Cancers

24 pages, 846 KiB

Open AccessReview

What Does N2 Lymph Node Involvement Mean for Patients with Non-Small Cell Lung Cancer (NSCLC)?—A Review of Implications for Diagnosis and Treatment

by Julio Linares Díaz, John Edwards, Anne-Leen Deleu, Niccolo Giaj-Levra, Elena Prisciandaro, Benoit Roch, Marianne Paesmans, Thierry Berghmans and Mariana Brandão

Cancers 2024, 16(15), 2673; https://doi.org/10.3390/cancers16152673 (registering DOI) - 26 Jul 2024

Abstract

Patients with stage III NSCLC with N2 lymph node involvement carry a complex and diverse disease entity. Challenges persist in the areas of diagnosis, staging, multimodal management, and the determination of surgical indications and resectability criteria. Therefore, this review focuses on the latest [...] Read more.

Patients with stage III NSCLC with N2 lymph node involvement carry a complex and diverse disease entity. Challenges persist in the areas of diagnosis, staging, multimodal management, and the determination of surgical indications and resectability criteria. Therefore, this review focuses on the latest updates in N2 disease staging and its prognostic and treatment implications. Emphasis is placed on the importance of accurate staging using imaging modalities such as [18F]FDG-PET/CT as well as minimally invasive mediastinal staging endoscopic techniques. The evolving role of surgery in the management of N2 disease is also explored. The benefits of neoadjuvant and adjuvant treatments have been demonstrated, along with the efficacy of a combined multimodal approach with chemo-immunotherapy in the perioperative setting, reigniting the debate of N2 disease subsets and optimal treatment options. Furthermore, this review addresses the controversies surrounding surgical approaches in upfront “borderline” resectable stage III NSCLC as well as the benefits of combined chemoradiotherapy with consolidation immunotherapy for patients with unresectable tumors. In conclusion, personalized diagnostic and treatment approaches tailored to individual patient characteristics, resource availability, and institutional expertise are essential for optimizing outcomes in patients with stage III-N2 NSCLC. Full article

(This article belongs to the Special Issue 2nd Edition: Imaging and Therapy in Lung Cancer and Mesothelioma)

10 pages, 652 KiB

Open AccessArticle

Phase IB Study of Oral Selinexor in Combination with Rituximab and Platinum Chemotherapy in Patients with Relapsed/Refractory B-Cell Lymphoma—Final Analysis

by Marie Maerevoet, Olivier Casasnovas, Guillaume Cartron, Franck Morschhauser, Catherine Thieblemont, Kamal Bouabdallah, Pierre Feugier, Vanessa Szablewski, Stephanie Becker and Herve Tilly

Cancers 2024, 16(15), 2672; https://doi.org/10.3390/cancers16152672 - 26 Jul 2024

Abstract

Purpose: Selinexor is an oral selective inhibitor of exportine-1 (XPO1) with efficacy as a single agent in heavily pretreated diffuse large B-cell lymphoma (DLBCL). We conducted a study investigating the combination of selinexor with rituximab and platinum-based chemotherapy in B-cell lymphoma. Patients [...] Read more.

Purpose: Selinexor is an oral selective inhibitor of exportine-1 (XPO1) with efficacy as a single agent in heavily pretreated diffuse large B-cell lymphoma (DLBCL). We conducted a study investigating the combination of selinexor with rituximab and platinum-based chemotherapy in B-cell lymphoma. Patients and methods: We conducted a phase 1b, dose-escalation, and expansion trial, which enrolled patients with relapsed or refractory B-cell non-Hodgkin lymphoma. Patients received oral selinexor according to a 3 + 3 design in combination with rituximab and dexamethasone, high-dose cytarabine, oxaliplatine (DHAOX) or gemcitabine, dexamethasone, and cisplatin (GDP) chemotherapy. Results: A total of 39 patients were enrolled, 27 during the escalation phase and 12 during the expansion phase. Most patients had diffuse large B-cell lymphoma (DLBCL; 77%). Group R-DHAOX was prematurely closed to inclusion due to a recommendation from the French drug agency, independent of this trial. A recommended phase 2 dose (RP2D) of selinexor in association with R-GPD was established at 40 mg on days 1, 8, and 15 of each 21-day cycle. In a population of 18 patients treated at this dose of selinexor, the most frequent grade 3–4 adverse events were hematological. With this regimen, seven obtained a complete metabolic response and five a partial response. The median PFS was 5.8 months. Conclusions: Among the patients with R/R B-cell lymphoma, selinexor at a weekly dose of 40 mg with R-GDP is feasible for outpatients, with a generally acceptable safety profile. Full article

(This article belongs to the Section Cancer Therapy)

20 pages, 598 KiB

Open AccessReview

Advancements in Research and Treatment Applications of Patient-Derived Tumor Organoids in Colorectal Cancer

by Denise van der Graaff, Sofie Seghers, Pieterjan Vanclooster, Christophe Deben, Timon Vandamme and Hans Prenen

Cancers 2024, 16(15), 2671; https://doi.org/10.3390/cancers16152671 - 26 Jul 2024

Abstract

Colorectal cancer (CRC) remains a significant health burden globally, being the second leading cause of cancer-related mortality. Despite significant therapeutic advancements, resistance to systemic antineoplastic agents remains an important obstacle, highlighting the need for innovative screening tools to tailor patient-specific treatment. This review [...] Read more.

Colorectal cancer (CRC) remains a significant health burden globally, being the second leading cause of cancer-related mortality. Despite significant therapeutic advancements, resistance to systemic antineoplastic agents remains an important obstacle, highlighting the need for innovative screening tools to tailor patient-specific treatment. This review explores the application of patient-derived tumor organoids (PDTOs), three-dimensional, self-organizing models derived from patient tumor samples, as screening tools for drug resistance in CRC. PDTOs offer unique advantages over traditional models by recapitulating the tumor architecture, cellular heterogeneity, and genomic landscape and are a valuable ex vivo predictive drug screening tool. This review provides an overview of the current literature surrounding the use of PDTOs as an instrument for predicting therapy responses in CRC. We also explore more complex models, such as co-cultures with important stromal cells, such as cancer-associated fibroblasts, and organ-on-a-chip models. Furthermore, we discuss the use of PDTOs for drug repurposing, offering a new approach to identify the existing drugs effective against drug-resistant CRC. Additionally, we explore how PDTOs serve as models to gain insights into drug resistance mechanisms, using newer techniques, such as single-cell RNA sequencing and CRISPR-Cas9 genome editing. Through this review, we aim to highlight the potential of PDTOs in advancing our understanding of predicting therapy responses, drug resistance, and biomarker identification in CRC management. Full article

(This article belongs to the Special Issue Drug Resistance in Colorectal Cancer)

11 pages, 370 KiB

Open AccessArticle

Analysis of Molecular Imaging and Laboratory Baseline Biomarkers in PSMA-RLT: Whole-Body Total Lesion PSMA (TLP) Predicts Overall Survival

by Connor Hein, Caroline Burgard, Arne Blickle, Moritz B. Bastian, Stephan Maus, Andrea Schaefer-Schuler, Manuela A. Hoffmann, Mathias Schreckenberger, Samer Ezziddin and Florian Rosar

Cancers 2024, 16(15), 2670; https://doi.org/10.3390/cancers16152670 - 26 Jul 2024

Abstract

The aim of this retrospective study was to identify pre-therapeutic predictive laboratory and molecular imaging biomarkers for response and overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT). Pre-therapeutic laboratory and [ [...] Read more.

The aim of this retrospective study was to identify pre-therapeutic predictive laboratory and molecular imaging biomarkers for response and overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT). Pre-therapeutic laboratory and [⁶⁸Ga]Ga-PSMA-11 PET/CT data of n = 102 mCRPC patients receiving [¹⁷⁷Lu]Lu-PSMA-617 RLT within a prospective registry (REALITY Study, NCT04833517) were analyzed including laboratory parameters such as alkaline phosphatase (ALP), prostate-specific antigen (PSA), gamma glutamyl transferase (GGT), glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), neuron specific enolase (NSE), hemoglobin (Hb), and imaging parameters such as maximum standardized uptake value of the tumor lesions (SUV_max), the mean standardized uptake value of all tumor lesions (SUV_mean), the whole-body molecular tumor volume (MTV), and the whole-body total lesion PSMA (TLP). Mann‒Whitney U test, univariate and multivariable Cox-regression were performed to test for association of the parameters with response and OS. The SUV_mean of all lesions was significantly different between responders and non-responders (SUV_mean responders 8.95 ± 2.83 vs. non-responders 7.88 ± 4.46, p = 0.003), whereas all other tested biochemical and imaging parameters did not reveal significant differences. Hb and the molecular imaging parameters MTV and TLP showed a significant association with OS (p = 0.013, p = 0.005; p = 0.009) in univariant Cox regression; however, only TLP remained significant in multivariable analysis (Hazard ratio 1.033, p = 0.009). This study demonstrates a statistically significant association between the quantitative PET/CT imaging parameter SUV_mean and PSA response, as well as between the baseline TLP and OS of mCRPC patients undergoing RLT. Full article

(This article belongs to the Section Cancer Biomarkers)

12 pages, 1528 KiB

Open AccessArticle

Can Delta Radiomics Improve the Prediction of Best Overall Response, Progression-Free Survival, and Overall Survival of Melanoma Patients Treated with Immune Checkpoint Inhibitors?

by Felix Peisen, Annika Gerken, Alessa Hering, Isabel Dahm, Konstantin Nikolaou, Sergios Gatidis, Thomas K. Eigentler, Teresa Amaral, Jan H. Moltz and Ahmed E. Othman

Cancers 2024, 16(15), 2669; https://doi.org/10.3390/cancers16152669 - 26 Jul 2024

Abstract

Background: The prevalence of metastatic melanoma is increasing, necessitating the identification of patients who do not benefit from immunotherapy. This study aimed to develop a radiomic biomarker based on the segmentation of all metastases at baseline and the first follow-up CT for the [...] Read more.

Background: The prevalence of metastatic melanoma is increasing, necessitating the identification of patients who do not benefit from immunotherapy. This study aimed to develop a radiomic biomarker based on the segmentation of all metastases at baseline and the first follow-up CT for the endpoints best overall response (BOR), progression-free survival (PFS), and overall survival (OS), encompassing various immunotherapies. Additionally, this study investigated whether reducing the number of segmented metastases per patient affects predictive capacity. Methods: The total tumour load, excluding cerebral metastases, from 146 baseline and 146 first follow-up CTs of melanoma patients treated with first-line immunotherapy was volumetrically segmented. Twenty-one random forest models were trained and compared for the endpoints BOR; PFS at 6, 9, and 12 months; and OS at 6, 9, and 12 months, using as input either only clinical parameters, whole-tumour-load delta radiomics plus clinical parameters, or delta radiomics from the largest ten metastases plus clinical parameters. Results: The whole-tumour-load delta radiomics model performed best for BOR (AUC 0.81); PFS at 6, 9, and 12 months (AUC 0.82, 0.80, and 0.77); and OS at 6 months (AUC 0.74). The model using delta radiomics from the largest ten metastases performed best for OS at 9 and 12 months (AUC 0.71 and 0.75). Although the radiomic models were numerically superior to the clinical model, statistical significance was not reached. Conclusions: The findings indicate that delta radiomics may offer additional value for predicting BOR, PFS, and OS in metastatic melanoma patients undergoing first-line immunotherapy. Despite its complexity, volumetric whole-tumour-load segmentation could be advantageous. Full article

(This article belongs to the Special Issue Cancer Biomarkers—Detection and Evaluation of Response to Therapy)

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17 pages, 1276 KiB

Open AccessReview

Impact of Preprocessing Parameters in Medical Imaging-Based Radiomic Studies: A Systematic Review

by Valeria Trojani, Maria Chiara Bassi, Laura Verzellesi and Marco Bertolini

Cancers 2024, 16(15), 2668; https://doi.org/10.3390/cancers16152668 - 26 Jul 2024

Abstract

Background: Lately, radiomic studies featuring the development of a signature to use in prediction models in diagnosis or prognosis outcomes have been increasingly published. While the results are shown to be promising, these studies still have many pitfalls and limitations. One of the [...] Read more.

Background: Lately, radiomic studies featuring the development of a signature to use in prediction models in diagnosis or prognosis outcomes have been increasingly published. While the results are shown to be promising, these studies still have many pitfalls and limitations. One of the main issues of these studies is that radiomic features depend on how the images are preprocessed before their computation. Since, in widely known and used software for radiomic features calculation, it is possible to set these preprocessing parameters before the calculation of the radiomic feature, there are ongoing studies assessing the stability and repeatability of radiomic features to find the most suitable preprocessing parameters for every used imaging modality. Materials and Methods: We performed a comprehensive literature search using four electronic databases: PubMed, Cochrane Library, Embase, and Scopus. Mesh terms and free text were modeled in search strategies for databases. The inclusion criteria were studies where preprocessing parameters’ influence on feature values and model predictions was addressed. Records lacking information on image acquisition parameters were excluded, and any eligible studies with full-text versions were included in the review process, while conference proceedings and monographs were disregarded. We used the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2) tool to investigate the risk of bias. We synthesized our data in a table divided by the imaging modalities subgroups. Results: After applying the inclusion and exclusion criteria, we selected 43 works. This review examines the impact of preprocessing parameters on the reproducibility and reliability of radiomic features extracted from multimodality imaging (CT, MRI, CBCT, and PET/CT). Standardized preprocessing is crucial for consistent radiomic feature extraction. Key preprocessing steps include voxel resampling, normalization, and discretization, which influence feature robustness and reproducibility. In total, 44% of the included works studied the effects of an isotropic voxel resampling, and most studies opted to employ a discretization strategy. From 2021, several studies started selecting the best set of preprocessing parameters based on models’ best performance. As for comparison metrics, ICC was the most used in MRI studies in 58% of the screened works. Conclusions: From our work, we highlighted the need to harmonize the use of preprocessing parameters and their values, especially in light of future studies of prospective studies, which are still lacking in the current literature. Full article

(This article belongs to the Special Issue Radiomics and Imaging in Cancer Analysis)

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19 pages, 4372 KiB

Open AccessReview

Imaging Recommendations for Diagnosis, Staging, and Management of Central Nervous System Neoplasms in Adults: CNS Metastases

by Kajari Bhattacharya, Abhishek Mahajan and Soujanya Mynalli

Cancers 2024, 16(15), 2667; https://doi.org/10.3390/cancers16152667 - 26 Jul 2024

Abstract

Brain metastases (BMs) are the most common central nervous system (CNS) neoplasms, with an increasing incidence that is due in part to an overall increase in primary cancers, improved neuroimaging modalities leading to increased detection, better systemic therapies, and longer patient survival. Objective: [...] Read more.

Brain metastases (BMs) are the most common central nervous system (CNS) neoplasms, with an increasing incidence that is due in part to an overall increase in primary cancers, improved neuroimaging modalities leading to increased detection, better systemic therapies, and longer patient survival. Objective: To identify cancer patients at a higher risk of developing CNS metastases and to evaluate associated prognostic factors. Methods: Review of imaging referral guidelines, response criteria, interval imaging assessment, modality of choice, as well as the association of clinical, serological, and imaging findings as per various cancer societies. Results: Quantitative response assessment of target and non-target brain metastases as well as an interval imaging protocol set up based on primary histological diagnosis and therapy status are discussed as per various cancer societies and imaging programs. Conclusion: Predictive factors in the primary tumor as well as independent variables of brain metastases like size, number, and response to therapy are necessary in management. The location of CNS metastases, symptomatic disease, as well as follow up imaging findings form a skeletal plan to prognosticate the disease, keeping in mind all the available new advanced therapy options of surgery, radiation, and immunotherapy that improve patient outcome significantly. Full article

(This article belongs to the Special Issue Brain and Spinal Cord Tumors: Symptoms, Diagnosis, and Treatment)

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17 pages, 1290 KiB

Open AccessArticle

Omission of Completion Axillary Lymph Node Dissection for Patients with Breast Cancer Treated by Upfront Mastectomy and Sentinel Node Isolated Tumor Cells or Micrometastases

by Gilles Houvenaeghel, Mellie Heinemann, Jean-Marc Classe, Catherine Bouteille, Pierre Gimbergues, Anne-Sophie Azuar, Marc Martino, Agnès Tallet, Monique Cohen and Alexandre de Nonneville

Cancers 2024, 16(15), 2666; https://doi.org/10.3390/cancers16152666 - 26 Jul 2024

Abstract

Omission of completion axillary lymph node dissection (cALND) in patients undergoing mastectomy with sentinel node (SN) isolated tumor cells (ITC) or micrometastases is debated due to potential under-treatment, with non-sentinel node (NSN) involvement detected in 7% to 18% of patients. This study evaluated [...] Read more.

Omission of completion axillary lymph node dissection (cALND) in patients undergoing mastectomy with sentinel node (SN) isolated tumor cells (ITC) or micrometastases is debated due to potential under-treatment, with non-sentinel node (NSN) involvement detected in 7% to 18% of patients. This study evaluated the survival impact of cALND omission in a cohort of breast cancer (BC) patients treated by mastectomy with SN ITC or micrometastases. Among 554 early BC patients (391 pN1mi, 163 ITC), the NSN involvement rate was 13.2% (49/371). With a median follow-up of 66.46 months, multivariate analysis revealed significant associations between cALND omission and overall survival (OS, HR: 2.583, p = 0.043), disease-free survival (DFS, HR: 2.538, p = 0.008), and metastasis-free survival (MFS, HR: 2.756, p = 0.014). For Her2-positive or triple-negative patients, DFS was significantly affected by cALND omission (HR: 38.451, p = 0.030). In ER-positive Her2-negative BC, DFS, OS, recurrence-free survival (RFS), and MFS were significantly associated with cALND omission (DFS HR: 2.358, p = 0.043; OS HR: 3.317; RFS HR: 2.538; MFS HR: 2.756). For 161 patients aged ≤50 years with ER-positive/Her2-negative cancer, OS and breast cancer-specific survival (BCSS) were notably impacted by cALND omission (OS HR: 103.47, p = 0.004; BCSS HR: 50.874, p = 0.035). These findings suggest a potential negative prognostic impact of cALND omission in patients with SN micrometastases or ITC. Further randomized trials are needed. Full article

(This article belongs to the Section Methods and Technologies Development)

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11 pages, 914 KiB

Open AccessArticle

Development of a Multidisciplinary Care Pathway for Fracture Prevention in Men with Prostate Cancer at Initiation of Androgen Deprivation Therapy

by Marsha M. van Oostwaard, Joop P. van den Bergh, Agnes J. van de Wouw, Marc de Jong, Maryska L. Janssen-Heijnen and Caroline E. Wyers

Cancers 2024, 16(15), 2665; https://doi.org/10.3390/cancers16152665 - 26 Jul 2024

Abstract

Fracture risk is increased in men with prostate cancer (PCa) receiving Androgen Deprivation Therapy (ADT). However, routine assessment of fracture risk is often not systematically applied. We aimed to establish a comprehensive care pathway for fracture prevention in men with PCa starting ADT. [...] Read more.

Fracture risk is increased in men with prostate cancer (PCa) receiving Androgen Deprivation Therapy (ADT). However, routine assessment of fracture risk is often not systematically applied. We aimed to establish a comprehensive care pathway for fracture prevention in men with PCa starting ADT. Therefore, a multidisciplinary working group designed and implemented a care pathway using the ‘Knowledge to Action’ framework, based on current Dutch guidelines for PCa, osteoporosis and fracture prevention, and an extensive literature review of other guidelines. The pathway was developed according to a five-step clinical approach including case finding, fracture risk assessment based on risk factors, bone mineral density test, vertebral fracture assessment, differential diagnosis, treatment, and annual follow-up. Our fracture prevention care pathway for patients with PCa at the time of ADT initiation was designed to promote a patient-centered, multidisciplinary approach to facilitate the implementation of early fracture prevention measures. Full article

(This article belongs to the Special Issue Contemporary Diagnosis and Management of Prostate Cancer)

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15 pages, 940 KiB

Open AccessReview

Radiomics in Oesogastric Cancer: Staging and Prediction of Preoperative Treatment Response: A Narrative Review and the Results of Personal Experience

by Giovanni Maria Garbarino, Michela Polici, Damiano Caruso, Andrea Laghi, Paolo Mercantini, Emanuela Pilozzi, Mark I. van Berge Henegouwen, Suzanne S. Gisbertz, Nicole C. T. van Grieken, Eva Berardi and Gianluca Costa

Cancers 2024, 16(15), 2664; https://doi.org/10.3390/cancers16152664 - 26 Jul 2024

Abstract

Background: Oesophageal, gastroesophageal, and gastric malignancies are often diagnosed at locally advanced stage and multimodal therapy is recommended to increase the chances of survival. However, given the significant variation in treatment response, there is a clear imperative to refine patient stratification. The aim [...] Read more.

Background: Oesophageal, gastroesophageal, and gastric malignancies are often diagnosed at locally advanced stage and multimodal therapy is recommended to increase the chances of survival. However, given the significant variation in treatment response, there is a clear imperative to refine patient stratification. The aim of this narrative review was to explore the existing evidence and the potential of radiomics to improve staging and prediction of treatment response of oesogastric cancers. Methods: The references for this review article were identified via MEDLINE (PubMed) and Scopus searches with the terms “radiomics”, “texture analysis”, “oesophageal cancer”, “gastroesophageal junction cancer”, “oesophagogastric junction cancer”, “gastric cancer”, “stomach cancer”, “staging”, and “treatment response” until May 2024. Results: Radiomics proved to be effective in improving disease staging and prediction of treatment response for both oesophageal and gastric cancer with all imaging modalities (TC, MRI, and 18F-FDG PET/CT). The literature data on the application of radiomics to gastroesophageal junction cancer are very scarce. Radiomics models perform better when integrating different imaging modalities compared to a single radiology method and when combining clinical to radiomics features compared to only a radiomics signature. Conclusions: Radiomics shows potential in noninvasive staging and predicting response to preoperative therapy among patients with locally advanced oesogastric cancer. As a future perspective, the incorporation of molecular subgroup analysis to clinical and radiomic features may even increase the effectiveness of these predictive and prognostic models. Full article

(This article belongs to the Special Issue Oesogastric Cancer: Treatment and Management)

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23 pages, 3729 KiB

Open AccessArticle

The Engineered Drug 3′UTRMYC1-18 Degrades the c-MYC-STAT5A/B-PD-L1 Complex In Vivo to Inhibit Metastatic Triple-Negative Breast Cancer

by Chidiebere U. Awah, Joo Sun Mun, Aloka Paragodaarachchi, Baris Boylu, Chika Ochu, Hiroshi Matsui and Olorunseun O. Ogunwobi

Cancers 2024, 16(15), 2663; https://doi.org/10.3390/cancers16152663 - 26 Jul 2024

Abstract

c-MYC is overexpressed in 70% of human cancers, including triple-negative breast cancer (TNBC), yet there is no clinically approved drug that directly targets it. Here, we engineered the mRNA-stabilizing poly U sequences within the 3′UTR of c-MYC to specifically destabilize and promote the [...] Read more.

c-MYC is overexpressed in 70% of human cancers, including triple-negative breast cancer (TNBC), yet there is no clinically approved drug that directly targets it. Here, we engineered the mRNA-stabilizing poly U sequences within the 3′UTR of c-MYC to specifically destabilize and promote the degradation of c-MYC transcripts. Interestingly, the engineered derivative outcompetes the endogenous overexpressed c-MYC mRNA, leading to reduced c-MYC mRNA and protein levels. The iron oxide nanocages (IO-nanocages) complexed with MYC-destabilizing constructs inhibited primary and metastatic tumors in mice bearing TNBC and significantly prolonged survival by degrading the c-MYC-STAT5A/B-PD-L1 complexes that drive c-MYC-positive TNBC. Taken together, we have described a novel therapy for c-MYC-driven TNBC and uncovered c-MYC-STAT5A/B-PD-L1 interaction as the target. Full article

(This article belongs to the Special Issue Triple Negative Breast Cancer Therapy Resistance and Metastasis)

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18 pages, 2806 KiB

Open AccessArticle

Topological Structures in the Space of Treatment-Naïve Patients with Chronic Lymphocytic Leukemia

by Reginald L. McGee II, Jake Reed, Caitlin E. Coombes, Carmen D. Herling, Michael J. Keating, Lynne V. Abruzzo and Kevin R. Coombes

Cancers 2024, 16(15), 2662; https://doi.org/10.3390/cancers16152662 - 26 Jul 2024

Abstract

Patients are complex and heterogeneous; clinical data sets are complicated by noise, missing data, and the presence of mixed-type data. Using such data sets requires understanding the high-dimensional “space of patients”, composed of all measurements that define all relevant phenotypes. The current state-of-the-art [...] Read more.

Patients are complex and heterogeneous; clinical data sets are complicated by noise, missing data, and the presence of mixed-type data. Using such data sets requires understanding the high-dimensional “space of patients”, composed of all measurements that define all relevant phenotypes. The current state-of-the-art merely defines spatial groupings of patients using cluster analyses. Our goal is to apply topological data analysis (TDA), a new unsupervised technique, to obtain a more complete understanding of patient space. We applied TDA to a space of 266 previously untreated patients with Chronic Lymphocytic Leukemia (CLL), using the “daisy” metric to compute distances between clinical records. We found clear evidence for both loops and voids in the CLL data. To interpret these structures, we developed novel computational and graphical methods. The most persistent loop and the most persistent void can be explained using three dichotomized, prognostically important factors in CLL: IGHV somatic mutation status, beta-2 microglobulin, and Rai stage. In conclusion, patient space turns out to be richer and more complex than current models suggest. TDA could become a powerful tool in a researcher’s arsenal for interpreting high-dimensional data by providing novel insights into biological processes and improving our understanding of clinical and biological data sets. Full article

(This article belongs to the Collection Oncology: State-of-the-Art Research in the USA)

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12 pages, 900 KiB

Open AccessArticle

Enhanced Lung Cancer Detection Using a Combined Ratio of Antigen–Autoantibody Immune Complexes against CYFRA 21-1 and p53

by Heyjin Kim, Jin Kyung Lee, Hye-Ryoun Kim and Young Jun Hong

Cancers 2024, 16(15), 2661; https://doi.org/10.3390/cancers16152661 - 26 Jul 2024

Abstract

The early detection of lung cancer (LC) improves patient outcomes, but current methods have limitations. Autoantibodies against tumor-associated antigens have potential as early biomarkers. This study evaluated the 9G test^TM Cancer/Lung, measuring circulating complexes of two antigen–autoantibody immune complexes (AIC) against their [...] Read more.

The early detection of lung cancer (LC) improves patient outcomes, but current methods have limitations. Autoantibodies against tumor-associated antigens have potential as early biomarkers. This study evaluated the 9G test^TM Cancer/Lung, measuring circulating complexes of two antigen–autoantibody immune complexes (AIC) against their respective free antigens (CYFRA 21-1 and p53) for LC diagnosis. We analyzed 100 LC patients and 119 healthy controls using the 9G test^TM Cancer/Lung, quantifying the levels of AICs (CYFRA 21-1-Anti-CYFRA 21-1 autoantibody immune complex (CIC) and p53-Anti-p53 autoantibody immune complex (PIC)), free antigens (CYFRA 21-1 and p53), and ratios of AICs/antigens (LC index). The levels of the CICs and PICs were significantly elevated in LC compared to the controls (p < 0.0062 and p < 0.0026), while free antigens showed no significant difference. The CIC/CYFRA 21-1 and PIC/p53 ratios were also significantly higher in LC (all, p < 0.0001). The LC index, when combining both ratios, exhibited the best diagnostic performance with an area under the curve (AUC) of 0.945, exceeding individual CICs, PICs, and free antigens (AUCs ≤ 0.887). At a cut-off of 3.60, the LC index achieved 81% sensitivity and 95% specificity for LC diagnosis. It detected early-stage (Stage I–II) LC with 87.5% sensitivity, exceeding its performance in advanced stages (72.7%). The LC index showed no significant differences based on age, gender, smoking status (former, current, or never smoker), or pack years smoked. The LC index demonstrates promising potential for early LC diagnosis, exceeding conventional free antigen markers. Full article

(This article belongs to the Special Issue Current Challenge and Future Advances for Lung Cancer: Genetics, Instrumental Diagnosis and Treatment 2.0)

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19 pages, 3077 KiB

Open AccessReview

Exploring the Dark Matter of Human Proteome: The Emerging Role of Non-Canonical Open Reading Frame (ncORF) in Cancer Diagnosis, Biology, and Therapy

by Anni Ge, Curtis Chan and Xiaolong Yang

Cancers 2024, 16(15), 2660; https://doi.org/10.3390/cancers16152660 - 26 Jul 2024

Abstract

Cancer develops from abnormal cell growth in the body, causing significant mortalities every year. To date, potent therapeutic approaches have been developed to eradicate tumor cells, but intolerable toxicity and drug resistance can occur in treated patients, limiting the efficiency of existing treatment [...] Read more.

Cancer develops from abnormal cell growth in the body, causing significant mortalities every year. To date, potent therapeutic approaches have been developed to eradicate tumor cells, but intolerable toxicity and drug resistance can occur in treated patients, limiting the efficiency of existing treatment strategies. Therefore, searching for novel genes critical for cancer progression and therapeutic response is urgently needed for successful cancer therapy. Recent advances in bioinformatics and proteomic techniques have allowed the identification of a novel category of peptides encoded by non-canonical open reading frames (ncORFs) from historically non-coding genomic regions. Surprisingly, many ncORFs express functional microproteins that play a vital role in human cancers. In this review, we provide a comprehensive description of different ncORF types with coding capacity and technological methods in discovering ncORFs among human genomes. We also summarize the carcinogenic role of ncORFs such as pTINCR and HOXB-AS3 in regulating hallmarks of cancer, as well as the roles of ncORFs such as HOXB-AS3 and CIP2A-BP in cancer diagnosis and prognosis. We also discuss how ncORFs such as AKT-174aa and DDUP are involved in anti-cancer drug response and the underestimated potential of ncORFs as therapeutic targets. Full article

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

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11 pages, 2207 KiB

Open AccessArticle

Clinical Outcomes and Prognostic Factors in Nonmetastatic Castration-Resistant Prostate Cancer Treated with Androgen Receptor Signaling Inhibitors Therapy

by Ryo Fujiwara, Shinya Yamamoto, Kosuke Takemura, Takeshi Yuasa, Noboru Numao, Tomohiko Oguchi, Yosuke Yasuda, Yusuke Yoneoka and Junji Yonese

Cancers 2024, 16(15), 2659; https://doi.org/10.3390/cancers16152659 - 26 Jul 2024

Abstract

We conducted a retrospective evaluation of the clinical outcomes and prognostic factors in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) treated with first-line androgen receptor signaling inhibitors (ARSI) in real-world clinical practice in Japan. Between 2012 and 2023, a total of 127 consecutive [...] Read more.

We conducted a retrospective evaluation of the clinical outcomes and prognostic factors in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) treated with first-line androgen receptor signaling inhibitors (ARSI) in real-world clinical practice in Japan. Between 2012 and 2023, a total of 127 consecutive patients with nmCRPC received ARSI treatment. Overall survival (OS), metastatic-free survival (MFS), and prostate-specific antigen–progression-free survival (PSA–PFS) from ARSI initiation were assessed using the Kaplan–Meier methodology. Clinical factors associated with OS in nmCRPC were analyzed using the Cox proportional hazards model. Among the patients, 72, 26, 12, and 17 received enzalutamide (ENZ), abiraterone (ABI), apalutamide (APA), and darolutamide (DARO) as first-line therapy. The median OS and MFS for all patients were 79.0 and 42.0 months, respectively. Median PSA–PFS was 27.0, 20.0, 10.0, and 14.0 months for patients treated with ENZ, ABI, APA, and DARO, respectively (p = 0.33). Multivariate analysis revealed that a baseline PSA level ≥ 3.67 ng/mL at ARSI initiation was significantly associated with poorer OS (p = 0.002). ARSI demonstrated favorable efficacy in nmCRPC patients. There were no significant differences in clinical outcomes among different types of ARSI therapy for nmCRP. Elevated baseline PSA at ARSI initiation was significantly associated with poorer OS. Full article

(This article belongs to the Special Issue Biomarkers in Prostate Cancers)

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12 pages, 1165 KiB

Open AccessArticle

The Effect of Immune Checkpoint Inhibitor Therapy on Pre-Existing Gastroparesis and New Onset of Symptoms of Delayed Gastric Emptying

by Andres C. Urias Rivera, Antonio Pizuorno Machado, Malek Shatila, George Triadafilopoulos, Jennifer L. McQuade, Mehmet Altan, Dan Zhao, Yinghong Wang and Mehnaz A. Shafi

Cancers 2024, 16(15), 2658; https://doi.org/10.3390/cancers16152658 - 26 Jul 2024

Abstract

Immune checkpoint inhibitors (ICIs) can cause myenteric plexopathy, which could result in delayed gastric emptying (GE) and possibly gastroparesis. We assessed the clinical outcomes of patients who had pre-existing gastroparesis or who developed symptoms of delayed GE following ICI therapy. We retrospectively identified [...] Read more.

Immune checkpoint inhibitors (ICIs) can cause myenteric plexopathy, which could result in delayed gastric emptying (GE) and possibly gastroparesis. We assessed the clinical outcomes of patients who had pre-existing gastroparesis or who developed symptoms of delayed GE following ICI therapy. We retrospectively identified adults with ICD-9 and ICD-10 codes for gastroparesis who received ICI therapy between 1 January 2020 and 31 December 2022 at a tertiary cancer center. Of 76 eligible patients, 37 had pre-existing gastroparesis; 39 (0.2% of the more than 18,000 screened) developed symptoms of delayed GE after ICI therapy, of which 27 (69%) patients had an alternative etiology for delayed GE. Four patients (11%) with pre-existing gastroparesis had a flare-up after ICI, and the median time to flare-up was 10.2 months (IQR, 0.7–28.6 months); for patients with new onset of suspected delayed GE after ICI, the median time to symptom onset was 12.8 months (IQR, 4.4–35.5 months). The clinical symptom duration of patients without an alternative etiology (74.5 days (IQR, 21.5–690 days)) and those with an alternative etiology (290 days (IQR, 147–387 days)) did not differ significantly (p = 1.00). Delayed GE after ICI therapy is a rare presentation but has a late onset and a prolonged symptom duration. Full article

(This article belongs to the Section Cancer Therapy)

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19 pages, 6710 KiB

Open AccessArticle

Development of a Bladder Cancer-on-a-Chip Model to Assess Bladder Cancer Cell Invasiveness

by Desiree J. Ewell, Nita Vue, Sakib M. Moinuddin, Tanoy Sarkar, Fakhrul Ahsan and Ruth L. Vinall

Cancers 2024, 16(15), 2657; https://doi.org/10.3390/cancers16152657 - 26 Jul 2024

Abstract

We have developed a bladder cancer-on-a-chip model which supports the 3D growth of cells and can be used to assess and quantify bladder cancer cell invasiveness in a physiologically appropriate environment. Three bladder cancer cell lines (T24, J82, and RT4) were resuspended in [...] Read more.

We have developed a bladder cancer-on-a-chip model which supports the 3D growth of cells and can be used to assess and quantify bladder cancer cell invasiveness in a physiologically appropriate environment. Three bladder cancer cell lines (T24, J82, and RT4) were resuspended in 50% Matrigel^® and grown within a multi-channel organ-on-a-chip system. The ability of live cells to invade across into an adjacent 50% Matrigel^®-only channel was assessed over a 2-day period. Cell lines isolated from patients with high-grade bladder cancer (T24 and J82) invaded across into the Matrigel^®-only channel at a much higher frequency compared to cells isolated from a patient with low-grade cancer (RT4) (p < 0.001). The T24 and J82 cells also invaded further distances into the Matrigel^®-only channel compared to the RT4 cells (p < 0.001). The cell phenotype within the model was maintained as assessed by cell morphology and immunohistochemical analysis of E-cadherin. Treatment with ATN-161, an α5β1 integrin inhibitor and well-known migrastatic drug, caused a dose-dependent decrease in the invasiveness of the J82 cells (p < 0.01). The combined data demonstrate that our bladder cancer-on-a-chip model supports the retention of the bladder cancer cell phenotype and can be used to reproducibly assess and quantify the invasiveness of live bladder cancer cells. Full article

(This article belongs to the Section Methods and Technologies Development)

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13 pages, 748 KiB

Open AccessArticle

Adverse Events in Anti-PD-1-Treated Adjuvant and First-Line Advanced Melanoma Patients

by Daan Jan Willem Rauwerdink, Olivier van Not, Melissa de Meza, Remco van Doorn, Jos van der Hage, A. J. M. van den Eertwegh, John B. Haanen, Maureen J. B. Aarts, Franchette W. P. J. van den Berkmortel, Christiaan U. Blank, Marye J. Boers-Sonderen, Jan Willem B. de Groot, Geke A. P. Hospers, Djura Piersma, Rozemarijn S. van Rijn, A. M. Stevense-den Boer, Astrid A. M. van der Veldt, Gerard Vreugdenhil, Michel W. J. M. Wouters, Karijn P. M. Suijkerbuijk and Ellen Kapiteijn Show full author list Hide full author list

Cancers 2024, 16(15), 2656; https://doi.org/10.3390/cancers16152656 - 26 Jul 2024

Abstract

Introduction: The difference in incidence and severity of anti-PD-1 therapy-related adverse events (irAEs) between adjuvant and advanced treated melanoma patients remains unclear, as no head-to-head studies have compared these groups. Methods: This multi-center cohort study analyzed melanoma patients treated with anti-PD-1 [...] Read more.

Introduction: The difference in incidence and severity of anti-PD-1 therapy-related adverse events (irAEs) between adjuvant and advanced treated melanoma patients remains unclear, as no head-to-head studies have compared these groups. Methods: This multi-center cohort study analyzed melanoma patients treated with anti-PD-1 in adjuvant or advanced settings between 2015 and 2021. Comorbidities and ECOG performance status were assessed before treatment, and grade III-IV irAEs were monitored during treatment. Univariate and multivariate regression analyses were conducted to identify factors associated with irAE development. Results: A total of 1465 advanced melanoma patients and 908 resected melanoma patients received anti-PD-1 therapy. Adjuvant-treated patients were younger, with a median age of 63 years compared to 69 years in the advanced group (p < 0.01), and had a better ECOG performance status (p < 0.01). Comorbidities were seen more frequently in advanced melanoma patients than in those receiving adjuvant treatment, 76% versus 68% (p < 0.01). Grade III-IV irAEs occurred in 214 (15%) advanced treated patients and in 119 (13%) adjuvant-treated patients. Multivariate analysis showed an increased risk of severe irAE development with the presence of any comorbidity (adjusted OR 1.22, 95% CI 1.02–1.44) and ECOG status greater than 1 (adjusted OR 2.00, 95% CI 1.20–3.32). Adjuvant therapy was not associated with an increased risk of irAE development compared to advanced treatment (adjusted OR 0.95, 95% CI 0.74–1.21) after correcting for comorbidities and ECOG performance score. Anti-PD-1 therapy was halted due to toxicity (any grade irAE) more often in the adjuvant setting than in the advanced setting, 20% versus 15% (p < 0.01). Conclusions: Higher ECOG performance status and presence of any comorbidity were independently associated with an increased risk of Grade III-IV irAE in adjuvant and advanced treated melanoma patients. Patients treated in the adjuvant setting did not have an increased risk of developing severe irAEs compared to advanced melanoma patients. These findings are of clinical significance in consulting patients for adjuvant anti-PD-1 treatment. Full article

(This article belongs to the Special Issue Feature Paper in Section “Cancer Therapy” in 2024)

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12 pages, 972 KiB

Open AccessArticle

Retrospective Analysis of Efficacy and Toxicity of Stereotactic Body Radiotherapy and Surgical Resection of Adrenal Metastases from Solid Tumors

by Jamie Lütscher, Hans Gelpke, Adrian Zehnder, Laetitia Mauti, Christian Padevit, Hubert John, Nidar Batifi, Daniel Rudolf Zwahlen, Robert Förster and Christina Schröder

Cancers 2024, 16(15), 2655; https://doi.org/10.3390/cancers16152655 - 26 Jul 2024

Abstract

Background: This single-center retrospective study aimed to evaluate the efficacy and toxicity profiles of stereotactic body radiotherapy (SBRT) and surgical resection in patients with adrenal metastases originating from solid tumors. Methods/Materials: Patients with advanced tumor conditions or comorbidities typically received SBRT, whereas those [...] Read more.

Background: This single-center retrospective study aimed to evaluate the efficacy and toxicity profiles of stereotactic body radiotherapy (SBRT) and surgical resection in patients with adrenal metastases originating from solid tumors. Methods/Materials: Patients with advanced tumor conditions or comorbidities typically received SBRT, whereas those considered physically fit underwent standard surgical treatment. Endpoints included local control (LC), progression free survival (PFS), overall survival (OS), and complication rates (CR). Results: 41 patients with 48 adrenal metastases were included, with 27 (65.9%) patients receiving SBRT and 14 (34.1%) patients undergoing adrenalectomy. One- and two-year LC values were 100% for both periods after adrenalectomy, and 70.0% and 52.5% after SBRT (p = 0.001). PFS showed values of 40.2% and 32.1% at one and two years after adrenalectomy and of 10.6% for both periods after SBRT (p = 0.223). OS was 83.3% both one and two years after surgery and 67.0% and 40.2% after SBRT (p = 0.031). There was no statistically significant difference between the two groups regarding acute complications (p = 0.123). Conclusion: Despite potential confounders, adrenalectomy exhibited statistically significant superior LC and OS compared to SBRT in managing adrenal metastases, while both treatment methods displayed acceptable toxicity profiles. However, patient selection bias must be taken into account when directly comparing the two therapy modalities. Nevertheless, the study provides new and important results for the scientific and medical communities regarding oncological outcomes after SBRT or surgical resection of adrenal metastases. Full article

(This article belongs to the Special Issue The Future of Radiation Research in Cancers, 2nd Edition)

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