Cancers

26 pages, 5968 KiB

Open AccessReview

Advancing Cancer Therapy: The Role of KIF20A as a Target for Inhibitor Development and Immunotherapy

by Dong Oh Moon

Cancers 2024, 16(17), 2958; https://doi.org/10.3390/cancers16172958 (registering DOI) - 24 Aug 2024

The analysis begins with a detailed examination of the gene expression and protein structure of KIF20A, highlighting its interaction with critical cellular components that influence key processes such as Golgi membrane transport and mitotic spindle assembly. The primary focus is on the development [...] Read more.

The analysis begins with a detailed examination of the gene expression and protein structure of KIF20A, highlighting its interaction with critical cellular components that influence key processes such as Golgi membrane transport and mitotic spindle assembly. The primary focus is on the development of specific KIF20A inhibitors, detailing their roles and the challenges encountered in enhancing their efficacy, such as achieving specificity, overcoming tumor resistance, and optimizing delivery systems. Additionally, it delves into the prognostic value of KIF20A across multiple cancer types, emphasizing its role as a novel tumor-associated antigen, which lays the groundwork for the development of targeted peptide vaccines. The therapeutic efficacy of these vaccines as demonstrated in recent clinical trials is discussed. Future directions are proposed, including the integration of precision medicine strategies to personalize treatments and the use of combination therapies to improve outcomes. By concentrating on the significant potential of KIF20A as both a direct target for inhibitors and an antigen in cancer vaccines, this review sets a foundation for future research aimed at harnessing KIF20A for effective cancer treatment. Full article

(This article belongs to the Special Issue Alternative Cell Death Modes in Regulating Cancer Stem Cells and Therapeutic Strategies)

14 pages, 673 KiB

Open AccessReview

Influence of Rurality on Oral Cancer Trends among Organisation for Economic Co-Operation and Development (OECD) Member Countries—A Scoping Review

by Poornima Ramamurthy, Dileep Sharma, Alan Clough and Peter Thomson

Cancers 2024, 16(17), 2957; https://doi.org/10.3390/cancers16172957 (registering DOI) - 24 Aug 2024

Abstract

Oral cancer is the general term used to describe cancers of the oral cavity and oropharyngeal region. These cancers are one of the leading causes of death in elderly residents within the Organisation for Economic Co-operation and Development (OECD) member countries in the [...] Read more.

Oral cancer is the general term used to describe cancers of the oral cavity and oropharyngeal region. These cancers are one of the leading causes of death in elderly residents within the Organisation for Economic Co-operation and Development (OECD) member countries in the 21st century. This scoping review was carried out to assess the influence of rurality on oral cancer trends and patterns among OECD member countries. Four online databases (Medline, PubMed, Scopus, and CINAHL) were searched for studies that reported on oral cancer trends in rural and remote areas in OECD member countries. A total of 1143 articles were obtained initially; among them, 995 papers were screened to include 18 articles for this scoping review. Studies have reported increasing incidence and prevalence in the United States, Australia, Canada, and European countries wherein risk factors such as tobacco, alcohol, and human papilloma virus (HPV) infections were associated with oral and oropharyngeal cancers. Awareness among people living in rural areas about HPV-related cancers was very low, while rates of tobacco and alcohol abuse were noted to be rising more rapidly than among their urban counterparts. Furthermore, the ageing population was most affected compared to the younger age groups of people with oral and oropharyngeal cancer that are prevalent in these regions. Overall, despite living in developed countries, rurality was noted to be a significant factor in the lower life expectancy of oral cancer patients, mainly due to the limited accessibility to tertiary cancer care centres and advanced medical care. Full article

(This article belongs to the Special Issue Emerging Trends in Global Cancer Epidemiology)

13 pages, 1408 KiB

Open AccessReview

Mutational Signatures in Colorectal Cancer: Translational Insights, Clinical Applications, and Limitations

by Giovanni Crisafulli

Cancers 2024, 16(17), 2956; https://doi.org/10.3390/cancers16172956 (registering DOI) - 24 Aug 2024

Abstract

A multitude of exogenous and endogenous processes have the potential to result in DNA damage. While the repair mechanisms are typically capable of correcting this damage, errors in the repair process can result in mutations. The findings of research conducted in 2012 indicate [...] Read more.

A multitude of exogenous and endogenous processes have the potential to result in DNA damage. While the repair mechanisms are typically capable of correcting this damage, errors in the repair process can result in mutations. The findings of research conducted in 2012 indicate that mutations do not occur randomly but rather follow specific patterns that can be attributed to known or inferred mutational processes. The process of mutational signature analysis allows for the inference of the predominant mutational process for a given cancer sample, with significant potential for clinical applications. A deeper comprehension of these mutational signatures in CRC could facilitate enhanced prevention strategies, facilitate the comprehension of genotoxic drug activity, predict responses to personalized treatments, and, in the future, inform the development of targeted therapies in the context of precision oncology. The efforts of numerous researchers have led to the identification of several mutational signatures, which can be categorized into different mutational signature references. In CRC, distinct mutational signatures are identified as correlating with mismatch repair deficiency, polymerase mutations, and chemotherapy treatment. In this context, a mutational signature analysis offers considerable potential for enhancing minimal residual disease (MRD) tests in stage II (high-risk) and stage III CRC post-surgery, stratifying CRC based on the impacts of genetic and epigenetic alterations for precision oncology, identifying potential therapeutic vulnerabilities, and evaluating drug efficacy and guiding therapy, as illustrated in a proof-of-concept clinical trial. Full article

(This article belongs to the Special Issue Novel Computational Approaches for Molecular Target Discovery in Colorectal Cancer)

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20 pages, 1301 KiB

Open AccessArticle

Rare Germline Variants in DNA Repair Genes Detected in BRCA-Negative Finnish Patients with Early-Onset Breast Cancer

by Viivi Kurkilahti, Venkat Subramaniam Rathinakannan, Erja Nynäs, Neha Goel, Kristiina Aittomäki, Heli Nevanlinna, Vidal Fey, Minna Kankuri-Tammilehto and Johanna Schleutker

Cancers 2024, 16(17), 2955; https://doi.org/10.3390/cancers16172955 (registering DOI) - 24 Aug 2024

Abstract

Background: Breast cancer is the most common malignancy, with a mean age of onset of approximately 60 years. Only a minority of breast cancer patients present with an early onset at or before 40 years of age. An exceptionally young age at diagnosis [...] Read more.

Background: Breast cancer is the most common malignancy, with a mean age of onset of approximately 60 years. Only a minority of breast cancer patients present with an early onset at or before 40 years of age. An exceptionally young age at diagnosis hints at a possible genetic etiology. Currently, known pathogenic genetic variants only partially explain the disease burden of younger patients. Thus, new knowledge is warranted regarding additional risk variants. In this study, we analyzed DNA repair genes to identify additional variants to shed light on the etiology of early-onset breast cancer. Methods: Germline whole-exome sequencing was conducted in a cohort of 63 patients diagnosed with breast cancer at or before 40 years of age (median 33, mean 33.02, range 23–40 years) with no known pathogenic variants in BRCA genes. After filtering, all detected rare variants were sorted by pathogenicity prediction scores (CADD score and REVEL) to identify the most damaging genetic changes. The remaining variants were then validated by comparison to a validation cohort of 121 breast cancer patients with no preselected age at cancer diagnosis (mean 51.4 years, range 28–80 years). Analysis of novel exonic variants was based on protein structure modeling. Results: Five novel, deleterious variants in the genes WRN, RNF8, TOP3A, ERCC2, and TREX2 were found in addition to a splice acceptor variant in RNF4 and two frameshift variants in EXO1 and POLE genes, respectively. There were also multiple previously reported putative risk variants in other DNA repair genes. Conclusions: Taken together, whole-exome sequencing yielded 72 deleterious variants, including 8 novel variants that may play a pivotal role in the development of early-onset breast cancer. Although more studies are warranted, we demonstrate that young breast cancer patients tend to carry multiple deleterious variants in one or more DNA repair genes. Full article

(This article belongs to the Section Cancer Causes, Screening and Diagnosis)

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18 pages, 2737 KiB

Open AccessSystematic Review

FDG PET-CT for the Detection of Occult Nodal Metastases in Head and Neck Cancer: A Systematic Review and Meta-Analysis

by Danaé Guedj, Sophie Neveü, Minerva Becker and Maxime Mermod

Cancers 2024, 16(17), 2954; https://doi.org/10.3390/cancers16172954 (registering DOI) - 24 Aug 2024

Abstract

Because of an estimated 20–30% prevalence of occult lymph node (LN) metastases in patients with head and neck squamous cell carcinoma (HNSCC), neck dissection is often proposed, despite its potential morbidity. In this systematic review and meta-analysis, the diagnostic performance of FDG PET-CT [...] Read more.

Because of an estimated 20–30% prevalence of occult lymph node (LN) metastases in patients with head and neck squamous cell carcinoma (HNSCC), neck dissection is often proposed, despite its potential morbidity. In this systematic review and meta-analysis, the diagnostic performance of FDG PET-CT in detecting occult LN metastases was evaluated in patients with clinically negative necks (cN0) and in whom histopathology of a neck dissection specimen served as gold standard. Overall, 16 studies out of 2062 screened on PubMed and EMBASE fulfilled the inclusion criteria (n = 1148 patients). Seven of these sixteen studies were split into two or three studies because they contained data that could be processed distinctly in our meta-analysis. For this reason, a total of 25 studies were identified and included in the analysis (n total = 1918 patients). The overall prevalence of metastatic nodes per patient was 22.67%. The pooled sensitivity, specificity, diagnostic odds ratios, and negative predictive value (NPV) were 0.71 (95%CI: 0.66–0.75), 0.90 (95%CI: 0.84–0.93), 20.03 (95%CI: 13.51–29.70), and 0.92 (95%CI: 0.89–0.95), respectively. The main causes of inter-study heterogeneity included different reference standards (evaluation per patient, per neck side, or per neck level). The current meta-analysis showed that FDG PET-CT has a high specificity and NPV for ruling out nodal involvement in cN0 necks, but a limited sensitivity. Full article

(This article belongs to the Section Systematic Review or Meta-Analysis in Cancer Research)

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16 pages, 6967 KiB

Open AccessArticle

Sialylation Inhibition Can Partially Revert Acquired Resistance to Enzalutamide in Prostate Cancer Cells

by Emily Archer Goode, Margarita Orozco-Moreno, Kirsty Hodgson, Amirah Nabilah, Meera Murali, Ziqian Peng, Jona Merx, Emiel Rossing, Johan F. A. Pijnenborg, Thomas J. Boltje, Ning Wang, David J. Elliott and Jennifer Munkley

Cancers 2024, 16(17), 2953; https://doi.org/10.3390/cancers16172953 (registering DOI) - 24 Aug 2024

Abstract

Prostate cancer is a lethal solid malignancy and a leading cause of cancer-related deaths in males worldwide. Treatments, including radical prostatectomy, radiotherapy, and hormone therapy, are available and have improved patient survival; however, recurrence remains a huge clinical challenge. Enzalutamide is a second-generation [...] Read more.

Prostate cancer is a lethal solid malignancy and a leading cause of cancer-related deaths in males worldwide. Treatments, including radical prostatectomy, radiotherapy, and hormone therapy, are available and have improved patient survival; however, recurrence remains a huge clinical challenge. Enzalutamide is a second-generation androgen receptor antagonist that is used to treat castrate-resistant prostate cancer. Among patients who initially respond to enzalutamide, virtually all acquire secondary resistance, and an improved understanding of the mechanisms involved is urgently needed. Aberrant glycosylation, and, in particular, alterations to sialylated glycans, have been reported as mediators of therapy resistance in cancer, but a link between tumour-associated glycans and resistance to therapy in prostate cancer has not yet been investigated. Here, using cell line models, we show that prostate cancer cells with acquired resistance to enzalutamide therapy have an upregulation of the sialyltransferase ST6 beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1) and increased levels of α2,6-sialylated N-glycans. Furthermore, using the sialyltransferase inhibitor P-SiaFNEtoc, we discover that acquired resistance to enzalutamide can be partially reversed by combining enzalutamide therapy with sialic acid blockade. Our findings identify a potential role for ST6GAL1-mediated aberrant sialylation in acquired resistance to enzalutamide therapy for prostate cancer and suggest that sialic acid blockade in combination with enzalutamide may represent a novel therapeutic approach in patients with advanced disease. Our study also highlights the potential to bridge the fields of cancer biology and glycobiology to develop novel combination therapies for prostate cancer. Full article

(This article belongs to the Special Issue The Prevention and Treatment of Prostate Cancer)

16 pages, 4716 KiB

Open AccessArticle

Osteopontin Regulates Treg Cell Stability and Function with Implications for Anti-Tumor Immunity and Autoimmunity

by Aigli G. Vakrakou, Evangelia Kourepini, Ioannis Skordos, Natalia Nieto, Vily Panoutsakopoulou and Nikolaos Paschalidis

Cancers 2024, 16(17), 2952; https://doi.org/10.3390/cancers16172952 (registering DOI) - 24 Aug 2024

Abstract

Foxp3-expressing regulatory T (Treg) cells represent the most highly immunosuppressive cell in the tumor microenvironment (TME) that halts effective anti-tumor immunity. Osteopontin (Opn), an extracellular matrix (ECM) glycophosphoprotein, plays key roles in many types of immune-related diseases and is associated with cancer aggressiveness [...] Read more.

Foxp3-expressing regulatory T (Treg) cells represent the most highly immunosuppressive cell in the tumor microenvironment (TME) that halts effective anti-tumor immunity. Osteopontin (Opn), an extracellular matrix (ECM) glycophosphoprotein, plays key roles in many types of immune-related diseases and is associated with cancer aggressiveness when expressed by tumor cells. However, its role in Foxp3Treg heterogeneity, function, and stability in the TME is poorly defined. We generated mice with a Foxp3-specific deletion of Opn and assessed the ability of Opn-deficient Tregs to suppress inflammation. As these mice aged, they developed a scurfy-like syndrome characterized by aberrant and excessive activation of effector T cells. We evaluated and further confirmed the reduced suppressive capacity of Opn-deficient Tregs in an in vivo suppression assay of colitis. We also found that mice with Opn-deficient Foxp3⁺ Tregs have enhanced anti-tumor immunity and reduced tumor burden, associated with an unstable Treg phenotype, paralleled by reduced Foxp3 expression in tumor-infiltrating lymphocytes. Finally, we observed reduced Foxp3 and Helios expression in Opn-deficient Tregs compared to wild-type controls after in vitro activation. Our findings indicate that targeting Opn in Tregs reveals vigorous and effective ways of promoting Treg instability and dysfunction in the TME, facilitating anti-tumor immunity. Full article

(This article belongs to the Special Issue Flow Cytometry in Cancer Research)

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20 pages, 1762 KiB

Open AccessSystematic Review

The Role of Radiomics in the Prediction of Clinically Significant Prostate Cancer in the PI-RADS v2 and v2.1 Era: A Systematic Review

by Andreu Antolin, Nuria Roson, Richard Mast, Javier Arce, Ramon Almodovar, Roger Cortada, Almudena Maceda, Manuel Escobar, Enrique Trilla and Juan Morote

Cancers 2024, 16(17), 2951; https://doi.org/10.3390/cancers16172951 (registering DOI) - 24 Aug 2024

Viewed by 64

Abstract

Early detection of clinically significant prostate cancer (csPCa) has substantially improved with the latest PI-RADS versions. However, there is still an overdiagnosis of indolent lesions (iPCa), and radiomics has emerged as a potential solution. The aim of this systematic review is to evaluate [...] Read more.

Early detection of clinically significant prostate cancer (csPCa) has substantially improved with the latest PI-RADS versions. However, there is still an overdiagnosis of indolent lesions (iPCa), and radiomics has emerged as a potential solution. The aim of this systematic review is to evaluate the role of handcrafted and deep radiomics in differentiating lesions with csPCa from those with iPCa and benign lesions on prostate MRI assessed with PI-RADS v2 and/or 2.1. The literature search was conducted in PubMed, Cochrane, and Web of Science databases to select relevant studies. Quality assessment was carried out with Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2), Radiomic Quality Score (RQS), and Checklist for Artificial Intelligence in Medical Imaging (CLAIM) tools. A total of 14 studies were deemed as relevant from 411 publications. The results highlighted a good performance of handcrafted and deep radiomics methods for csPCa detection, but without significant differences compared to radiologists (PI-RADS) in the few studies in which it was assessed. Moreover, heterogeneity and restrictions were found in the studies and quality analysis, which might induce bias. Future studies should tackle these problems to encourage clinical applicability. Prospective studies and comparison with radiologists (PI-RADS) are needed to better understand its potential. Full article

(This article belongs to the Special Issue MRI in Prostate Cancer)

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13 pages, 1640 KiB

Open AccessArticle

Investigating the Obesity Paradox in Colorectal Cancer: An Analysis of Prospectively Collected Data in a Diverse Cohort

by Shria Kumar, Catherine Blandon, Alla Sikorskii, David E. Kaplan, Shivan J. Mehta, Grace L. Su, David S. Goldberg and Tracy E. Crane

Cancers 2024, 16(17), 2950; https://doi.org/10.3390/cancers16172950 (registering DOI) - 24 Aug 2024

Viewed by 101

Abstract

Background: Prior studies are inconclusive regarding the effect of obesity on mortality in persons with colorectal cancer (CRC). We sought to determine the association of pre-diagnosis body mass index (BMI) trajectories on mortality after CRC diagnosis. Methods: Utilizing the Multiethnic Cohort, we included [...] Read more.

Background: Prior studies are inconclusive regarding the effect of obesity on mortality in persons with colorectal cancer (CRC). We sought to determine the association of pre-diagnosis body mass index (BMI) trajectories on mortality after CRC diagnosis. Methods: Utilizing the Multiethnic Cohort, we included adults aged 18–75 between 1 January 1993 and 1 January 2019 with a diagnosis of CRC and at least three available BMIs. The primary exposure, BMI, was subjected to group-based trajectory modeling (GBTM). We evaluated all-cause and CRC-specific mortality, using Cox proportional hazard (PH) models. Results: Of 924 persons, the median age was 60 years, and 54% were female. There was no statistically significant association between pre-cancer BMI trajectory and either all-cause or cancer-specific mortality. In competing risk analysis, the risk of CRC-specific mortality was higher for African Americans (HR = 1.56, 95% CI [1.00–2.43], p = 0.048) and smokers (HR = 1.59, 95% CI [1.10–2.32], p = 0.015). Risk of all-cause mortality was higher for Hawaiian persons (HR = 2.85, 95% CI [1.31–6.21], p = 0.009) and persons with diabetes (HR = 1.83, 95% CI [1.08–3.10], p = 0.026). Conclusions: Pre-diagnosis BMI trajectories were not associated with mortality after CRC diagnosis, whereas race/ethnicity, diabetes, and smoking were associated with an increased risk of death. Our findings suggest the obesity paradox alone does not account for mortality after CRC diagnosis. Full article

(This article belongs to the Special Issue Obesity and Cancers)

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21 pages, 4095 KiB

Open AccessArticle

Genome-Wide CRISPR Screen Identifies KEAP1 Perturbation as a Vulnerability of ARID1A-Deficient Cells

by Louis-Alexandre Fournier, Forouh Kalantari, James P. Wells, Joon Seon Lee, Genny Trigo-Gonzalez, Michelle M. Moksa, Theodore Smith, Justin White, Alynn Shanks, Siyun L. Wang, Edmund Su, Yemin Wang, David G. Huntsman, Martin Hirst and Peter C. Stirling

Cancers 2024, 16(17), 2949; https://doi.org/10.3390/cancers16172949 (registering DOI) - 24 Aug 2024

Viewed by 117

Abstract

ARID1A is the core DNA-binding subunit of the BAF chromatin remodeling complex and is mutated in about 8% of all cancers. The frequency of ARID1A loss varies between cancer subtypes, with clear cell ovarian carcinoma (CCOC) presenting the highest incidence at > 50% [...] Read more.

ARID1A is the core DNA-binding subunit of the BAF chromatin remodeling complex and is mutated in about 8% of all cancers. The frequency of ARID1A loss varies between cancer subtypes, with clear cell ovarian carcinoma (CCOC) presenting the highest incidence at > 50% of cases. Despite a growing understanding of the consequences of ARID1A loss in cancer, there remains limited targeted therapeutic options for ARID1A-deficient cancers. Using a genome-wide CRISPR screening approach, we identify KEAP1 as a genetic dependency of ARID1A in CCOC. Depletion or chemical perturbation of KEAP1 results in selective growth inhibition of ARID1A-KO cell lines and edited primary endometrial epithelial cells. While we confirm that KEAP1-NRF2 signalling is dysregulated in ARID1A-KO cells, we suggest that this synthetic lethality is not due to aberrant NRF2 signalling. Rather, we find that KEAP1 perturbation exacerbates genome instability phenotypes associated with ARID1A deficiency. Together, our findings identify a potentially novel synthetic lethal interaction of ARID1A-deficient cells. Full article

(This article belongs to the Special Issue Exploiting Liabilities in Mechanism of DNA Repair for Cancer Therapy)

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11 pages, 5478 KiB

Open AccessReview

Epidemiology of Gastric Cancer—Changing Trends and Global Disparities

by Manami Inoue

Cancers 2024, 16(17), 2948; https://doi.org/10.3390/cancers16172948 (registering DOI) - 24 Aug 2024

Viewed by 136

Abstract

Overall, the past century has seen a substantial decline in gastric cancer, attributable to decreases in risk factors such as H. pylori infection, tobacco smoking, and the intake of salt-preserved food. One potential preventive strategy for those at high risk is H. pylori [...] Read more.

Overall, the past century has seen a substantial decline in gastric cancer, attributable to decreases in risk factors such as H. pylori infection, tobacco smoking, and the intake of salt-preserved food. One potential preventive strategy for those at high risk is H. pylori eradication for infected subjects, but confirmation of this effect awaits longer follow-up. Obesity continues to advance and may cause increases in cardia cancer, particularly in Western populations, and careful monitoring of this outcome is warranted in both Western and Asian populations. These changes in gastric cancer epidemiology foreshadow a new era in gastric cancer control and warrant further monitoring of descriptive patterns and risk factors. Full article

(This article belongs to the Special Issue Gastric Cancer: Evolving Landscape and Emerging Therapies)

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20 pages, 7209 KiB

Open AccessArticle

DM–AHR: A Self-Supervised Conditional Diffusion Model for AI-Generated Hairless Imaging for Enhanced Skin Diagnosis Applications

by Bilel Benjdira, Anas M. Ali, Anis Koubaa, Adel Ammar and Wadii Boulila

Cancers 2024, 16(17), 2947; https://doi.org/10.3390/cancers16172947 - 23 Aug 2024

Viewed by 198

Abstract

Accurate skin diagnosis through end-user applications is important for early detection and cure of severe skin diseases. However, the low quality of dermoscopic images hampers this mission, especially with the presence of hair on these kinds of images. This paper introduces DM–AHR, [...] Read more.

Accurate skin diagnosis through end-user applications is important for early detection and cure of severe skin diseases. However, the low quality of dermoscopic images hampers this mission, especially with the presence of hair on these kinds of images. This paper introduces DM–AHR, a novel, self-supervised conditional diffusion model designed specifically for the automatic generation of hairless dermoscopic images to improve the quality of skin diagnosis applications. The current research contributes in three significant ways to the field of dermatologic imaging. First, we develop a customized diffusion model that adeptly differentiates between hair and skin features. Second, we pioneer a novel self-supervised learning strategy that is specifically tailored to optimize performance for hairless imaging. Third, we introduce a new dataset, named DERMAHAIR (DERMatologic Automatic HAIR Removal Dataset), that is designed to advance and benchmark research in this specialized domain. These contributions significantly enhance the clarity of dermoscopic images, improving the accuracy of skin diagnosis procedures. We elaborate on the architecture of DM–AHR and demonstrate its effective performance in removing hair while preserving critical details of skin lesions. Our results show an enhancement in the accuracy of skin lesion analysis when compared to existing techniques. Given its robust performance, DM–AHR holds considerable promise for broader application in medical image enhancement. Full article

(This article belongs to the Special Issue Skin Cancer: Imaging and Radiotherapy)

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17 pages, 1287 KiB

Open AccessReview

Escalation and De-Escalation of Adjuvant Radiotherapy in Early Breast Cancer: Strategies for Risk-Adapted Optimization

by Guenther Gruber

Cancers 2024, 16(17), 2946; https://doi.org/10.3390/cancers16172946 - 23 Aug 2024

Viewed by 178

Abstract

Postoperative radiotherapy (RT) is recommended after breast-conserving surgery and mastectomy (with risk factors). Consideration of pros and cons, including potential side effects, demands the optimization of adjuvant RT and a risk-adapted approach. There is clear de-escalation in fractionation—hypofractionation should be considered standard. For [...] Read more.

Postoperative radiotherapy (RT) is recommended after breast-conserving surgery and mastectomy (with risk factors). Consideration of pros and cons, including potential side effects, demands the optimization of adjuvant RT and a risk-adapted approach. There is clear de-escalation in fractionation—hypofractionation should be considered standard. For selected low-risk situations, PBI only or even the omission of RT might be appropriate. In contrast, tendencies toward escalating RT are obvious. Preoperative RT seems attractive for patients in whom breast reconstruction is planned or for defining the tumor location more precisely with the potential of giving ablative doses. Dose escalation by a (simultaneous integrated) boost or the combination with new compounds/systemic treatments may increase antitumor efficacy but also toxicity. Despite low evidence, RT for oligometastatic disease is becoming increasingly popular. The omission of axillary dissection in node-positive disease led to an escalation of regional RT. Studies are ongoing to test if any axillary treatment can be omitted and which oligometastatic patients do really benefit from RT. Besides technical improvements, the incorporation of molecular risk profiles and also the response to neoadjuvant systemic therapy have the potential to optimize the decision-making concerning if and how local and/or regional RT should be administered. Full article

(This article belongs to the Special Issue Clinical Research and Progress in the Treatment of Breast Cancer)

9 pages, 408 KiB

Open AccessArticle

Real-World Cardiotoxicity in Metastatic Melanoma Patients Treated with Encorafenib and Binimetinib

by Sidsel Pedersen, Marc Østergaard Nielsen, Marco Donia, Inge Marie Svane, Bo Zerahn and Eva Ellebaek

Cancers 2024, 16(17), 2945; https://doi.org/10.3390/cancers16172945 - 23 Aug 2024

Viewed by 179

Abstract

Modern therapies targeting the BRAF gene mutation in advanced melanoma have significantly improved patient outcomes but pose cardiovascular risks. This retrospective study in Eastern Denmark (2019–2022) assessed 108 melanoma patients treated with encorafenib and binimetinib. Patients were monitored for heart function using multigated [...] Read more.

Modern therapies targeting the BRAF gene mutation in advanced melanoma have significantly improved patient outcomes but pose cardiovascular risks. This retrospective study in Eastern Denmark (2019–2022) assessed 108 melanoma patients treated with encorafenib and binimetinib. Patients were monitored for heart function using multigated acquisition (MUGA) scans. The study defined major cardiotoxicity as a decline in left ventricular ejection fraction (LVEF) by more than 10 percentage points to below 50%, and minor cardiotoxicity as a decrease in LVEF by more than 15 points but remaining above 50%. Results showed that 19 patients (18%) developed minor cardiotoxicity and were asymptomatic, while 7 (6%) experienced major cardiotoxicity, with two requiring intervention. Notably, no significant declines in LVEF were observed after six months of treatment. The study concluded that significant cardiotoxicity occurred in 6% of cases, mostly asymptomatic and reversible, and suggests that monitoring LVEF could potentially be reduced after 6–9 months if no early signs of cardiotoxicity are detected. This provides valuable insights into the cardiac safety of these treatments in real-world settings. Full article

(This article belongs to the Special Issue Melanoma: Clinical Trials and Translational Research)

15 pages, 959 KiB

Open AccessArticle

MRI T2w Radiomics-Based Machine Learning Models in Imaging Simulated Biopsy Add Diagnostic Value to PI-RADS in Predicting Prostate Cancer: A Retrospective Diagnostic Study

by Jia-Cheng Liu, Xiao-Hao Ruan, Tsun-Tsun Chun, Chi Yao, Da Huang, Hoi-Lung Wong, Chun-Ting Lai, Chiu-Fung Tsang, Sze-Ho Ho, Tsui-Lin Ng, Dan-Feng Xu and Rong Na

Cancers 2024, 16(17), 2944; https://doi.org/10.3390/cancers16172944 - 23 Aug 2024

Viewed by 163

Abstract

Background: Currently, prostate cancer (PCa) prebiopsy medical image diagnosis mainly relies on mpMRI and PI-RADS scores. However, PI-RADS has its limitations, such as inter- and intra-radiologist variability and the potential for imperceptible features. The primary objective of this study is to evaluate the [...] Read more.

Background: Currently, prostate cancer (PCa) prebiopsy medical image diagnosis mainly relies on mpMRI and PI-RADS scores. However, PI-RADS has its limitations, such as inter- and intra-radiologist variability and the potential for imperceptible features. The primary objective of this study is to evaluate the effectiveness of a machine learning model based on radiomics analysis of MRI T2-weighted (T2w) images for predicting PCa in prebiopsy cases. Method: A retrospective analysis was conducted using 820 lesions (363 cases, 457 controls) from The Cancer Imaging Archive (TCIA) Database for model development and validation. An additional 83 lesions (30 cases, 53 controls) from Hong Kong Queen Mary Hospital were used for independent external validation. The MRI T2w images were preprocessed, and radiomic features were extracted. Feature selection was performed using Cross Validation Least Angle Regression (CV-LARS). Using three different machine learning algorithms, a total of 18 prediction models and 3 shape control models were developed. The performance of the models, including the area under the curve (AUC) and diagnostic values such as sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), were compared to the PI-RADS scoring system for both internal and external validation. Results: All the models showed significant differences compared to the shape control model (all p < 0.001, except SVM model PI-RADS+2 Features p = 0.004, SVM model PI-RADS+3 Features p = 0.002). In internal validation, the best model, based on the LR algorithm, incorporated 3 radiomic features (AUC = 0.838, sensitivity = 76.85%, specificity = 77.36%). In external validation, the LR (3 features) model outperformed PI-RADS in predictive value with AUC 0.870 vs. 0.658, sensitivity 56.67% vs. 46.67%, specificity 92.45% vs. 84.91%, PPV 80.95% vs. 63.64%, and NPV 79.03% vs. 73.77%. Conclusions: The machine learning model based on radiomics analysis of MRI T2w images, along with simulated biopsy, provides additional diagnostic value to the PI-RADS scoring system in predicting PCa. Full article

(This article belongs to the Topic AI in Medical Imaging and Image Processing)

17 pages, 410 KiB

Open AccessReview

Inflammatory Bowel Disease and Colorectal Cancer

by Jacopo Fanizza, Sarah Bencardino, Mariangela Allocca, Federica Furfaro, Alessandra Zilli, Tommaso Lorenzo Parigi, Gionata Fiorino, Laurent Peyrin-Biroulet, Silvio Danese and Ferdinando D’Amico

Cancers 2024, 16(17), 2943; https://doi.org/10.3390/cancers16172943 - 23 Aug 2024

Viewed by 143

Abstract

Patients with inflammatory bowel diseases (IBDs), including both ulcerative colitis (UC) and Crohn’s disease (CD), are at a higher risk of developing colorectal cancer (CRC). However, advancements in endoscopic imaging techniques, integrated surveillance programs, and improved medical therapies have led to a decrease [...] Read more.

Patients with inflammatory bowel diseases (IBDs), including both ulcerative colitis (UC) and Crohn’s disease (CD), are at a higher risk of developing colorectal cancer (CRC). However, advancements in endoscopic imaging techniques, integrated surveillance programs, and improved medical therapies have led to a decrease in the incidence of CRC among IBD patients. Currently, the management of patients with IBD who have a history of or ongoing active malignancy is an unmet need. This involves balancing the risk of cancer recurrence/progression with the potential exacerbation of IBD if the medications are discontinued. The objective of this review is to provide an updated summary of the epidemiology, causes, risk factors, and surveillance approaches for CRC in individuals with IBD, and to offer practical guidance on managing IBD patients with history of previous or active cancer. Full article

(This article belongs to the Special Issue Beginning of a New Era: Current Progress in Colorectal Cancer Detection, Treatment, and Prognosis)

21 pages, 3545 KiB

Open AccessArticle

Agent-Based Modeling of Virtual Tumors Reveals the Critical Influence of Microenvironmental Complexity on Immunotherapy Efficacy

by Yixuan Wang, Daniel R. Bergman, Erica Trujillo, Anthony A. Fernald, Lie Li, Alexander T. Pearson, Randy F. Sweis and Trachette L. Jackson

Cancers 2024, 16(17), 2942; https://doi.org/10.3390/cancers16172942 - 23 Aug 2024

Viewed by 180

Abstract

Since the introduction of the first immune checkpoint inhibitor (ICI), immunotherapy has changed the landscape of molecular therapeutics for cancers. However, ICIs do not work equally well on all cancers and for all patients. There has been a growing interest in using mathematical [...] Read more.

Since the introduction of the first immune checkpoint inhibitor (ICI), immunotherapy has changed the landscape of molecular therapeutics for cancers. However, ICIs do not work equally well on all cancers and for all patients. There has been a growing interest in using mathematical and computational models to optimize clinical responses. Ordinary differential equations (ODEs) have been widely used for mechanistic modeling in immuno-oncology and immunotherapy. They allow rapid simulations of temporal changes in the cellular and molecular populations involved. Nonetheless, ODEs cannot describe the spatial structure in the tumor microenvironment or quantify the influence of spatially-dependent characteristics of tumor-immune dynamics. For these reasons, agent-based models (ABMs) have gained popularity because they can model more detailed phenotypic and spatial heterogeneity that better reflect the complexity seen in vivo. In the context of anti-PD-1 ICIs, we compare treatment outcomes simulated from an ODE model and an ABM to show the importance of including spatial components in computational models of cancer immunotherapy. We consider tumor cells of high and low antigenicity and two distinct cytotoxic T lymphocyte (CTL) killing mechanisms. The preferred mechanism differs based on the antigenicity of tumor cells. Our ABM reveals varied phenotypic shifts within the tumor and spatial organization of tumor and CTLs despite similarities in key immune parameters, initial simulation conditions, and early temporal trajectories of the cell populations. Full article

(This article belongs to the Special Issue Mathematical Oncology: Using Mathematics to Enable Cancer Discoveries)

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21 pages, 2992 KiB

Open AccessArticle

Sulfamoylated Estradiol Analogs Targeting the Actin and Microtubule Cytoskeletons Demonstrate Anti-Cancer Properties In Vitro and In Ovo

by Anne Elisabeth Mercier, Anna Margaretha Joubert, Renaud Prudent, Jean Viallet, Agnes Desroches-Castan, Leanne De Koning, Peace Mabeta, Jolene Helena, Michael Sean Pepper and Laurence Lafanechère

Cancers 2024, 16(17), 2941; https://doi.org/10.3390/cancers16172941 - 23 Aug 2024

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Abstract

The microtubule-disrupting agent 2-methoxyestradiol (2-ME) displays anti-tumor and anti-angiogenic properties, but its clinical development is halted due to poor pharmacokinetics. We therefore designed two 2-ME analogs in silico—an ESE-15-one and an ESE-16 one—with improved pharmacological properties. We investigated the effects of these compounds [...] Read more.

The microtubule-disrupting agent 2-methoxyestradiol (2-ME) displays anti-tumor and anti-angiogenic properties, but its clinical development is halted due to poor pharmacokinetics. We therefore designed two 2-ME analogs in silico—an ESE-15-one and an ESE-16 one—with improved pharmacological properties. We investigated the effects of these compounds on the cytoskeleton in vitro, and their anti-angiogenic and anti-metastatic properties in ovo. Time-lapse fluorescent microscopy revealed that sub-lethal doses of the compounds disrupted microtubule dynamics. Phalloidin fluorescent staining of treated cervical (HeLa), metastatic breast (MDA-MB-231) cancer, and human umbilical vein endothelial cells (HUVECs) displayed thickened, stabilized actin stress fibers after 2 h, which rearranged into a peripheral radial pattern by 24 h. Cofilin phosphorylation and phosphorylated ezrin/radixin/moesin complexes appeared to regulate this actin response. These signaling pathways overlap with anti-angiogenic, extra-cellular communication and adhesion pathways. Sub-lethal concentrations of the compounds retarded both cellular migration and invasion. Anti-angiogenic and extra-cellular matrix signaling was evident with TIMP2 and P-VEGF receptor-2 upregulation. ESE-15-one and ESE-16 exhibited anti-tumor and anti-metastatic properties in vivo, using the chick chorioallantoic membrane assay. In conclusion, the sulfamoylated 2-ME analogs displayed promising anti-tumor, anti-metastatic, and anti-angiogenic properties. Future studies will assess the compounds for myeloproliferative effects, as seen in clinical applications of other drugs in this class. Full article

(This article belongs to the Special Issue Cell Signaling in Cancer and Cancer Therapy)

35 pages, 1420 KiB

Open AccessReview

Therapeutic Antisense Oligonucleotides in Oncology: From Bench to Bedside

by Elif Çakan, Olivia D. Lara, Anna Szymanowska, Emine Bayraktar, Arturo Chavez-Reyes, Gabriel Lopez-Berestein, Paola Amero and Cristian Rodriguez-Aguayo

Cancers 2024, 16(17), 2940; https://doi.org/10.3390/cancers16172940 - 23 Aug 2024

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Abstract

Advancements in our comprehension of tumor biology and chemoresistance have spurred the development of treatments that precisely target specific molecules within the body. Despite the expanding landscape of therapeutic options, there persists a demand for innovative approaches to address unmet clinical needs. RNA [...] Read more.

Advancements in our comprehension of tumor biology and chemoresistance have spurred the development of treatments that precisely target specific molecules within the body. Despite the expanding landscape of therapeutic options, there persists a demand for innovative approaches to address unmet clinical needs. RNA therapeutics have emerged as a promising frontier in this realm, offering novel avenues for intervention such as RNA interference and the utilization of antisense oligonucleotides (ASOs). ASOs represent a versatile class of therapeutics capable of selectively targeting messenger RNAs (mRNAs) and silencing disease-associated proteins, thereby disrupting pathogenic processes at the molecular level. Recent advancements in chemical modification and carrier molecule design have significantly enhanced the stability, biodistribution, and intracellular uptake of ASOs, thereby bolstering their therapeutic potential. While ASO therapy holds promise across various disease domains, including oncology, coronary angioplasty, neurological disorders, viral, and parasitic diseases, our review manuscript focuses specifically on the application of ASOs in targeted cancer therapies. Through a comprehensive examination of the latest research findings and clinical developments, we delve into the intricacies of ASO-based approaches to cancer treatment, shedding light on their mechanisms of action, therapeutic efficacy, and prospects. Full article

(This article belongs to the Section Cancer Therapy)

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14 pages, 533 KiB

Open AccessReview

The Effects of Radiotherapy on the Sequence and Eligibility of Breast Reconstruction: Current Evidence and Controversy

by Andrew R. Campbell, Alexander J. Didier, Taha M. Sheikh, Sami Ansari, Dean E. Watkins, Alan M. Fahoury, Swamroop V. Nandwani and Mohammad Rashid

Cancers 2024, 16(17), 2939; https://doi.org/10.3390/cancers16172939 - 23 Aug 2024

Viewed by 228

Abstract

Immediate breast reconstruction (IBR) following a mastectomy, combined with radiotherapy, presents a multifaceted approach to breast cancer treatment, balancing oncological safety and aesthetic outcomes. IBR, typically involving the use of implants or autologous tissue, aims to restore breast morphology directly after a mastectomy, [...] Read more.

Immediate breast reconstruction (IBR) following a mastectomy, combined with radiotherapy, presents a multifaceted approach to breast cancer treatment, balancing oncological safety and aesthetic outcomes. IBR, typically involving the use of implants or autologous tissue, aims to restore breast morphology directly after a mastectomy, minimizing the psychological and physical impacts. However, integrating radiotherapy with IBR is complex due to the potential adverse effects on reconstructed tissues. Radiotherapy, essential for reducing local recurrence, can induce fibrosis, capsular contracture, and compromised aesthetic results. This narrative review covers the current trends in the sequencing of breast reconstruction and radiotherapy. We discuss patient selection, timing of radiotherapy, and reconstructive techniques, with special attention paid to quality-of-life outcomes that are increasingly reported in clinical trials. Emerging evidence supports the feasibility of IBR with careful patient selection and tailored therapeutic approaches, although ongoing research is necessary to refine protocols and enhance outcomes. Overall, IBR in the context of radiotherapy remains a promising but intricate treatment modality, requiring a nuanced balance between cancer control and aesthetic restoration. Full article

(This article belongs to the Special Issue Trends in Mastectomy and Breast Reconstruction for Cancer)

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13 pages, 2148 KiB

Open AccessSystematic Review

Comparative Meta-Analysis of Triplet vs. Quadruplet Induction Regimens in Newly Diagnosed, Treatment Naïve, Multiple Myeloma

by Barry Paul, Faiz Anwer, Shahzad Raza, Aytaj Mammadzadeh, Bayan Khasawneh, Sara Shatnawi, Joseph McGuirk, Nausheen Ahmed, Zahra Mahmoudjafari, Muhammad Mushtaq, Al-Ola Abdallah and Shebli Atrash

Cancers 2024, 16(17), 2938; https://doi.org/10.3390/cancers16172938 - 23 Aug 2024

Viewed by 264

Abstract

The use of 4-drug induction regimens for treatment naïve newly diagnosed multiple myeloma (NDMM) is associated with improved depth of response and progression-free survival (PFS). However, head-to-head trials of 4-drug combinations are lacking, and instead, these regimens are typically compared to 3-drug backbones; [...] Read more.

The use of 4-drug induction regimens for treatment naïve newly diagnosed multiple myeloma (NDMM) is associated with improved depth of response and progression-free survival (PFS). However, head-to-head trials of 4-drug combinations are lacking, and instead, these regimens are typically compared to 3-drug backbones; limiting the ability to discern whether any additional benefit (or toxicity) is simply additive or represents a synergy (or interaction). We conducted a meta-analysis of phase 2 and phase 3 clinical trials that randomized treatment naïve NDMM patients to either a 4-drug or 3-drug induction regimen. We included 11 trials which represented 6509 unique patients. PFS for all trials in the meta-analysis was 54 months with a 4-drug induction and 8.9 months with a 3-drug induction (HR: 0.49; 95% CI: 0.45; 0.54), but there was no benefit to using a 4-drug induction that did not include an anti-CD38 antibody (PFS 4-drug 8.1 months, PFS 3-drug 8.0 months; HR 0.95; 95% CI 0.86; 1.06). Adverse events were more frequent with the quadruplet regimens but were predominately mild. High-grade (≥3) adverse events (AEs) that were more common with 4-drug regimens were infections (RR: 1.34; 95% CI 1.17; 1.54) and thrombocytopenia (RR: 1.39; 95% CI 1.12; 1.74). This study suggests that 4-drug induction regimens which include an anti-CD38 antibody improve efficacy although with additional toxicity in NDMM patients. Full article

(This article belongs to the Special Issue State-of-the-Art Research on Multiple Myeloma Progression)

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11 pages, 3308 KiB

Open AccessSystematic Review

Efficacy and Safety of Cryoablation in Barrett’s Esophagus and Comparison with Radiofrequency Ablation: A Meta-Analysis

by Apostolis Papaefthymiou, Benjamin Norton, Andrea Telese, Daryl Ramai, Alberto Murino, Paraskevas Gkolfakis, John Vargo and Rehan J. Haidry

Cancers 2024, 16(17), 2937; https://doi.org/10.3390/cancers16172937 - 23 Aug 2024

Viewed by 153

Abstract

Background: The mainstay approach in endoscopic eradication therapy (EET) for dysplastic Barrett’s esophagus (BE) includes the endoscopic resection of visible lesions, accompanied by ablation of the residual metaplastic epithelium. Cryoablation therapy is one such emerging ablation technique in this field. This systematic review [...] Read more.

Background: The mainstay approach in endoscopic eradication therapy (EET) for dysplastic Barrett’s esophagus (BE) includes the endoscopic resection of visible lesions, accompanied by ablation of the residual metaplastic epithelium. Cryoablation therapy is one such emerging ablation technique in this field. This systematic review with a meta-analysis aims to accumulate pooled data on cryoablation performance in the treatment of patients with BE and to compare this technique to the standard of care radiofrequency ablation (RFA). Methods: The MEDLINE, Cochrane, and Scopus databases were searched until June 2024 for studies evaluating BE management using cryoablation for cumulative results. The primary outcome was the complete eradication of dysplasia (CED) and intestinal metaplasia (CEIM) in BE compared to RFA, while secondary outcomes included the respective pooled rates using cryoablation, recurrence, and adverse events, with a separate analysis for strictures. The meta-analyses were based on a random-effects model, and the results were reported as odds ratios (ORs) with 95% confidence intervals (CIs). Subgroup analyses by type of cryoablation were also performed. Results: Twenty-three studies (1604 patients) were finally included, four of which were comparative. CED and CEIM did not differ significantly between cryoablation and RFA [OR= 0.95 (95%CI: 0.50–1.81) and OR = 0.57 (95%CI: 0.20–1.63), respectively)]. The pooled rates of CED, CEIM, and recurrence after cryoablation were 84.2% (95%CI: 79.1–89.3), 64.1% (95%CI: 49.2–79.0), and 8.3% (95%CI: 4.7–11.9), accompanied by high rates of heterogeneity. Adverse events were noted in 14.5% (95%CI: 9.9–19.2) of cases, and 6.5% (95%CI: 4.1–9.0) developed strictures. In the subgroup analysis, the cryoballoon achieved a reduction in heterogeneity in CED, adverse events, and stricture formation, whereas spray catheters provided homogenous results in terms of recurrence. Conclusions: Cryoablation provides equal outcomes compared to RFA in the treatment of patients with BE, with the cryoballoon achieving relatively homogenous rates of CED and adverse events. Full article

(This article belongs to the Special Issue Advances in Surgical Endoscopy for Upper GI Cancers)

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14 pages, 2893 KiB

Open AccessArticle

Evaluation of Hi-C Sequencing for Detection of Gene Fusions in Hematologic and Solid Tumor Pediatric Cancer Samples

by Anthony D. Schmitt, Kristin Sikkink, Atif A. Ahmed, Shadi Melnyk, Derek Reid, Logan Van Meter, Erin M. Guest, Lisa A. Lansdon, Tomi Pastinen, Irina Pushel, Byunggil Yoo and Midhat S. Farooqi

Cancers 2024, 16(17), 2936; https://doi.org/10.3390/cancers16172936 - 23 Aug 2024

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Abstract

Hi-C sequencing is a DNA-based next-generation sequencing method that preserves the 3D genome conformation and has shown promise in detecting genomic rearrangements in translational research studies. To evaluate Hi-C as a potential clinical diagnostic platform, analytical concordance with routine laboratory testing was assessed [...] Read more.

Hi-C sequencing is a DNA-based next-generation sequencing method that preserves the 3D genome conformation and has shown promise in detecting genomic rearrangements in translational research studies. To evaluate Hi-C as a potential clinical diagnostic platform, analytical concordance with routine laboratory testing was assessed using primary pediatric leukemia and sarcoma specimens. Archived viable and non-viable frozen leukemic cells and formalin-fixed paraffin-embedded (FFPE) tumor specimens were analyzed. Pediatric acute myeloid leukemia (AML) and alveolar rhabdomyosarcoma (A-RMS) specimens with known genomic rearrangements were subjected to Hi-C to assess analytical concordance. Subsequently, a discovery cohort consisting of AML and acute lymphoblastic leukemia (ALL) cases without known genomic rearrangements based on prior clinical diagnostic testing was evaluated to determine whether Hi-C could detect rearrangements. Using a standard sequencing depth of 50 million raw read-pairs per sample, or approximately 5X raw genomic coverage, we observed 100% concordance between Hi-C and previous clinical cytogenetic and molecular testing. In the discovery cohort, a clinically relevant gene fusion was detected in 45% of leukemia cases (5/11). This study provides an institutional proof of principle evaluation of Hi-C sequencing to medical diagnostic testing as it identified several clinically relevant rearrangements, including those that were missed by current clinical testing workflows. Full article

(This article belongs to the Section Cancer Pathophysiology)

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15 pages, 5500 KiB

Open AccessReview

Minimally Invasive Management of Inguinal Lymph Nodes in Penile Cancer: Recent Progress and Remaining Challenges

by Ahmet Murat Aydin, Emily Biben, Alice Yu, Nicholas H. Chakiryan, Reza Mehrazin and Philippe E. Spiess

Cancers 2024, 16(17), 2935; https://doi.org/10.3390/cancers16172935 - 23 Aug 2024

Viewed by 171

Abstract

The diagnosis of occult inguinal lymph node metastasis in clinically node-negative invasive penile squamous cell carcinoma (PSCC) has remained a challenge, with substantial perioperative complications. The recent refinements in the technique of dynamic sentinel lymph node biopsy (DSLNB) demonstrated high diagnostic accuracy with [...] Read more.

The diagnosis of occult inguinal lymph node metastasis in clinically node-negative invasive penile squamous cell carcinoma (PSCC) has remained a challenge, with substantial perioperative complications. The recent refinements in the technique of dynamic sentinel lymph node biopsy (DSLNB) demonstrated high diagnostic accuracy with considerably lower morbidity compared to conventional open modified/superficial inguinal lymph node dissection (ILND). Although DSLNB, if available, has been endorsed as the preferred method for nodal staging in patients with invasive PSCC and no palpable inguinal lymphadenopathy in the recent penile cancer guidelines, its utilization has been quite limited so far. Laparoscopic and robotic-assisted ILND have emerged as alternatives for nodal staging in this patient population and are shown to improve the rate of wound infections and postoperative pain. For management of nodal metastasis in patients with clinically palpable inguinal lymph nodes, minimally invasive ILND has shown promising results as well. Nonetheless, given the rarity of PSCC and the absence of prospective studies and clinical trials, nodal staging and treatment of nodal metastasis in clinical practice will likely continue to vary across the medical centers in the following years. In this review, we first summarize the evolution of DSLNB and minimally invasive ILND and discuss the advantages and drawbacks of each management strategy. We further discuss the remaining challenges and future perspectives in the management of inguinal lymph nodes in patients with PSCC. Full article

(This article belongs to the Special Issue Research on Current Progress in Penile Cancer)

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13 pages, 3117 KiB

Open AccessArticle

Vitamin D₃ Upregulated Protein 1 Deficiency Promotes Azoxymethane/Dextran Sulfate Sodium-Induced Colorectal Carcinogenesis in Mice

by Ki Hwan Park, Hyoung-Chin Kim, Young-Suk Won, Won Kee Yoon, Inpyo Choi, Sang-Bae Han and Jong Soon Kang

Cancers 2024, 16(17), 2934; https://doi.org/10.3390/cancers16172934 - 23 Aug 2024

Viewed by 164

Abstract

VDUP1 acts as a tumor suppressor gene in various cancers. VDUP1 is expressed at low levels in sporadic and ulcerative-colitis-associated colorectal cancer. However, the effects of VDUP1 deficiency on CAC remain unclear. In this study, we found that VDUP1 deficiency promoted CAC development [...] Read more.

VDUP1 acts as a tumor suppressor gene in various cancers. VDUP1 is expressed at low levels in sporadic and ulcerative-colitis-associated colorectal cancer. However, the effects of VDUP1 deficiency on CAC remain unclear. In this study, we found that VDUP1 deficiency promoted CAC development in mice. Wild-type (WT) and VDUP1 KO mice were used to investigate the role of VDUP1 in the development of azoxymethane (AOM)- and dextran sulfate sodium (DSS)-induced CAC. VDUP1 levels significantly decreased in the colonic tumor and adjacent nontumoral tissues of WT mice after AOM/DSS treatment. Moreover, AOM/DSS-treated VDUP1 KO mice exhibited a worse survival rate, disease activity index, and tumor burden than WT mice. VDUP1 deficiency significantly induced cell proliferation and anti-apoptosis in tumor tissues of VDUP1 KO mice compared to WT littermates. Additionally, mRNA levels of interleukin-6 and tumor necrosis factor-alpha and active forms of signal transducer and activator of transcription 3 and nuclear factor-kappa B p65 were significantly increased in the tumor tissues of VDUP1 KO mice. Overall, this study demonstrated that the loss of VDUP1 promoted AOM/DSS-induced colon tumorigenesis in mice, highlighting the potential of VDUP1-targeting strategies for colon cancer prevention and treatment. Full article

(This article belongs to the Special Issue Genes in Cancer)

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12 pages, 2801 KiB

Open AccessArticle

Cost-Effectiveness of Lung Cancer Screening with Low-Dose Computed Tomography: Comparing Hungarian Screening Protocols with the US NLST

by Tanya Rajabi, László Szilberhorn, Dávid Győrbíró, Manna Tatár, Zoltán Vokó and Balázs Nagy

Cancers 2024, 16(17), 2933; https://doi.org/10.3390/cancers16172933 - 23 Aug 2024

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Abstract

We aimed to directly compare the cost-effectiveness of Hungarian (following the NELSON trial) and NLST screening protocols, two trials influencing lung-cancer-screening implementation internationally. A decision-analytic model analyzing the cost-effectiveness of Hungarian protocols was manipulated to reflect the protocols of the NLST, while maintaining [...] Read more.

We aimed to directly compare the cost-effectiveness of Hungarian (following the NELSON trial) and NLST screening protocols, two trials influencing lung-cancer-screening implementation internationally. A decision-analytic model analyzing the cost-effectiveness of Hungarian protocols was manipulated to reflect the protocols of the NLST, while maintaining features specific to the Hungarian healthcare setting. In the Hungarian protocol, there are three possible outcomes to the initial round of screening, positive, negative, and indeterminate, indicating an uncertain degree of suspicion for lung cancer. This protocol differs from the NLST, in which the only possible screening outcomes are positive or negative, with no indeterminate option. The NLST pathway for smokers aged 55–74 resulted in a EUR 43 increase in the total average lifetime costs compared to the Hungarian screening pathway and resulted in a lifetime gain of 0.006 QALYs. The incremental costs and QALYs yielded an ICER of 7875 EUR/QALY. Our results demonstrate that assigning any suspicious LDCT screen as a positive result (NLST protocol) rather than indeterminate (Hungarian protocol) can reduce patient uncertainty and yield a slight QALY gain that is worth the additional use of resources according to Hungary’s willingness-to-pay threshold. A stratified analysis by age was also conducted, revealing decreasing cost-effectiveness when screening older cohorts. Our study provides insight into the cost-effectiveness, advantages, and disadvantages of various LDCT screening protocols for lung cancer and can assist other countries as they implement their screening programs. Full article

(This article belongs to the Special Issue Prevention and Quality of Life of Lung Cancer)

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13 pages, 1158 KiB

Open AccessArticle

Prognostic Factors in Patients Diagnosed with Gallbladder Cancer over a Period of 20 Years: A Cohort Study

by Nima Toussi, Krishna Daida, Michael Moser, Duc Le, Kimberly Hagel, Rani Kanthan, John Shaw, Adnan Zaidi, Haji Chalchal and Shahid Ahmed

Cancers 2024, 16(17), 2932; https://doi.org/10.3390/cancers16172932 - 23 Aug 2024

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Abstract

Background: Gallbladder cancer (GBC) is an uncommon cancer. This study aimed to determine the outcomes of GBC in relation to geographic, demographic, and clinical factors in a Canadian province from 2000 to 2019. Methods: This population-based retrospective cohort study included all patients diagnosed [...] Read more.

Background: Gallbladder cancer (GBC) is an uncommon cancer. This study aimed to determine the outcomes of GBC in relation to geographic, demographic, and clinical factors in a Canadian province from 2000 to 2019. Methods: This population-based retrospective cohort study included all patients diagnosed with gallbladder cancer (GBC) in Saskatchewan, Canada, from 2000 to 2019. Cox proportional multivariate regression analysis was conducted to identify factors associated with poorer outcomes. Results: In total, 331 patients with a median age of 74 years and male–female ratio of 1:2 were identified. Of these patients, 305 (92%) had a pathological diagnosis of GBC. Among patients with documented staging data, 64% had stage IV disease. A total of 217 (66%) patients were rural residents, and 149 (45%) were referred to a cancer center. The multivariate analysis for patients with stage I–III GBC showed that stage III disease [hazard ratio (HR), 2.63; 95% confidence interval (CI), 1.09–6.34)] and urban residence (HR, 2.20; 95% CI, 1.1–4.39) were correlated with inferior disease-free survival. For all patients, stage IV disease (HR, 3.02; 95% CI, 1.85–4.94), no referral to a cancer center (HR, 2.64; 95% CI, 1.51–4.62), lack of surgery (HR, 1.63; 95% CI, 1.03–2.57), a neutrophil–lymphocyte ratio of >3.2 (HR, 1.57; 1.05–2.36), and age of ≥70 years (HR, 1.51; 95% CI, 1.04–2.19) were correlated with inferior overall survival. Conclusions: In this real-world context, the majority of patients with GBC were diagnosed at a late stage and were not referred to a cancer center. For those with early-stage GBC, living in an urban area and having stage III disease were linked to worse outcomes. Across all stages of GBC, stage IV disease, older age, absence of surgery, lack of referral to a cancer center, and a high neutrophil-to-lymphocyte ratio were associated with poorer survival. Full article

(This article belongs to the Special Issue Contemporary Management for Gallbladder Cancer: From Diagnosis to Treatment)

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20 pages, 330 KiB

Open AccessReview

Updates on Therapeutic Strategies in the Treatment of Relapsed/Refractory Multiple Myeloma

by Deevyashali S. Parekh, Yun Kyoung Ryu Tiger, Kevin Tony Jamouss, Justin Hassani, Maroun Bou Zerdan and Shahzad Raza

Cancers 2024, 16(17), 2931; https://doi.org/10.3390/cancers16172931 - 23 Aug 2024

Viewed by 287

Abstract

Multiple myeloma is a heterogeneous condition characterized by the proliferation of monoclonal B-cells, for which there is currently no curative treatment available. Relapses are, unfortunately, common after first-line treatment. While the prognosis for relapsed refractory multiple myeloma is generally poor, advances in the [...] Read more.

Multiple myeloma is a heterogeneous condition characterized by the proliferation of monoclonal B-cells, for which there is currently no curative treatment available. Relapses are, unfortunately, common after first-line treatment. While the prognosis for relapsed refractory multiple myeloma is generally poor, advances in the treatment of relapsed or refractory multiple myeloma offer hope. However, the expansion of effective options in targeted treatment offers renewed optimism and hope that patients who fail on older therapies may respond to newer modalities, which are often used in combination. We review currently approved and novel investigational agents classified by mechanisms of action, efficacy, approved setting, and adverse events. We delve into future directions of treatment for relapsed/refractory multiple myeloma, reviewing novel agents and therapeutic targets for the future. Full article

(This article belongs to the Special Issue State-of-the-Art Research on Multiple Myeloma Progression)

9 pages, 719 KiB

Open AccessArticle

Risk Factors for Positive Resection Margins in Breast-Conserving Surgery for Breast Cancer—Retrospective Analysis

by Rares Georgescu, Flavian Tutuianu, Orsolya Bauer, Anca Toganel, Zalan Benedek, Eugeniu Darii, Sabin Turdean and Cristina Tutuianu Radoi

Cancers 2024, 16(17), 2930; https://doi.org/10.3390/cancers16172930 - 23 Aug 2024

Viewed by 180

Abstract

The primary objective of this study was to identify preoperative factors that could be associated with positive resection margins. We also tried to analyze the local recurrence and overall survival in patients who received conservative treatment for early-stage breast cancer and correlate these [...] Read more.

The primary objective of this study was to identify preoperative factors that could be associated with positive resection margins. We also tried to analyze the local recurrence and overall survival in patients who received conservative treatment for early-stage breast cancer and correlate these parameters with preoperative factors. A retrospective examination was conducted on the medical records and pathological reports of 143 patients who underwent breast-conserving surgery (BCS) for breast cancer in our department from 2009 to 2017. Postoperative outcomes were assessed through phone contact and statistical analyses, including GraphPad Prism, and Fisher’s exact test, the Chi-square test, and the log-rank test were employed. The results revealed positive resection margins in 7.69% (11 cases) of the 143 patients, with an overall mortality rate of 16.66% for those with positive margins and 6.59% for those with negative margins. Statistical analysis indicated no significant differences in the overall (p = 0.5) or specific (p = 0.53) survival between the positive and negative margin groups. The positive margins were significantly associated with neoadjuvant chemotherapy (p < 0.0001) and the presence of ductal carcinoma in situ (DCIS) (p = 0.01). Among the analyzed factors, two out of sixteen were significantly linked to positive resection margins in BCS, emphasizing their importance in surgical management planning for early-stage breast cancer. Full article

(This article belongs to the Special Issue Research on Early-Stage Breast Cancer: Management and Treatment)

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22 pages, 4383 KiB

Open AccessArticle

Circulating Multiple Myeloma Cells (CMMCs) as Prognostic and Predictive Markers in Multiple Myeloma and Smouldering MM Patients

by Ilaria Vigliotta, Vincenza Solli, Silvia Armuzzi, Marina Martello, Andrea Poletti, Barbara Taurisano, Ignazia Pistis, Gaia Mazzocchetti, Enrica Borsi, Lucia Pantani, Giulia Marzocchi, Nicoletta Testoni, Elena Zamagni, Mario Terracciano, Paola Tononi, Marianna Garonzi, Alberto Ferrarini, Nicolò Manaresi, Michele Cavo and Carolina Terragna

Cancers 2024, 16(17), 2929; https://doi.org/10.3390/cancers16172929 - 23 Aug 2024

Viewed by 237

Abstract

In recent years, liquid biopsy has emerged as a promising alternative to the bone marrow (BM) examination, since it is a minimally invasive technique allowing serial monitoring. Circulating multiple myeloma cells (CMMCs) enumerated using CELLSEARCH^® were correlated with patients’ prognosis and measured [...] Read more.

In recent years, liquid biopsy has emerged as a promising alternative to the bone marrow (BM) examination, since it is a minimally invasive technique allowing serial monitoring. Circulating multiple myeloma cells (CMMCs) enumerated using CELLSEARCH^® were correlated with patients’ prognosis and measured under treatment to assess their role in monitoring disease dynamics. Forty-four MM and seven smouldering MM (SMM) patients were studied. The CMMC medians at diagnosis were 349 (1 to 39,940) and 327 (range 22–2463) for MM and SMM, respectively. In the MM patients, the CMMC count was correlated with serum albumin, calcium, β2-microglobulin, and monoclonal components (p < 0.04). Under therapy, the CMMCs were consistently detectable in 15/40 patients (coMMstant = 1) and were undetectable or decreasing in 25/40 patients (coMMstant = 0). High-quality response rates were lower in the coMMstant = 1 group (p = 0.04), with a 7.8-fold higher risk of death (p = 0.039), suggesting that continuous CMMC release is correlated with poor responses. In four MM patients, a single-cell DNA sequencing analysis on residual CMMCs confirmed the genomic pattern of the aberrations observed in the BM samples, also highlighting the presence of emerging clones. The CMMC kinetics during treatment were used to separate the patients into two subgroups based on the coMMstant index, with different responses and survival probabilities, providing evidence that CMMC persistence is associated with a poor disease course. Full article

(This article belongs to the Special Issue Liquid Biopsy in Cancer 2.0)

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