more.
Background: The prevalence and incidence of oropharyngeal squamous cell carcinomas (OPSCCs) driven by human papillomavirus (HPV) infection are increasing worldwide, being higher in high-income countries. However, data from Italy are scanty. p16INK4a overexpression is the standard in determining HPV-driven carcinogenesis, but disease prevalence impacts on its positive predictive value. Methods: This is a multicenter retrospective study enrolling 390 consecutive patients aged ≥18 years, diagnosed with pathologically confirmed OPSCC in Northeastern Italy between 2000 and 2022. High-risk HPV-DNA and p16INK4a status were retrieved from medical records or evaluated in formalin-fixed paraffin-embedded specimens. A tumor was defined as HPV-driven when double positive for high-risk HPV-DNA and p16INK4a overexpression. Results: Overall, 125 cases (32%) were HPV-driven, with a significant upward temporal trend from 12% in 2000–2006 to 50% in 2019–2022. The prevalence of HPV-driven cancer of the tonsil and base of the tongue increased up to 59%, whereas it remained below 10% in other subsites. Consequently, the p16INK4a positive predictive value was 89% for the former and 29% for the latter. Conclusions: The prevalence of HPV-driven OPSCC continued to increase, even in the most recent period. When using p16INK4a overexpression as a surrogate marker of transforming HPV infection, each institution should consider the subsite-specific prevalence rates of HPV-driven OPSCC as these significantly impact on its positive predictive value. Full article
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17 pages, 4610 KiB  
Article
Antiproliferative Activity of Krukovine by Regulating Transmembrane Protein 139 (TMEM139) in Oxaliplatin-Resistant Pancreatic Cancer Cells
by Jee-Hyung Lee, Sang-Hyub Lee, Sang-Kook Lee, Jin-Ho Choi, Seohyun Lim, Min-Song Kim, Kyung-Min Lee, Min-Woo Lee, Ja-Lok Ku, Dae-Hyun Kim, In-Rae Cho, Woo-Hyun Paik, Ji-Kon Ryu and Yong-Tae Kim
Cancers 2023, 15(9), 2642; https://doi.org/10.3390/cancers15092642 - 07 May 2023
Cited by 2 | Viewed by 1582
Abstract
Krukovine (KV) is an alkaloid isolated from the bark of Abuta grandifolia (Mart.) Sandw. (Menispermaceae) with anticancer potential in some cancers with KRAS mutations. In this study, we explored the anticancer efficacy and mechanism of KV in oxaliplatin-resistant pancreatic cancer cells and patient-derived [...] Read more.
Krukovine (KV) is an alkaloid isolated from the bark of Abuta grandifolia (Mart.) Sandw. (Menispermaceae) with anticancer potential in some cancers with KRAS mutations. In this study, we explored the anticancer efficacy and mechanism of KV in oxaliplatin-resistant pancreatic cancer cells and patient-derived pancreatic cancer organoids (PDPCOs) with KRAS mutation. After treatment with KV, mRNA and protein levels were determined by RNA-seq and Western blotting, respectively. Cell proliferation, migration, and invasion were measured by MTT, scratch wound healing assay, and transwell analysis, respectively. Patient-derived pancreatic cancer organoids (PDPCOs) with KRAS mutations were treated with KV, oxaliplatin (OXA), and a combination of KV and OXA. KV suppresses tumor progression via the downregulation of the Erk-RPS6K-TMEM139 and PI3K-Akt-mTOR pathways in oxaliplatin-resistant AsPC-1 cells. Furthermore, KV showed an antiproliferative effect in PDPCOs, and the combination of OXA and KV inhibited PDPCO growth more effectively than either drug alone. Full article
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1 pages, 165 KiB  
Correction
Correction: Sankaranarayanan et al. Auger Emitter Conjugated PARP Inhibitor for Therapy in Triple Negative Breast Cancers: A Comparative In-Vitro Study. Cancers 2022, 14, 230
by Ramya Ambur Sankaranarayanan, Jennifer Peil, Andreas T. J. Vogg, Carsten Bolm, Steven Terhorst, Arno Classen, Matthias Bauwens, Jochen Maurer, Felix Mottaghy and Agnieszka Morgenroth
Cancers 2023, 15(9), 2641; https://doi.org/10.3390/cancers15092641 - 06 May 2023
Viewed by 792
Abstract
The authors wish to replace the ‘Author Contributions’ statement and the affiliation for Jochen Maurer of this article [...] Full article
(This article belongs to the Special Issue Radiopharmaceuticals for Oncological Diseases)
14 pages, 657 KiB  
Review
The Cross Talk between Cellular Senescence and Melanoma: From Molecular Pathogenesis to Target Therapies
by Jiahua Liu, Runzi Zheng, Yanghuan Zhang, Shuting Jia, Yonghan He and Jing Liu
Cancers 2023, 15(9), 2640; https://doi.org/10.3390/cancers15092640 - 06 May 2023
Cited by 5 | Viewed by 2472
Abstract
Melanoma is a malignant skin tumor that originates from melanocytes. The pathogenesis of melanoma involves a complex interaction that occurs between environmental factors, ultraviolet (UV)-light damage, and genetic alterations. UV light is the primary driver of the skin aging process and development of [...] Read more.
Melanoma is a malignant skin tumor that originates from melanocytes. The pathogenesis of melanoma involves a complex interaction that occurs between environmental factors, ultraviolet (UV)-light damage, and genetic alterations. UV light is the primary driver of the skin aging process and development of melanoma, which can induce reactive oxygen species (ROS) production and the presence of DNA damage in the cells, and results in cell senescence. As cellular senescence plays an important role in the relationship that exists between the skin aging process and the development of melanoma, the present study provides insight into the literature concerning the topic at present and discusses the relationship between skin aging and melanoma, including the mechanisms of cellular senescence that drive melanoma progression, the microenvironment in relation to skin aging and melanoma factors, and the therapeutics concerning melanoma. This review focuses on defining the role of cellular senescence in the process of melanoma carcinogenesis and discusses the targeting of senescent cells through therapeutic approaches, highlighting the areas that require more extensive research in the field. Full article
(This article belongs to the Special Issue Latest Development in Melanoma Research)
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22 pages, 2386 KiB  
Review
Updated Epidemiology of Gastric Cancer in Asia: Decreased Incidence but Still a Big Challenge
by Wing Sum Shin, Fuda Xie, Bonan Chen, Peiyao Yu, Jun Yu, Ka Fai To and Wei Kang
Cancers 2023, 15(9), 2639; https://doi.org/10.3390/cancers15092639 - 06 May 2023
Cited by 9 | Viewed by 3362
Abstract
Despite the decline in incidence and mortality rates, gastric cancer (GC) is the fifth leading cause of cancer deaths worldwide. The incidence and mortality of GC are exceptionally high in Asia due to high H. pylori infection, dietary habits, smoking behaviors, and heavy [...] Read more.
Despite the decline in incidence and mortality rates, gastric cancer (GC) is the fifth leading cause of cancer deaths worldwide. The incidence and mortality of GC are exceptionally high in Asia due to high H. pylori infection, dietary habits, smoking behaviors, and heavy alcohol consumption. In Asia, males are more susceptible to developing GC than females. Variations in H. pylori strains and prevalence rates may contribute to the differences in incidence and mortality rates across Asian countries. Large-scale H. pylori eradication was one of the effective ways to reduce GC incidences. Treatment methods and clinical trials have evolved, but the 5-year survival rate of advanced GC is still low. Efforts should be put towards large-scale screening and early diagnosis, precision medicine, and deep mechanism studies on the interplay of GC cells and microenvironments for dealing with peritoneal metastasis and prolonging patients’ survival. Full article
(This article belongs to the Special Issue Targeted Therapy in Gastrointestinal Cancer)
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31 pages, 4120 KiB  
Article
Design and Biological Evaluation of Small-Molecule PET-Tracers for Imaging of Programmed Death Ligand 1
by Fabian Krutzek, Cornelius K. Donat, Martin Ullrich, Kristof Zarschler, Marie-Charlotte Ludik, Anja Feldmann, Liliana R. Loureiro, Klaus Kopka and Sven Stadlbauer
Cancers 2023, 15(9), 2638; https://doi.org/10.3390/cancers15092638 - 06 May 2023
Cited by 10 | Viewed by 2265
Abstract
Noninvasive molecular imaging of the PD-1/PD-L1 immune checkpoint is of high clinical relevance for patient stratification and therapy monitoring in cancer patients. Here we report nine small-molecule PD-L1 radiotracers with solubilizing sulfonic acids and a linker–chelator system, designed by molecular docking experiments and [...] Read more.
Noninvasive molecular imaging of the PD-1/PD-L1 immune checkpoint is of high clinical relevance for patient stratification and therapy monitoring in cancer patients. Here we report nine small-molecule PD-L1 radiotracers with solubilizing sulfonic acids and a linker–chelator system, designed by molecular docking experiments and synthesized according to a new, convergent synthetic strategy. Binding affinities were determined both in cellular saturation and real-time binding assay (LigandTracer), revealing dissociation constants in the single digit nanomolar range. Incubation in human serum and liver microsomes proved in vitro stability of these compounds. Small animal PET/CT imaging, in mice bearing PD-L1 overexpressing and PD-L1 negative tumors, showed moderate to low uptake. All compounds were cleared primarily through the hepatobiliary excretion route and showed a long circulation time. The latter was attributed to strong blood albumin binding effects, discovered during our binding experiments. Taken together, these compounds are a promising starting point for further development of a new class of PD-L1 targeting radiotracers. Full article
(This article belongs to the Section Cancer Biomarkers)
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15 pages, 660 KiB  
Systematic Review
Takotsubo Cardiomyopathy in Cancer Patients Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Summary of Included Cases
by Ioannis P. Trontzas, Ioannis A. Vathiotis, Konstantinos G. Kyriakoulis, Amalia Sofianidi, Zoi Spyropoulou, Andriani Charpidou, Elias A. Kotteas, Konstantinos N. Syrigos and ImmunoTTS Collaborative Group
Cancers 2023, 15(9), 2637; https://doi.org/10.3390/cancers15092637 - 06 May 2023
Cited by 1 | Viewed by 2349
Abstract
Background: There are emerging reports of Takotsubo syndrome (TTS) in cancer patients treated with immune checkpoint inhibitors (ICIs); however, the association of the two remains uncertain. Methods: A systematic literature review was performed in the PubMed database and web sources (Google Scholar) according [...] Read more.
Background: There are emerging reports of Takotsubo syndrome (TTS) in cancer patients treated with immune checkpoint inhibitors (ICIs); however, the association of the two remains uncertain. Methods: A systematic literature review was performed in the PubMed database and web sources (Google Scholar) according to the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) guidelines. Case reports/series or studies including cancer patients treated with ICIs and presenting with TTS were considered. Results: Seventeen cases were included in the systematic review. Most patients were males (59%) with median age of 70 years (30–83). Most common tumor types were lung cancer (35%) and melanoma (29%). Most patients were on first-line immunotherapy (35%) and after the first cycle (54%) of treatment. The median time on immunotherapy at the time of TTS presentation was 77 days (1–450). The most used agents were pembrolizumab and the combination of nivolumab–ipilimumab (35%, respectively). Potential stressors were recognized in 12 cases (80%). Six patients (35%) presented with concurrent cardiac complications. Corticosteroids were used in the management of eight patients (50%). Fifteen patients (88%) recovered from TTS, two patients (12%) relapsed, and one patient died. Immunotherapy was reintroduced in five cases (50%). Conclusion: TTS may be associated with immunotherapy for cancer. Physicians should be alert for TTS diagnosis in any patient with myocardial infarction-like presentation under treatment with ICIs. Full article
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17 pages, 8169 KiB  
Article
Computational Optimization of Irradiance and Fluence for Interstitial Photodynamic Therapy Treatment of Patients with Malignant Central Airway Obstruction
by Emily Oakley, Evgueni Parilov, Karl Beeson, Mary Potasek, Nathaniel Ivanick, Lawrence Tworek, Alan Hutson and Gal Shafirstein
Cancers 2023, 15(9), 2636; https://doi.org/10.3390/cancers15092636 - 06 May 2023
Viewed by 1187
Abstract
There are no effective treatments for patients with extrinsic malignant central airway obstruction (MCAO). In a recent clinical study, we demonstrated that interstitial photodynamic therapy (I-PDT) is a safe and potentially effective treatment for patients with extrinsic MCAO. In previous preclinical studies, we [...] Read more.
There are no effective treatments for patients with extrinsic malignant central airway obstruction (MCAO). In a recent clinical study, we demonstrated that interstitial photodynamic therapy (I-PDT) is a safe and potentially effective treatment for patients with extrinsic MCAO. In previous preclinical studies, we reported that a minimum light irradiance and fluence should be maintained within a significant volume of the target tumor to obtain an effective PDT response. In this paper, we present a computational approach to personalized treatment planning of light delivery in I-PDT that simultaneously optimizes the delivered irradiance and fluence using finite element method (FEM) solvers of either Comsol Multiphysics® or Dosie™ for light propagation. The FEM simulations were validated with light dosimetry measurements in a solid phantom with tissue-like optical properties. The agreement between the treatment plans generated by two FEMs was tested using typical imaging data from four patients with extrinsic MCAO treated with I-PDT. The concordance correlation coefficient (CCC) and its 95% confidence interval (95% CI) were used to test the agreement between the simulation results and measurements, and between the two FEMs treatment plans. Dosie with CCC = 0.994 (95% CI, 0.953–0.996) and Comsol with CCC = 0.999 (95% CI, 0.985–0.999) showed excellent agreement with light measurements in the phantom. The CCC analysis showed very good agreement between Comsol and Dosie treatment plans for irradiance (95% CI, CCC: 0.996–0.999) and fluence (95% CI, CCC: 0.916–0.987) in using patients’ data. In previous preclinical work, we demonstrated that effective I-PDT is associated with a computed light dose of ≥45 J/cm2 when the irradiance is ≥8.6 mW/cm2 (i.e., the effective rate-based light dose). In this paper, we show how to use Comsol and Dosie packages to optimize rate-based light dose, and we present Dosie’s newly developed domination sub-maps method to improve the planning of the delivery of the effective rate-based light dose. We conclude that image-based treatment planning using Comsol or Dosie FEM-solvers is a valid approach to guide the light dosimetry in I-PDT of patients with MCAO. Full article
(This article belongs to the Section Cancer Therapy)
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11 pages, 613 KiB  
Article
Effect on Germline Mutation Rate in a High-Risk Chinese Breast Cancer Cohort after Compliance with The National Comprehensive Cancer Network (NCCN) 2023 v.1 Testing Criteria
by Ava Kwong, Cecilia Y. S. Ho, Wing-Pan Luk, Ling-Hiu Fung, Chun-Hang Au and Edmond S. K. Ma
Cancers 2023, 15(9), 2635; https://doi.org/10.3390/cancers15092635 - 06 May 2023
Viewed by 1449
Abstract
Background: The National Comprehensive Cancer Network (NCCN) testing criteria for the high-penetrance breast cancer susceptibility genes, specifically BRCA1, BRCA2, CDH1, PALB2, PTEN, and TP53, have been recently modified in 2023 to 2023 v.1. The following criteria have [...] Read more.
Background: The National Comprehensive Cancer Network (NCCN) testing criteria for the high-penetrance breast cancer susceptibility genes, specifically BRCA1, BRCA2, CDH1, PALB2, PTEN, and TP53, have been recently modified in 2023 to 2023 v.1. The following criteria have been changed: (1) from a person diagnosed with breast cancer at ≤45 to ≤50; (2) from aged 45–50 of personal breast diagnosis to any age of diagnosis with multiple breast cancers; and (3) from aged ≥51 of personal breast diagnosis to any age of diagnosis with family history listed in NCCN 2022 v.2. Methods: High-risk breast cancer patients (n = 3797) were recruited from the Hong Kong Hereditary Breast Cancer Family Registry between 2007 and 2022. Patients were grouped according to NCCN testing criteria 2023 v.1 and 2022 v.2. A 30-gene panel for hereditary breast cancer was performed. The mutation rates on high-penetrance breast cancer susceptibility genes were compared. Results: About 91.2% of the patients met the 2022 v.2 criteria, while 97.5% of the patients met the 2023 v.1 criteria. An extra 6.4% of the patients were included after the revision of the criteria, and 2.5% of the patients did not meet both testing criteria. The germline BRCA1/2 mutation rates for patients meeting the 2022 v.2 and 2023 v.1 criteria were 10.1% and 9.6%, respectively. The germline mutation rates of all 6 high-penetrance genes in these two groups were 12.2% and 11.6%, respectively. Among the additional 242 patients who were included using the new selection criteria, the mutation rates were 2.1% and 2.5% for BRCA1/2 and all 6 high-penetrance genes, respectively. Patients who did not meet both testing criteria were those with multiple personal cancers, a strong family history of cancers not listed in the NCCN, unclear pathology information, or the patient’s voluntary intention to be tested. The mutation rates of BRCA1/2 and the 6 high-penetrance genes in these patients were 5.3% and 6.4%, respectively. Conclusion: This study provided a real-world application of the revision of NCCN guidelines and its effect on the germline mutation rate in the Chinese population. Applying the updated criteria for further genetic investigation would increase the positive detection rate, and potentially more patients would benefit. The balance between the resource and outcome requires careful consideration. Full article
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13 pages, 555 KiB  
Article
Prognostic Value of Erythroblastic Leukemia Viral Oncogene Homolog 2 and Neuregulin 4 in Hepatocellular Carcinoma
by Woo Sun Rou, Hyuk Soo Eun, Sorim Choung, Hong Jae Jeon, Jong Seok Joo, Sun Hyung Kang, Eaum Seok Lee, Seok Hyun Kim, In Sun Kwon, Bon Jeong Ku and Byung Seok Lee
Cancers 2023, 15(9), 2634; https://doi.org/10.3390/cancers15092634 - 06 May 2023
Cited by 1 | Viewed by 1270
Abstract
Although the roles of erythroblastic leukemia viral oncogene homolog 2 (ERBB2), neuregulin 4 (NRG4), and mitogen-inducible gene 6 (MIG6) in epidermal growth factor receptor signaling in hepatocellular carcinoma (HCC) and other malignancies have been previously investigated, the prognostic value of their serum levels [...] Read more.
Although the roles of erythroblastic leukemia viral oncogene homolog 2 (ERBB2), neuregulin 4 (NRG4), and mitogen-inducible gene 6 (MIG6) in epidermal growth factor receptor signaling in hepatocellular carcinoma (HCC) and other malignancies have been previously investigated, the prognostic value of their serum levels in HCC remains undetermined. In the present study, correlations between serum levels and tumor characteristics, overall survival, and tumor recurrence were analyzed. Furthermore, the prognostic potential of the serum levels of these biomarkers was evaluated relative to that of alpha-fetoprotein. Both ERBB2 and NRG4 correlated with the Barcelona Clinic Liver Cancer stage, ERBB2 correlated with the tumor-maximal diameter, and NRG4 correlated with a tumor number. Cox proportional hazards regression analysis revealed that ERBB2 (hazard ratio [HR], 2.719; p = 0.007) was an independent prognostic factor for overall survival. Furthermore, ERBB2 (HR, 2.338; p = 0.002) and NRG4 (HR, 431.763; p = 0.001) were independent prognostic factors for tumor recurrence. The products of ERBB2 and NRG4 had a better area under the curve than alpha-fetoprotein for predicting 6-month, 1-year, 3-year, and 5-year mortality. Therefore, these factors could be used to evaluate prognosis and monitor treatment response in patients with HCC. Full article
(This article belongs to the Special Issue Recent Advances in Hepatobiliary Cancers: From Diagnosis to Treatment)
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