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17 pages, 1956 KiB

Open AccessSystematic Review

Comparative Efficacy of Neoadjuvant Nivolumab Plus Chemotherapy versus Conventional Comparator Treatments in Resectable Non-Small-Cell Lung Cancer: A Systematic Literature Review and Network Meta-Analysis

by Nicolas Girard, Mariam Besada, Basia Rogula, Stefano Lucherini, Lien Vo, Mohammad A. Chaudhary, Sarah Goring, Greta Lozano-Ortega, Mia Tran, Nebibe Varol, Nathalie Waser, Jay M. Lee and Jonathan Spicer

Cancers 2024, 16(13), 2492; https://doi.org/10.3390/cancers16132492 (registering DOI) - 8 Jul 2024

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Abstract

Background: This study aimed to estimate the relative efficacy of neoadjuvant nivolumab in combination with chemotherapy (neoNIVO + CT) compared to relevant treatments amongst resectable non-metastatic non-small-cell lung cancer (rNSCLC) patients. Methods: Treatment comparisons were based on a network meta-analysis (NMA) using randomized [...] Read more.

Background: This study aimed to estimate the relative efficacy of neoadjuvant nivolumab in combination with chemotherapy (neoNIVO + CT) compared to relevant treatments amongst resectable non-metastatic non-small-cell lung cancer (rNSCLC) patients. Methods: Treatment comparisons were based on a network meta-analysis (NMA) using randomized clinical trial data identified via systematic literature review (SLR). The outcomes of interest were event-free survival (EFS) and pathological complete response (pCR). NeoNIVO + CT was compared to neoadjuvant chemotherapy (neoCT), neoadjuvant chemoradiotherapy (neoCRT), adjuvant chemotherapy (adjCT), and surgery alone (S). Due to the potential for effect modification by stage, all-stage and stage-specific networks were considered. Fixed-effect (FE) and random-effects Bayesian NMA models were run (EFS = hazard ratios [HR]; pCR = odds ratios [OR]; 95% credible intervals [CrI]). Results: Sixty-one RCTs were identified (base case = 9 RCTs [n = 1978 patients]). In the all-stages FE model, neoNIVO + CT had statistically significant EFS improvements relative to neoCT (HR = 0.68 [95% CrI: 0.49, 0.94]), S (0.59 [0.42, 0.82]), adjCT (0.66 [0.45, 0.96]), but not relative to neoCRT (HR = 0.77 [0.52, 1.16]). NeoNIVO + CT (5 RCTs) had statistically significant higher odds of pCR relative to neoCT (OR = 12.53 [5.60, 33.82]) and neoCRT (7.15 [2.31, 24.34]). Stage-specific model findings were consistent. CONCLUSIONS: This NMA signals improved EFS and/or pCR of neoNIVO + CT relative to comparators among patients with rNSCLC. Full article

(This article belongs to the Section Cancer Therapy)

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22 pages, 3817 KiB

Open AccessArticle

Enhancing Immunotherapy Response Prediction in Metastatic Lung Adenocarcinoma: Leveraging Shallow and Deep Learning with CT-Based Radiomics across Single and Multiple Tumor Sites

by Cécile Masson-Grehaigne, Mathilde Lafon, Jean Palussière, Laura Leroy, Benjamin Bonhomme, Eva Jambon, Antoine Italiano, Sophie Cousin and Amandine Crombé

Cancers 2024, 16(13), 2491; https://doi.org/10.3390/cancers16132491 - 8 Jul 2024

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Abstract

This study aimed to evaluate the potential of pre-treatment CT-based radiomics features (RFs) derived from single and multiple tumor sites, and state-of-the-art machine-learning survival algorithms, in predicting progression-free survival (PFS) for patients with metastatic lung adenocarcinoma (MLUAD) receiving first-line treatment including immune checkpoint [...] Read more.

This study aimed to evaluate the potential of pre-treatment CT-based radiomics features (RFs) derived from single and multiple tumor sites, and state-of-the-art machine-learning survival algorithms, in predicting progression-free survival (PFS) for patients with metastatic lung adenocarcinoma (MLUAD) receiving first-line treatment including immune checkpoint inhibitors (CPIs). To do so, all adults with newly diagnosed MLUAD, pre-treatment contrast-enhanced CT scan, and performance status ≤ 2 who were treated at our cancer center with first-line CPI between November 2016 and November 2022 were included. RFs were extracted from all measurable lesions with a volume ≥ 1 cm³ on the CT scan. To capture intra- and inter-tumor heterogeneity, RFs from the largest tumor of each patient, as well as lowest, highest, and average RF values over all lesions per patient were collected. Intra-patient inter-tumor heterogeneity metrics were calculated to measure the similarity between each patient lesions. After filtering predictors with univariable Cox p < 0.100 and analyzing their correlations, five survival machine-learning algorithms (stepwise Cox regression [SCR], LASSO Cox regression, random survival forests, gradient boosted machine [GBM], and deep learning [Deepsurv]) were trained in 100-times repeated 5-fold cross-validation (rCV) to predict PFS on three inputs: (i) clinicopathological variables, (ii) all radiomics-based and clinicopathological (full input), and (iii) uncorrelated radiomics-based and clinicopathological variables (uncorrelated input). The Models’ performances were evaluated using the concordance index (c-index). Overall, 140 patients were included (median age: 62.5 years, 36.4% women). In rCV, the highest c-index was reached with Deepsurv (c-index = 0.631, 95%CI = 0.625–0.647), followed by GBM (c-index = 0.603, 95%CI = 0.557–0.646), significantly outperforming standard SCR whatever its input (c-index range: 0.560–0.570, all p < 0.0001). Thus, single- and multi-site pre-treatment radiomics data provide valuable prognostic information for predicting PFS in MLUAD patients undergoing first-line CPI treatment when analyzed with advanced machine-learning survival algorithms. Full article

(This article belongs to the Special Issue Imaging and Molecular Biology as Biomarkers for Lung Cancer)

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20 pages, 9054 KiB

Open AccessArticle

Transcriptomic Analysis Reveals Early Alterations Associated with Intrinsic Resistance to Targeted Therapy in Lung Adenocarcinoma Cell Lines

by Mario Perez-Medina, Jose S. Lopez-Gonzalez, Jesus J. Benito-Lopez, Santiago Ávila-Ríos, Maribel Soto-Nava, Margarita Matias-Florentino, Alfonso Méndez-Tenorio, Miriam Galicia-Velasco, Rodolfo Chavez-Dominguez, Sergio E. Meza-Toledo and Dolores Aguilar-Cazares

Cancers 2024, 16(13), 2490; https://doi.org/10.3390/cancers16132490 - 8 Jul 2024

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Abstract

Lung adenocarcinoma is the most prevalent form of lung cancer, and drug resistance poses a significant obstacle in its treatment. This study aimed to investigate the overexpression of long non-coding RNAs (lncRNAs) as a mechanism that promotes intrinsic resistance in tumor cells from [...] Read more.

Lung adenocarcinoma is the most prevalent form of lung cancer, and drug resistance poses a significant obstacle in its treatment. This study aimed to investigate the overexpression of long non-coding RNAs (lncRNAs) as a mechanism that promotes intrinsic resistance in tumor cells from the onset of treatment. Drug-tolerant persister (DTP) cells are a subset of cancer cells that survive and proliferate after exposure to therapeutic drugs, making them an essential object of study in cancer treatment. The molecular mechanisms underlying DTP cell survival are not fully understood; however, long non-coding RNAs (lncRNAs) have been proposed to play a crucial role. DTP cells from lung adenocarcinoma cell lines were obtained after single exposure to tyrosine kinase inhibitors (TKIs; erlotinib or osimertinib). After establishing DTP cells, RNA sequencing was performed to investigate the differential expression of the lncRNAs. Some lncRNAs and one mRNA were overexpressed in DTP cells. The clinical relevance of lncRNAs was evaluated in a cohort of patients with lung adenocarcinoma from The Cancer Genome Atlas (TCGA). RT–qPCR validated the overexpression of lncRNAs and mRNA in the residual DTP cells and LUAD biopsies. Knockdown of these lncRNAs increases the sensitivity of DTP cells to therapeutic drugs. This study provides an opportunity to investigate the involvement of lncRNAs in the genetic and epigenetic mechanisms that underlie intrinsic resistance. The identified lncRNAs and CD74 mRNA may serve as potential prognostic markers or therapeutic targets to improve the overall survival (OS) of patients with lung cancer. Full article

(This article belongs to the Special Issue Mechanisms of Therapy Resistance in Lung Cancer)

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14 pages, 8994 KiB

Open AccessArticle

Release of Exosomal PD-L1 in Bone and Soft Tissue Sarcomas and Its Relationship to Radiotherapy

by Keisuke Yoshida, Kunihiro Asanuma, Yumi Matsuyama, Takayuki Okamoto, Tomohito Hagi, Tomoki Nakamura and Akihiro Sudo

Cancers 2024, 16(13), 2489; https://doi.org/10.3390/cancers16132489 - 8 Jul 2024

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Abstract

(1) Background: Exosomal PD-L1 has garnered attention owing to its role in instigating systemic immune suppression. The objective of this study is to elucidate whether bone and soft tissue sarcoma cells possess the capacity to secrete functionally active exosomal PD-L1 and whether radiotherapy [...] Read more.

(1) Background: Exosomal PD-L1 has garnered attention owing to its role in instigating systemic immune suppression. The objective of this study is to elucidate whether bone and soft tissue sarcoma cells possess the capacity to secrete functionally active exosomal PD-L1 and whether radiotherapy (RT) induces the exosomal PD-L1 release. (2) Methods: Human osteosarcoma cell line 143B and human fibrosarcoma cell line HT1080 were utilized. Exosomes were isolated from the culture medium and blood via ultracentrifugation. The expression of PD-L1 on both tumor cells and exosomes was evaluated. The inhibitory effect on PBMC was employed to assess the activity of exosomal PD-L1. Post radiotherapy, changes in PD-L1 expression were compared. (3) Results: Exosomal PD-L1 was detected in the culture medium of tumor cells but was absent in the culture medium of PD-L1 knockout cells. Exosomal PD-L1 exhibited an inhibitory effect on PBMC activation. In tumor-bearing mice, human-derived exosomal PD-L1 was detected in the bloodstream. Following radiotherapy, tumor cells upregulated PD-L1, and human-derived exosomal PD-L1 were detected in the bloodstream. (4) Conclusions: Exosomal PD-L1 emanates from bone and soft tissue sarcoma cells and is disseminated into the circulatory system. The levels of PD-L1 in tumor cells and the release of exosomal PD-L1 were augmented after irradiation with RT. Full article

(This article belongs to the Special Issue Combination Immunotherapy for Cancer Treatment)

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14 pages, 856 KiB

Open AccessArticle

A Probabilistic Approach to Estimate the Temporal Order of Pathway Mutations Accounting for Intra-Tumor Heterogeneity

by Menghan Wang, Yanqi Xie, Jinpeng Liu, Austin Li, Li Chen, Arnold Stromberg, Susanne M. Arnold, Chunming Liu and Chi Wang

Cancers 2024, 16(13), 2488; https://doi.org/10.3390/cancers16132488 - 8 Jul 2024

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Abstract

The development of cancer involves the accumulation of somatic mutations in several essential biological pathways. Delineating the temporal order of pathway mutations during tumorigenesis is crucial for comprehending the biological mechanisms underlying cancer development and identifying potential targets for therapeutic intervention. Several computational [...] Read more.

The development of cancer involves the accumulation of somatic mutations in several essential biological pathways. Delineating the temporal order of pathway mutations during tumorigenesis is crucial for comprehending the biological mechanisms underlying cancer development and identifying potential targets for therapeutic intervention. Several computational and statistical methods have been introduced for estimating the order of somatic mutations based on mutation profile data from a cohort of patients. However, one major issue of current methods is that they do not take into account intra-tumor heterogeneity (ITH), which limits their ability to accurately discern the order of pathway mutations. To address this problem, we propose PATOPAI, a probabilistic approach to estimate the temporal order of mutations at the pathway level by incorporating ITH information as well as pathway and functional annotation information of mutations. PATOPAI uses a maximum likelihood approach to estimate the probability of pathway mutational events occurring in a specific sequence, wherein it focuses on the orders that are consistent with the phylogenetic structure of the tumors. Applications to whole exome sequencing data from The Cancer Genome Atlas (TCGA) illustrate our method’s ability to recover the temporal order of pathway mutations in several cancer types. Full article

(This article belongs to the Collection Application of Bioinformatics in Cancers)

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19 pages, 7504 KiB

Open AccessReview

Differential Diagnosis of Pigmented Lesions in the Oral Mucosa: A Clinical Based Overview and Narrative Review

by Silvio Abati, Giacomo Francesco Sandri, Leonardo Finotello and Elisabetta Polizzi

Cancers 2024, 16(13), 2487; https://doi.org/10.3390/cancers16132487 - 8 Jul 2024

Viewed by 252

Abstract

This paper examines the clinical differentiation of pigmented lesions in the oral mucosa, which poses significant diagnostic challenges across dental and medical disciplines due to their spectrum from benign to potentially malignant conditions. Through a literature review and analysis of clinical cases, this [...] Read more.

This paper examines the clinical differentiation of pigmented lesions in the oral mucosa, which poses significant diagnostic challenges across dental and medical disciplines due to their spectrum from benign to potentially malignant conditions. Through a literature review and analysis of clinical cases, this study clarifies current diagnostic methodologies, with an emphasis on differential diagnosis, to provide a practical guide for clinicians. The classification of pigmented lesions, such as endogenous, focal melanocytic, and multifocal pigmentation, based on clinical and histological features, highlights the necessity for a structured and informed approach. A retrospective examination of cases from our oral medicine and pathology clinic, coupled with analysis of photographic and histological records, aids in classifying these lesions. This fosters a better understanding and promotes informed discussions among clinicians, ultimately aiming to enhance early and precise diagnosis, thus improving patient management and outcomes. Full article

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

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12 pages, 1447 KiB

Open AccessArticle

Head and Neck Cancer: A Potential Risk Factor for Parkinson’s Disease?

by Il Hwan Lee and Dong-Kyu Kim

Cancers 2024, 16(13), 2486; https://doi.org/10.3390/cancers16132486 - 8 Jul 2024

Viewed by 235

Abstract

Head and neck cancers (HNC) are frequently associated with neurodegeneration. However, the association between HNC and Parkinson’s disease (PD) remains unclear. This study aimed to clarify the relationship between HNC and subsequent PD. This retrospective study used data from a nationally representative cohort. [...] Read more.

Head and neck cancers (HNC) are frequently associated with neurodegeneration. However, the association between HNC and Parkinson’s disease (PD) remains unclear. This study aimed to clarify the relationship between HNC and subsequent PD. This retrospective study used data from a nationally representative cohort. Patients with HNC were identified based on the presence of corresponding diagnostic codes. Participants without cancer were selected using 4:1 propensity score matching based on sociodemographic factors and year of enrollment; 2296 individuals without HNC and 574 individuals with HNC were included in the study. Hazard ratios (HR) for the incidence of PD in patients with HNC were calculated using 95% confidence intervals (CI). The incidence of PD was 4.17 and 2.18 per 1000 person-years in the HNC and control groups, respectively (adjusted HR = 1.89, 95% CI = 1.08–3.33). The HNC group also showed an increased risk of subsequent PD development. The risk of PD was higher in middle-aged (55–69 years) patients with HNC and oral cavity cancer. Our findings suggest that middle-aged patients with HNC have an increased incidence of PD, specifically those with oral cavity cancer. Therefore, our findings provide new insights into the development of PD in patients with HNC. Full article

(This article belongs to the Special Issue Head and Neck Cancer: Epidemiology, Prevention, Treatment, and Quality of Life)

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15 pages, 297 KiB

Open AccessArticle

Enhancing Cervical Cancer Screening with 7-Type HPV mRNA E6/E7 Testing on Self-Collected Samples: Multicentric Insights from Mexico

by Carlos Eduardo Aranda Flores, Bente Marie Falang, Laura Gómez-Laguna, Guillermo Gómez Gutiérrez, Jorge Miguel Ortiz León, Miguel Uribe, Omar Cruz and Sveinung Wergeland Sørbye

Cancers 2024, 16(13), 2485; https://doi.org/10.3390/cancers16132485 - 8 Jul 2024

Viewed by 245

Abstract

Cervical cancer remains a significant public health issue, particularly in regions with low screening uptake. This study evaluates the effectiveness of self-sampling and the 7-type HPV mRNA E6/E7 test in improving cervical cancer screening outcomes among a referral population in Mexico. A cohort [...] Read more.

Cervical cancer remains a significant public health issue, particularly in regions with low screening uptake. This study evaluates the effectiveness of self-sampling and the 7-type HPV mRNA E6/E7 test in improving cervical cancer screening outcomes among a referral population in Mexico. A cohort of 418 Mexican women aged 25 to 65, referred for colposcopy and biopsy due to abnormal cytology results (ASC-US+), participated in this study. Self-samples were analyzed using both the 14-type HPV DNA test and the 7-type HPV mRNA E6/E7 test. The study assessed the sensitivity, specificity, positive predictive value (PPV), and the necessity of colposcopies to detect CIN3+ lesions. Participant acceptability of self-sampling was also evaluated through a questionnaire. The 7-type HPV mRNA E6/E7 test demonstrated equivalent sensitivity but significantly higher specificity (77.0%) and PPV for CIN3+ detection compared to the 14-type HPV DNA test (specificity: 45.8%, p < 0.001). The use of the HPV mRNA test as a triage tool reduced the number of colposcopies needed per CIN3+ case detected from 16.6 to 7.6 (p < 0.001). Self-sampling was highly accepted among participants, with the majority reporting confidence in performing the procedure, minimal discomfort, and willingness to undertake self-sampling at home. Self-sampling combined with the 7-type HPV mRNA E6/E7 testing offers a promising strategy to enhance cervical cancer screening by improving accessibility and ensuring precise diagnostics. Implementing these app roaches could lead to a significant reduction in cervical cancer morbidity and mortality, especially in underserved populations. Future research should focus on the long-term impact of integrating these methods into national screening programs and explore the cost-effectiveness of widespread implementation. Full article

(This article belongs to the Special Issue Clinicopathological Study of Gynecologic Cancer)

33 pages, 5027 KiB

Open AccessReview

Devices and Methods for Dosimetry of Personalized Photodynamic Therapy of Tumors: A Review on Recent Trends

by Polina Alekseeva, Vladimir Makarov, Kanamat Efendiev, Artem Shiryaev, Igor Reshetov and Victor Loschenov

Cancers 2024, 16(13), 2484; https://doi.org/10.3390/cancers16132484 - 8 Jul 2024

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Abstract

Significance: Despite the widespread use of photodynamic therapy in clinical practice, there is a lack of personalized methods for assessing the sufficiency of photodynamic exposure on tumors, depending on tissue parameters that change during light irradiation. This can lead to different treatment results. [...] Read more.

Significance: Despite the widespread use of photodynamic therapy in clinical practice, there is a lack of personalized methods for assessing the sufficiency of photodynamic exposure on tumors, depending on tissue parameters that change during light irradiation. This can lead to different treatment results. Aim: The objective of this article was to conduct a comprehensive review of devices and methods employed for the implicit dosimetric monitoring of personalized photodynamic therapy for tumors. Methods: The review included 88 peer-reviewed research articles published between January 2010 and April 2024 that employed implicit monitoring methods, such as fluorescence imaging and diffuse reflectance spectroscopy. Additionally, it encompassed computer modeling methods that are most often and successfully used in preclinical and clinical practice to predict treatment outcomes. The Internet search engine Google Scholar and the Scopus database were used to search the literature for relevant articles. Results: The review analyzed and compared the results of 88 peer-reviewed research articles presenting various methods of implicit dosimetry during photodynamic therapy. The most prominent wavelengths for PDT are in the visible and near-infrared spectral range such as 405, 630, 660, and 690 nm. Conclusions: The problem of developing an accurate, reliable, and easily implemented dosimetry method for photodynamic therapy remains a current problem, since determining the effective light dose for a specific tumor is a decisive factor in achieving a positive treatment outcome. Full article

(This article belongs to the Special Issue Advanced Diagnostics and Optical Imaging Technologies in Cancer Research)

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11 pages, 2328 KiB

Open AccessArticle

Modulating Tumor Immunity by Targeting Tumor Fibrotic Stroma and Angiogenic Vessels for Lung Cancer Treatment

by Yi Yuan, Falguni Mishra, Bin Li, Guangda Peng, Payton Chan, Jenny Yang and Zhiren Liu

Cancers 2024, 16(13), 2483; https://doi.org/10.3390/cancers16132483 - 8 Jul 2024

Viewed by 255

Abstract

Fibrotic stroma and angiogenic tumor vessels play an important role in modulating tumor immunity. We previously reported a rationally designed protein (ProAgio) that targets integrin α_vβ₃ at a novel site. ProAgio induces the apoptosis of cells that express high levels [...] Read more.

Fibrotic stroma and angiogenic tumor vessels play an important role in modulating tumor immunity. We previously reported a rationally designed protein (ProAgio) that targets integrin α_vβ₃ at a novel site. ProAgio induces the apoptosis of cells that express high levels of the integrin. Both activated cancer-associated fibroblasts (CAFs) and angiogenic endothelial cells (aECs) in tumors express high levels of integrin α_vβ₃. ProAgio simultaneously and specifically induces apoptosis in CAFs and aECs in tumors. We provide evidence here that the depletion of CAFs and the elimination of leaky tumor angiogenic vessels by ProAgio alter tumor immunity. ProAgio reduces CD₄⁺ Treg and Myeloid-derived suppressor cells (MDSCs), increases CD₈⁺ T-cells, and increases the M1/M2 macrophage ratio in the tumor. The depletion of dense fibrotic stroma (CAFs) by ProAgio decreases the Programmed Death Ligand 1 (PDL-1) levels in the stroma areas surrounding the tumors, and thus strongly increases the delivery of anti-PDL-1 antibody to the target cancer cells. The impact of ProAgio on tumor immunity provides strong synergistical effects of checkpoint inhibitors on lung cancer treatment. Full article

(This article belongs to the Special Issue Immunosuppression and Protective Immunity in Tumor Microenvironment)

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16 pages, 1758 KiB

Open AccessArticle

Germline Sequencing of DNA Damage Repair Genes in Two Hereditary Prostate Cancer Cohorts Reveals New Disease Risk-Associated Gene Variants

by Georgea R. Foley, James R. Marthick, Sionne E. Lucas, Kelsie Raspin, Annette Banks, Janet L. Stanford, Elaine A. Ostrander, Liesel M. FitzGerald and Joanne L. Dickinson

Cancers 2024, 16(13), 2482; https://doi.org/10.3390/cancers16132482 - 7 Jul 2024

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Abstract

Rare, inherited variants in DNA damage repair (DDR) genes have a recognised role in prostate cancer (PrCa) susceptibility. In addition, these genes are therapeutically targetable. While rare variants are informing clinical management in other common cancers, defining the rare disease-associated variants in PrCa [...] Read more.

Rare, inherited variants in DNA damage repair (DDR) genes have a recognised role in prostate cancer (PrCa) susceptibility. In addition, these genes are therapeutically targetable. While rare variants are informing clinical management in other common cancers, defining the rare disease-associated variants in PrCa has been challenging. Here, whole-genome and -exome sequencing data from two independent, high-risk Australian and North American familial PrCa datasets were interrogated for novel DDR risk variants. Rare DDR gene variants (predicted to be damaging and present in two or more family members) were identified and subsequently genotyped in 1963 individuals (700 familial and 459 sporadic PrCa cases, 482 unaffected relatives, and 322 screened controls), and association analyses accounting for relatedness (M_QLS) undertaken. In the combined datasets, rare ERCC3 (rs145201970, p = 2.57 × 10⁻⁴) and BRIP1 (rs4988345, p = 0.025) variants were significantly associated with PrCa risk. A PARP2 (rs200603922, p = 0.028) variant in the Australian dataset and a MUTYH (rs36053993, p = 0.031) variant in the North American dataset were also associated with risk. Evaluation of clinicopathological characteristics provided no evidence for a younger age or higher-grade disease at diagnosis in variant carriers, which should be taken into consideration when determining genetic screening eligibility criteria for targeted, gene-based treatments in the future. This study adds valuable knowledge to our understanding of PrCa-associated DDR genes, which will underpin effective clinical screening and treatment strategies. Full article

(This article belongs to the Section Cancer Epidemiology and Prevention)

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20 pages, 722 KiB

Open AccessReview

Breast Cancer Stem Cells and Tumor Heterogeneity: Characteristics and Therapeutic Strategies

by Aleksandra Romaniuk-Drapała, Ewa Totoń, Magdalena Taube, Malgorzata Idzik, Błażej Rubiś and Natalia Lisiak

Cancers 2024, 16(13), 2481; https://doi.org/10.3390/cancers16132481 - 7 Jul 2024

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Abstract

Breast cancer is one of the most frequently detected malignancies worldwide. It is responsible for more than 15% of all death cases caused by cancer in women. Breast cancer is a heterogeneous disease representing various histological types, molecular characteristics, and clinical profiles. However, [...] Read more.

Breast cancer is one of the most frequently detected malignancies worldwide. It is responsible for more than 15% of all death cases caused by cancer in women. Breast cancer is a heterogeneous disease representing various histological types, molecular characteristics, and clinical profiles. However, all breast cancers are organized in a hierarchy of heterogeneous cell populations, with a small proportion of cancer stem cells (breast cancer stem cells (BCSCs)) playing a putative role in cancer progression, and they are responsible for therapeutic failure. In different molecular subtypes of breast cancer, they present different characteristics, with specific marker profiles, prognoses, and treatments. Recent efforts have focused on tackling the Wnt, Notch, Hedgehog, PI3K/Akt/mTOR, and HER2 signaling pathways. Developing diagnostics and therapeutic strategies enables more efficient elimination of the tumor mass together with the stem cell population. Thus, the knowledge about appropriate therapeutic methods targeting both “normal” breast cancer cells and breast cancer stem cell subpopulations is crucial for success in cancer elimination. Full article

(This article belongs to the Special Issue Feature Review for Cancer Therapy)

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Graphical abstract

10 pages, 679 KiB

Open AccessArticle

Lack of Clinically Significant Relationships of Age or Body Mass Index with Merkel Cell Carcinoma Immunotherapy Outcomes

by Rian Alam, Xinyi Fan, Daniel S. Hippe, Lisa M. Tachiki, Emily Gong, Emily Huynh, Paul Nghiem and Song Youn Park

Cancers 2024, 16(13), 2480; https://doi.org/10.3390/cancers16132480 - 7 Jul 2024

Viewed by 268

Abstract

Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer with a high risk of metastasis. The development of anti-PD-1/PD-L1 immunotherapy has improved outcomes for advanced MCC, yet about 50% of such patients do not achieve durable responses. This study analyzed the [...] Read more.

Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer with a high risk of metastasis. The development of anti-PD-1/PD-L1 immunotherapy has improved outcomes for advanced MCC, yet about 50% of such patients do not achieve durable responses. This study analyzed the effects of age and body mass index (BMI) on immunotherapy response in 183 advanced MCC patients from a single-center longitudinal database. Using Fine–Gray or Cox regression models, treatment response, progression-free survival (PFS), MCC-specific survival, and overall survival (OS) were evaluated. Age showed a significant non-linear relationship with treatment response (p = 0.04), with patients much older or younger than 70 years less likely to respond. However, age was not significantly associated with PFS (p = 0.21), MCC-specific survival (p = 0.72), or OS (p = 0.36). Similarly, BMI was not significantly correlated with treatment response (p = 0.41), PFS (p = 0.52), MCC-specific survival (p = 0.78), or OS (p = 0.71). Unlike previous studies suggesting that obesity and advanced age improve outcomes in other cancers, these associations were not observed in MCC. These findings suggest that age and BMI should not influence eligibility for immunotherapy in MCC patients, emphasizing the importance of unbiased patient selection for this treatment. Full article

(This article belongs to the Section Cancer Immunology and Immunotherapy)

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15 pages, 1345 KiB

Open AccessReview

Overcoming Chemoresistance in Cancer: The Promise of Crizotinib

by Sanaa Musa, Noor Amara, Adan Selawi, Junbiao Wang, Cristina Marchini, Abed Agbarya and Jamal Mahajna

Cancers 2024, 16(13), 2479; https://doi.org/10.3390/cancers16132479 - 7 Jul 2024

Viewed by 472

Abstract

Chemoresistance is a major obstacle in cancer treatment, often leading to disease progression and poor outcomes. It arises through various mechanisms such as genetic mutations, drug efflux pumps, enhanced DNA repair, and changes in the tumor microenvironment. These processes allow cancer cells to [...] Read more.

Chemoresistance is a major obstacle in cancer treatment, often leading to disease progression and poor outcomes. It arises through various mechanisms such as genetic mutations, drug efflux pumps, enhanced DNA repair, and changes in the tumor microenvironment. These processes allow cancer cells to survive despite chemotherapy, underscoring the need for new strategies to overcome resistance and improve treatment efficacy. Crizotinib, a first-generation multi-target kinase inhibitor, is approved by the FDA for the treatment of ALK-positive or ROS1-positive non-small cell lung cancer (NSCLC), refractory inflammatory (ALK)-positive myofibroblastic tumors (IMTs) and relapsed/refractory ALK-positive anaplastic large cell lymphoma (ALCL). Crizotinib exists in two enantiomeric forms: (R)-crizotinib and its mirror image, (S)-crizotinib. It is assumed that the R-isomer is responsible for the carrying out various processes reviewed here The S-isomer, on the other hand, shows a strong inhibition of MTH1, an enzyme important for DNA repair mechanisms. Studies have shown that crizotinib is an effective multi-kinase inhibitor targeting various kinases such as c-Met, native/T315I Bcr/Abl, and JAK2. Its mechanism of action involves the competitive inhibition of ATP binding and allosteric inhibition, particularly at Bcr/Abl. Crizotinib showed synergistic effects when combined with the poly ADP ribose polymerase inhibitor (PARP), especially in ovarian cancer harboring BRCA gene mutations. In addition, crizotinib targets a critical vulnerability in many p53-mutated cancers. Unlike its wild-type counterpart, the p53 mutant promotes cancer cell survival. Crizotinib can cause the degradation of the p53 mutant, sensitizing these cancer cells to DNA-damaging substances and triggering apoptosis. Interestingly, other reports demonstrated that crizotinib exhibits anti-bacterial activity, targeting Gram-positive bacteria. Also, it is active against drug-resistant strains. In summary, crizotinib exerts anti-tumor effects through several mechanisms, including the inhibition of kinases and the restoration of drug sensitivity. The potential of crizotinib in combination therapies is emphasized, particularly in cancers with a high prevalence of the p53 mutant, such as triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC). Full article

(This article belongs to the Collection Innovations in Cancer Drug Development Research)

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25 pages, 1545 KiB

Open AccessPerspective

Emerging Therapeutic Strategies to Overcome Drug Resistance in Cancer Cells

by Pankaj Garg, Jyoti Malhotra, Prakash Kulkarni, David Horne, Ravi Salgia and Sharad S. Singhal

Cancers 2024, 16(13), 2478; https://doi.org/10.3390/cancers16132478 - 7 Jul 2024

Viewed by 455

Abstract

The rise of drug resistance in cancer cells presents a formidable challenge in modern oncology, necessitating the exploration of innovative therapeutic strategies. This review investigates the latest advancements in overcoming drug resistance mechanisms employed by cancer cells, focusing on emerging therapeutic modalities. The [...] Read more.

The rise of drug resistance in cancer cells presents a formidable challenge in modern oncology, necessitating the exploration of innovative therapeutic strategies. This review investigates the latest advancements in overcoming drug resistance mechanisms employed by cancer cells, focusing on emerging therapeutic modalities. The intricate molecular insights into drug resistance, including genetic mutations, efflux pumps, altered signaling pathways, and microenvironmental influences, are discussed. Furthermore, the promising avenues offered by targeted therapies, combination treatments, immunotherapies, and precision medicine approaches are highlighted. Specifically, the synergistic effects of combining traditional cytotoxic agents with molecularly targeted inhibitors to circumvent resistance pathways are examined. Additionally, the evolving landscape of immunotherapeutic interventions, including immune checkpoint inhibitors and adoptive cell therapies, is explored in terms of bolstering anti-tumor immune responses and overcoming immune evasion mechanisms. Moreover, the significance of biomarker-driven strategies for predicting and monitoring treatment responses is underscored, thereby optimizing therapeutic outcomes. For insights into the future direction of cancer treatment paradigms, the current review focused on prevailing drug resistance challenges and improving patient outcomes, through an integrative analysis of these emerging therapeutic strategies. Full article

(This article belongs to the Special Issue Molecular Insights into Drug Resistance in Cancer)

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12 pages, 784 KiB

Open AccessArticle

Short- and Long-Term Advantages of Laparoscopic Gastrectomy for Elderly Patients with Locally Advanced Cancer

by Francesco Puccetti, Lorenzo Cinelli, Stefano Turi, Davide Socci, Riccardo Rosati, Ugo Elmore and on behalf of the OSR CCeR Collaborative Group

Cancers 2024, 16(13), 2477; https://doi.org/10.3390/cancers16132477 - 7 Jul 2024

Viewed by 315

Abstract

Minimally invasive surgery has provided several clinical advantages in locally advanced gastric cancer (LAGC) care, although a consensus on its application criteria remains unclear. Surgery remains a careful choice in elderly patients, who frequently present with frailty, comorbidities, and other disabling diseases. This [...] Read more.

Minimally invasive surgery has provided several clinical advantages in locally advanced gastric cancer (LAGC) care, although a consensus on its application criteria remains unclear. Surgery remains a careful choice in elderly patients, who frequently present with frailty, comorbidities, and other disabling diseases. This study aims to assess the possible advantages of laparoscopic gastric resections in elderly patients presenting with LAGC. This retrospective study analyzed a single-center series of elderly patients (≥75 years) undergoing curative resections for LAGC between 2015 and 2020. A comparative analysis of open versus laparoscopic approaches was conducted, focusing on postoperative complications, length of hospital stay (LOS), and long-term survival. A total of 62 patients underwent gastrectomy through an open or a laparoscopic approach (31 pts each). The study population did not show statistically significant differences in demographics, operative risk, and neoadjuvant chemotherapy. The laparoscopic group reported significantly minimized overall complications (45.2 vs. 71%, p = 0.039) and pulmonary complications (0 vs. 9.7%, p = 0.038) as well as a shorter LOS (8 vs. 12 days, p = 0.007). Lymph node harvest was equal between the groups, although long-term overall survival presented significantly better after laparoscopic gastrectomy (p = 0.048), without a relevant difference in terms of disease-free and disease-specific survivals. Laparoscopic gastrectomy proves effective in elderly LAGC patients, offering substantial short- and long-term postoperative benefits. Full article

(This article belongs to the Special Issue Preoperative Optimisation in Patients Undergoing Cancer Surgery)

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17 pages, 3686 KiB

Open AccessArticle

Citrullinated Histone H3, a Marker for Neutrophil Extracellular Traps, Is Associated with Poor Prognosis in Cutaneous Squamous Cell Carcinoma Developing in Patients with Recessive Dystrophic Epidermolysis Bullosa

by Hélène Ragot, Sonia Gaucher, Mathilde Bonnet des Claustres, Justine Basset, Rose Boudan, Maxime Battistella, Emmanuelle Bourrat, Alain Hovnanian and Matthias Titeux

Cancers 2024, 16(13), 2476; https://doi.org/10.3390/cancers16132476 - 6 Jul 2024

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Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare severe hereditary skin disease characterized by skin and mucosa fragility, resulting in blister formation. The most severe complication in RDEB patients is the development of cutaneous squamous cell carcinoma (SCC), leading to premature death. There [...] Read more.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare severe hereditary skin disease characterized by skin and mucosa fragility, resulting in blister formation. The most severe complication in RDEB patients is the development of cutaneous squamous cell carcinoma (SCC), leading to premature death. There is a great deal of evidence suggesting a permissive tumor microenvironment (TME) as a driver of SCC development in RDEB patients. In a cohort of RDEB patients, we characterized the immune profiles of RDEB-SCCs and compared them with clinical, histopathological, and prognostic features. RDEB-SCCs were subdivided into four groups based on their occurrence (first onset or recurrences) and grading according to clinical, histopathological parameters of aggressiveness. Thirty-eight SCCs from 20 RDEB patients were analyzed. Five RDEB patients experienced an unfavorable course after the diagnosis of the first SCC, with early recurrence or metastasis, whereas 15 patients developed multiple SCCs without metastasis. High-risk primary RDEB-SCCs showed a higher neutrophil-to-lymphocyte ratio in the tumor microenvironment and an increased proportion of neutrophil extracellular traps (NETs). Additionally, citrullinated histone H3, a marker of NETs, was increased in the serum of RDEB patients with high-risk primary SCC, suggesting that this modified form of histone H3 may serve as a potential blood marker of unfavorable prognosis in RDEB-SCCs. Full article

(This article belongs to the Section Cancer Biomarkers)

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21 pages, 3423 KiB

Open AccessArticle

Phosphodiesterase Inhibition to Sensitize Non-Small-Cell Lung Cancer to Pemetrexed: A Double-Edged Strategy

by Anna V. Ivanina Foureau, David M. Foureau, Cody C. McHale, Fei Guo, Carol J. Farhangfar and Kathryn F. Mileham

Cancers 2024, 16(13), 2475; https://doi.org/10.3390/cancers16132475 - 6 Jul 2024

Viewed by 329

Abstract

Phosphosidesterases (PDEs) are key regulators of cyclic nucleotide signaling, controlling many hallmarks of cancer and playing a role in resistance to chemotherapy in non-small-cell lung cancer (NSCLC). We evaluated the anti-tumor activity of the anti-folate agent pemetrexed (PMX), alone or combined with biochemical [...] Read more.

Phosphosidesterases (PDEs) are key regulators of cyclic nucleotide signaling, controlling many hallmarks of cancer and playing a role in resistance to chemotherapy in non-small-cell lung cancer (NSCLC). We evaluated the anti-tumor activity of the anti-folate agent pemetrexed (PMX), alone or combined with biochemical inhibitors of PDE5, 8, 9, or 10, against squamous and non-squamous NCSLC cells. Genomic alterations to PDE genes (PDE^mut) or PDE biochemical inhibition (PDEi) can sensitize NSCLC to PMX in vitro (observed in 50% NSCLC evaluated). The synergistic activity of PDEi with PMX required microdosing of the anti-folate drug. As single agents, none of the PDEis evaluated have anti-tumor activity. PDE biochemical inhibitors, targeting either cAMP or cGMP signaling (or both), resulted in significant cross-modulation of downstream pathways. The use of PDEi may present a new strategy to overcome PMX resistance of PDE^wt NSCLC tumors but comes with important caveats, including the use of subtherapeutic PMX doses. Full article

(This article belongs to the Special Issue Chemotherapy and Immunotherapy of Lung Cancer)

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16 pages, 1254 KiB

Open AccessSystematic Review

Cardiotoxicity in Acute Myeloid Leukemia in Adults: A Scoping Study

by Ioannis Konstantinidis, Sophia Tsokkou, Savvas Grigoriadis, Lalayianni Chrysavgi and Eleni Gavriilaki

Cancers 2024, 16(13), 2474; https://doi.org/10.3390/cancers16132474 - 6 Jul 2024

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Abstract

Introduction: According to the National Cancer Institute of the NIH, acute myeloid leukemia (AML) is a rapidly growing cancer with a large quantity of myeloblasts. AML is most often observed in adults over the age of 35, accounting for 1% of all cancer [...] Read more.

Introduction: According to the National Cancer Institute of the NIH, acute myeloid leukemia (AML) is a rapidly growing cancer with a large quantity of myeloblasts. AML is most often observed in adults over the age of 35, accounting for 1% of all cancer types. In 2023, the number of new cases being reported was estimated to reach around 20,380 in total and the rate of mortality in the same year was 1.9%, or 11,310 cases, in the US. Purpose: This scoping study aims to extensively assess and explore the degree of cardiotoxicity in patients with AML that can be caused due to pharmaceutical treatments prescribed by hematologists. This is achieved by performing extensive searches of different scientific databases including PubMed, Scopus, and ScienceDirect. Results: A variety of options are available that are summarized in tables included herein, with each having their advantages and risks of adverse effects, among these being cardiotoxicity. Important medications found to play a significant role include gemtuzumab ozogamicin, venetoclax, and vyxeos. Conclusions: It is understandable that being familiar with all the treatment options available and every potential adverse effect is impossible. However, hematologists and, in general, physicians must try to be updated with the most recent information released to improve the quality of life of their patients and minimize the risk of additional complications. Full article

(This article belongs to the Special Issue Hematologic Malignancies and Related Disorders: Challenges from Diagnosis to Treatment)

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16 pages, 1160 KiB

Open AccessArticle

Plasma Metabolome Signatures to Predict Responsiveness to Neoadjuvant Chemotherapy in Breast Cancer

by Alex Ap. Rosini Silva, Marcella R. Cardoso, Danilo Cardoso de Oliveira, Pedro Godoy, Maria Cecília R. Talarico, Junier Marrero Gutiérrez, Raquel M. Rodrigues Peres, Lucas M. de Carvalho, Natália Angelo da Silva Miyaguti, Luis O. Sarian, Alessandra Tata, Sophie F. M. Derchain and Andreia M. Porcari

Cancers 2024, 16(13), 2473; https://doi.org/10.3390/cancers16132473 - 6 Jul 2024

Viewed by 346

Abstract

Background: Neoadjuvant chemotherapy (NACT) has arisen as a treatment option for breast cancer (BC). However, the response to NACT is still unpredictable and dependent on cancer subtype. Metabolomics is a tool for predicting biomarkers and chemotherapy response. We used plasma to verify metabolomic [...] Read more.

Background: Neoadjuvant chemotherapy (NACT) has arisen as a treatment option for breast cancer (BC). However, the response to NACT is still unpredictable and dependent on cancer subtype. Metabolomics is a tool for predicting biomarkers and chemotherapy response. We used plasma to verify metabolomic alterations in BC before NACT, relating to clinical data. Methods: Liquid chromatography coupled to mass spectrometry (LC-MS) was performed on pre-NACT plasma from patients with BC (n = 75). After data filtering, an SVM model for classification was built and validated with 75%/25% of the data, respectively. Results: The model composed of 19 identified metabolites effectively predicted NACT response for training/validation sets with high sensitivity (95.4%/93.3%), specificity (91.6%/100.0%), and accuracy (94.6%/94.7%). In both sets, the panel correctly classified 95% of resistant and 94% of sensitive females. Most compounds identified by the model were lipids and amino acids and revealed pathway alterations related to chemoresistance. Conclusion: We developed a model for predicting patient response to NACT. These metabolite panels allow clinical gain by building precision medicine strategies based on tumor stratification. Full article

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

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25 pages, 1910 KiB

Open AccessReview

The Roles of RAC1 and RAC1B in Colorectal Cancer and Their Potential Contribution to Cetuximab Resistance

by Claudia C. Wahoski and Bhuminder Singh

Cancers 2024, 16(13), 2472; https://doi.org/10.3390/cancers16132472 - 6 Jul 2024

Viewed by 376

Abstract

Colorectal cancer (CRC) is one of the most diagnosed cancers and a leading contributor to cancer-related deaths in the United States. Clinically, standard treatment regimens include surgery, radiation, and chemotherapy; however, there has been increasing development and clinical use of targeted therapies for [...] Read more.

Colorectal cancer (CRC) is one of the most diagnosed cancers and a leading contributor to cancer-related deaths in the United States. Clinically, standard treatment regimens include surgery, radiation, and chemotherapy; however, there has been increasing development and clinical use of targeted therapies for CRC. Unfortunately, many patients develop resistance to these treatments. Cetuximab, the first targeted therapy approved to treat advanced CRC, is a monoclonal antibody that targets the epidermal growth factor receptor and inhibits downstream pathway activation to restrict tumor cell growth and proliferation. CRC resistance to cetuximab has been well studied, and common resistance mechanisms include constitutive signal transduction through downstream protein mutations and promotion of the epithelial-to-mesenchymal transition. While the most common resistance mechanisms are known, a proportion of patients develop resistance through unknown mechanisms. One protein predicted to contribute to therapy resistance is RAC1, a small GTPase that is involved in cytoskeleton rearrangement, cell migration, motility, and proliferation. RAC1 has also been shown to be overexpressed in CRC. Despite evidence that RAC1 and its alternative splice isoform RAC1B play important roles in CRC and the pathways known to contribute to cetuximab resistance, there is a need to directly study the relationship between RAC1 and RAC1B and cetuximab resistance. This review highlights the recent studies investigating RAC1 and RAC1B in the context of CRC and suggests that these proteins could play a role in resistance to cetuximab. Full article

(This article belongs to the Special Issue Molecular Insights into Drug Resistance in Cancer)

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15 pages, 5108 KiB

Open AccessArticle

Association of Serum Proteases and Acute Phase Factors Levels with Survival Outcomes in Patients with Colorectal Cancer

by Tadeusz Sebzda, Jakub Karwacki, Anna Cichoń, Katarzyna Modrzejewska, Jerzy Heimrath, Mirosław Łątka, Jan Gnus and Jakub Gburek

Cancers 2024, 16(13), 2471; https://doi.org/10.3390/cancers16132471 - 6 Jul 2024

Viewed by 276

Abstract

Colorectal cancer (CRC) represents a substantial burden on global healthcare, contributing to significant morbidity and mortality worldwide. Despite advances in screening methodologies, its incidence remains high, necessitating continued efforts in early detection and treatment. Neoplastic invasion and metastasis are primary determinants of CRC [...] Read more.

Colorectal cancer (CRC) represents a substantial burden on global healthcare, contributing to significant morbidity and mortality worldwide. Despite advances in screening methodologies, its incidence remains high, necessitating continued efforts in early detection and treatment. Neoplastic invasion and metastasis are primary determinants of CRC lethality, emphasizing the urgency of understanding underlying mechanisms to develop effective therapeutic strategies. This study aimed to explore the potential of serum biomarkers in predicting survival outcomes in CRC patients, with a focus on cathepsin B (CB), leukocytic elastase (LE), total sialic acid (TSA), lipid-associated sialic acid (LASA), antitrypsin activity (ATA), C-reactive protein (CRP), and cystatin C (CC). We recruited 185 CRC patients and 35 healthy controls, assessing demographic variables, tumor characteristics, and 7 serum biomarker levels, including (1) CB, (2) LE, (3) TSA, (4) LASA, (5) ATA, (6) CRP, and (7) CC. Statistical analyses included ANOVA with Tukey’s post hoc tests and MANOVA for continuous variables. Student’s t-test was used for dependent samples, while non-parametric tests like Mann–Whitney U and Wilcoxon signed-rank tests were applied for variables deviating from the normal distribution. Categorical variables were assessed using chi-square and Kruskal-Wallis tests. Spearman’s rank correlation coefficient was utilized to examine variable correlations. Survival analysis employed the Kaplan–Meier method with a log-rank test for comparing survival times between groups. Significant associations were observed between CB (p = 0.04), LE (p = 0.01), and TSA (p = 0.008) levels and survival outcomes in CRC patients. Dukes’ classification stages also showed a significant correlation with survival (p = 0.001). However, no significant associations were found for LASA, ATA, CRP, and CC. Multivariate analysis of LE, TSA, and ATA demonstrated a notable correlation with survival (p = 0.041), notwithstanding ATA’s lack of significance in univariate analysis (p = 0.13). CB, LE, and TSA emerged as promising diagnostic markers with prognostic value in CRC, potentially aiding in early diagnosis and treatment planning. Further research is needed to validate these findings and explore additional prognostic indicators. Full article

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

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16 pages, 286 KiB

Open AccessReview

Current and Future of Robotic Surgery in Thyroid Cancer Treatment

by Joonseon Park and Kwangsoon Kim

Cancers 2024, 16(13), 2470; https://doi.org/10.3390/cancers16132470 - 6 Jul 2024

Viewed by 392

Abstract

Thyroid cancer is among the most common endocrine malignancies, necessitating effective surgical interventions. Traditional open cervicotomy has long been the standard approach for thyroidectomy. However, the advent of robotic surgery has introduced new possibilities for minimally invasive procedures with benefits in terms of [...] Read more.

Thyroid cancer is among the most common endocrine malignancies, necessitating effective surgical interventions. Traditional open cervicotomy has long been the standard approach for thyroidectomy. However, the advent of robotic surgery has introduced new possibilities for minimally invasive procedures with benefits in terms of cosmetic outcomes, enhanced precision, comparable complication rates, and reduced recovery time. This study mainly reviewed the most widely used and well-known robotic thyroidectomy approaches: the transaxillary approach, the bilateral axillo–breast approach, and the transoral approach. This review examines the current status and future potential of robotic surgery in thyroid cancer treatment, comparing its efficacy, safety, and outcomes with those of conventional open cervicotomy. Challenges such as a longer operative time and higher costs exist. Future directions include technological advancements, tele-surgery, single-port surgery, and the integration of artificial intelligence. Robotic surgery holds promise in optimizing patient outcomes in thyroid cancer treatment. Full article

(This article belongs to the Special Issue Feature Review for Cancer Therapy)

15 pages, 4234 KiB

Open AccessArticle

Fractal Dimension, Circularity, and Solidity of Cell Clusters in Liquid-Based Endometrial Cytology Are Potentially Useful for Endometrial Cancer Detection and Prognosis Prediction

by Toshimichi Onuma, Akiko Shinagawa, Tetsuji Kurokawa, Makoto Orisaka and Yoshio Yoshida

Cancers 2024, 16(13), 2469; https://doi.org/10.3390/cancers16132469 - 6 Jul 2024

Viewed by 319

Abstract

Endometrial cancer (EC) in women is increasing globally, necessitating improved diagnostic methods and prognosis prediction. While endometrial histology is the conventional approach, liquid-based endometrial cytology may benefit from novel analytical techniques for cell clusters. A clinical study was conducted at the University of [...] Read more.

Endometrial cancer (EC) in women is increasing globally, necessitating improved diagnostic methods and prognosis prediction. While endometrial histology is the conventional approach, liquid-based endometrial cytology may benefit from novel analytical techniques for cell clusters. A clinical study was conducted at the University of Fukui Hospital from 2012 to 2018, involving 210 patients with endometrial cytology. The liquid-based cytology images were analyzed using cell cluster analysis with Image J software. Logistic regression, ROC analysis, and survival analysis were employed to assess the diagnostic accuracy and prognosis between cell cluster analysis and EC/atypical endometrial hyperplasia (AEH). Circularity and fractal dimension demonstrated significant associations with EC and AEH, regardless of age and cytology results. The ROC analysis revealed improved diagnostic accuracy when combining fractal dimension with cytology, particularly in menopausal age groups. Lower circularity and solidity were independently associated with poor overall survival, while higher fractal dimension values correlated with poorer overall survival in Grades 2 and 3 endometrial cancers. The combination of circularity and fractal dimension with cytology improved diagnostic accuracy for both EC and AEH. Moreover, circularity, solidity, and fractal dimension may serve as prognostic indicators for endometrial cancer, contributing to the development of more refined screening and diagnostic strategies. Full article

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

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12 pages, 1916 KiB

Open AccessSystematic Review

The Impact of Pain Education Interventions for Cancer Survivors and Caregivers: A Systematic Review with Meta-Analysis

by Sofía Hernández-Hernández, Alejandro Heredia-Ciuró, Javier Martín-Núñez, Andrés Calvache-Mateo, Alba Navas-Otero, Laura López-López and Marie Carmen Valenza

Cancers 2024, 16(13), 2468; https://doi.org/10.3390/cancers16132468 - 5 Jul 2024

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Abstract

Introduction: Cancer-related pain is a global health-related problem associated with functional impairment, anxiety, depression, and reduced quality of life. The use of educational interventions for patients and their caregivers has been proposed as a promising tool for overcoming pain in cancer. The aim [...] Read more.

Introduction: Cancer-related pain is a global health-related problem associated with functional impairment, anxiety, depression, and reduced quality of life. The use of educational interventions for patients and their caregivers has been proposed as a promising tool for overcoming pain in cancer. The aim of this study was to summarize by means of a standardized methodological systematic revision the actual pain education intervention used in cancer patients and their caregivers and to analyze its effects on pain. Methods: A search was conducted through PubMed, Web of Science, Scopus and Cinhal from their inception to September 2022. Randomized controlled trials which included pain education interventions were identified. Two reviewers performed independent data extraction and methodologic quality assessments of these studies. Results: A total of seven studies was included in the study. The meta-analysis showed that pain education interventions have a significant effect on the worst pain; however, there was no effect on average pain. Conclusions: Pain education interventions addressed to patients and their caregivers could have positive effects on cancer-related pain. It is recommended that a minimum of three sessions of about one hour’s duration be held once a week. Further research needs to be carried out and analyzed on the effects over the long term. Pain education interventions show positive results in improving pain in cancer patients regardless of etiology or extent of the cancer. Studies with better methodological quality should be carried out to address specific components related to education interventions. Full article

(This article belongs to the Topic Pathogenetic, Diagnostic and Therapeutic Perspectives in Head and Neck Cancer)

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12 pages, 2074 KiB

Open AccessArticle

Real-World Clinical Utility of Targeted RNA Sequencing in Leukemia Diagnosis and Management

by Seo Wan Kim, Namsoo Kim, Yu Jeong Choi, Seung-Tae Lee, Jong Rak Choi and Saeam Shin

Cancers 2024, 16(13), 2467; https://doi.org/10.3390/cancers16132467 - 5 Jul 2024

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Abstract

Gene fusions are key drivers in acute leukemia, impacting diagnosis and treatment decisions. We analyzed 264 leukemia patients using targeted RNA sequencing with conventional karyotyping and reverse transcription polymerase chain reaction (RT-PCR). Leukemic fusions were detected in 127 patients (48.1%). The new guidelines [...] Read more.

Gene fusions are key drivers in acute leukemia, impacting diagnosis and treatment decisions. We analyzed 264 leukemia patients using targeted RNA sequencing with conventional karyotyping and reverse transcription polymerase chain reaction (RT-PCR). Leukemic fusions were detected in 127 patients (48.1%). The new guidelines introduced additional diagnostic criteria, expanding the spectrum of gene fusions. We discovered three novel fusions (RUNX1::DOPEY2, RUNX1::MACROD2, and ZCCHC7::LRP1B). We analyzed recurrent breakpoints for the KMT2A and NUP98 rearrangements. Targeted RNA sequencing showed consistent results with RT-PCR in all tested samples. However, when compared to conventional karyotyping, we observed an 83.3% concordance rate, with 29 cases found only in targeted RNA sequencing, 7 cases with discordant results, and 5 cases found only in conventional karyotyping. For the five cases where known leukemic gene rearrangements were suspected only in conventional karyotyping, we conducted additional messenger RNA sequencing in four cases and proved no pathogenic gene rearrangements. Targeted RNA sequencing proved advantageous for the rapid and accurate interpretation of gene rearrangements. The concurrent use of multiple methods was essential for a comprehensive evaluation. Comprehensive molecular analysis enhances our understanding of leukemia’s genetic basis, aiding diagnosis and classification. Advanced molecular techniques improve clinical decision-making, offering potential benefits. Full article

(This article belongs to the Section Cancer Informatics and Big Data)

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22 pages, 523 KiB

Open AccessReview

New Frontiers in the Treatment of Patients with HER2+ Cancer and Brain Metastases: Is Radiotherapy Always Useful?

by Giuseppa Scandurra, Valentina Lombardo, Giuseppe Scibilia, Daniela Sambataro, Vittorio Gebbia, Paolo Scollo, Basilio Pecorino and Maria Rosaria Valerio

Cancers 2024, 16(13), 2466; https://doi.org/10.3390/cancers16132466 - 5 Jul 2024

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Abstract

Brain metastases (BM) pose a significant challenge in the management of HER2+ breast cancer since almost 50% of patients with HER2+ breast cancer develop brain tumors. The complex process of brain metastases involves genetic mutations, adaptations and mechanisms to overcome the blood–brain barrier. [...] Read more.

Brain metastases (BM) pose a significant challenge in the management of HER2+ breast cancer since almost 50% of patients with HER2+ breast cancer develop brain tumors. The complex process of brain metastases involves genetic mutations, adaptations and mechanisms to overcome the blood–brain barrier. While radiotherapy is still fundamental in local therapy, its use is associated with cognitive adverse effects and limited long-term control, necessitating the exploration of alternative treatments. Targeted therapies, including tyrosine kinase inhibitors, monoclonal antibodies, and antibody–drug conjugates, offer promising options for HER2+ breast cancer patients with BM. Clinical trials have demonstrated the efficacy of these agents in controlling tumor growth and improving patient outcomes, posing the question of whether radiotherapy is always the unique choice in treating this cancer. Ongoing research into novel anti-HER2 antibodies and innovative combination therapies holds promise for advancing treatment outcomes and enhancing patient care in this clinical scenario. This narrative review provides a comprehensive overview of traditional medical treatments, molecularly targeted therapy and investigational agents in the management of HER2+ breast cancer with BM, highlighting the evolving landscape and potential future directions in treatment strategies to improve patient survival and quality of life. Full article

(This article belongs to the Special Issue New Approaches in Radiotherapy for Cancer)

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16 pages, 963 KiB

Open AccessReview

Treatment and Staging Intensification Strategies Associated with Radical Prostatectomy for High-Risk Prostate Cancer: Efficacy Evaluation and Exploration of Novel Approaches

by Giuseppe Reitano, Tommaso Ceccato, Simone Botti, Martina Bruniera, Salvatore Carrozza, Eleonora Bovolenta, Gianmarco Randazzo, Davide Minardi, Lorenzo Ruggera, Mario Gardi, Giacomo Novara, Fabrizio Dal Moro and Fabio Zattoni

Cancers 2024, 16(13), 2465; https://doi.org/10.3390/cancers16132465 - 5 Jul 2024

Viewed by 222

Abstract

The management of high-risk prostate cancer (PCa) presents a significant clinical challenge, often necessitating treatment intensification due to the potential presence of micrometastases. While radical prostatectomy (RP) constitutes one of the primary treatment modalities, the integration of neoadjuvant and adjuvant therapies suggests a [...] Read more.

The management of high-risk prostate cancer (PCa) presents a significant clinical challenge, often necessitating treatment intensification due to the potential presence of micrometastases. While radical prostatectomy (RP) constitutes one of the primary treatment modalities, the integration of neoadjuvant and adjuvant therapies suggests a paradigm shift towards more aggressive treatment strategies, also guided by new imaging modalities like positron emission tomography using prostate-specific membrane antigen (PSMA-PET). Despite the benefits, treatment intensification raises concerns regarding increased side effects. This review synthesizes the latest evidence on perioperative treatment intensification and de-escalation for high-risk localized and locally advanced PCa patients eligible for surgery. Through a non-systematic literature review conducted via PubMed, Scopus, Web of Science, and ClinicalTrials.gov, we explored various dimensions of perioperative treatments, including neoadjuvant systemic therapies, adjuvant therapies, and the role of novel diagnostic technologies. Emerging evidence provides more support for neoadjuvant systemic therapies. Preliminary results from studies suggest the potential for treatments traditionally reserved for metastatic PCa to show apparent benefit in a non-metastatic setting. The role of adjuvant treatments remains debated, particularly the use of androgen deprivation therapy (ADT) and adjuvant radiotherapy in patients at higher risk of biochemical recurrence. The potential role of radio-guided PSMA lymph node dissection emerges as a cutting-edge approach, offering a targeted method for eradicating disease with greater precision. Innovations such as artificial intelligence and machine learning are potential game-changers, offering new avenues for personalized treatment and improved prognostication. The intensification of surgical treatment in high-risk PCa patients is a dynamic and evolving field, underscored by the integration of traditional and novel therapeutic approaches. As evidence continues to emerge, these strategies will refine patient selection, enhance treatment efficacy, and mitigate the risk of progression, although with an attentive consideration of the associated side effects. Full article

(This article belongs to the Special Issue Treatment Intensification in Localized Prostate Cancer: What Route with What Car?)

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19 pages, 3723 KiB

Open AccessArticle

Identification of miRNAs Present in Cell- and Plasma-Derived Extracellular Vesicles—Possible Biomarkers of Colorectal Cancer

by Marzena Lenart, Izabela Siemińska, Rafał Szatanek, Anna Mordel, Antoni Szczepanik, Mateusz Rubinkiewicz, Maciej Siedlar and Monika Baj-Krzyworzeka

Cancers 2024, 16(13), 2464; https://doi.org/10.3390/cancers16132464 - 5 Jul 2024

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Abstract

Globally, an increasing prevalence of colorectal cancer (CRC) prompts a need for the development of new methods for early tumor detection. MicroRNAs (also referred to as miRNAs) are short non-coding RNA molecules that play a pivotal role in the regulation of gene expression. [...] Read more.

Globally, an increasing prevalence of colorectal cancer (CRC) prompts a need for the development of new methods for early tumor detection. MicroRNAs (also referred to as miRNAs) are short non-coding RNA molecules that play a pivotal role in the regulation of gene expression. MiRNAs are effectively transferred to extracellular vesicle (EVs) membrane sacs commonly released by cells. Our study aimed to examine the expression of miRNAs in four CRC cell lines and EVs derived from them (tumor EVs) in comparison to the normal colon epithelium cell line and its EVs. EVs were isolated by ultracentrifugation from the culture supernatant of SW480, SW620, SW1116, HCT116 and normal CCD841CoN cell lines and characterized according to the MISEV2023 guidelines. MiRNAs were analyzed by small RNA sequencing and validated by quantitative PCR. The performed analysis revealed 22 common miRNAs highly expressed in CRC cell lines and effectively transferred to tumor EVs, including miR-9-5p, miR-182-5p, miR-196b-5p, miR-200b-5p, miR-200c-3p, miR-425-5p and miR-429, which are associated with development, proliferation, invasion and migration of colorectal cancer cells, as well as in vesicle maturation and transport-associated pathways. In parallel, normal cells expressed miRNAs, such as miR-369 and miR-143, which play a role in proinflammatory response and tumor suppression. The analysis of selected miRNAs in plasma-derived EVs and tumor samples from CRC patients showed the similarity of miRNA expression profile between the patients’ samples and CRC cell lines. Moreover, miR-182-5p, miR-196-5p, miR-425-5p and miR-429 were detected in several EV samples isolated from patients’ plasma. Our results suggest that miR-182-5p, miR-196b-5p and miR-429 are differentially expressed between EVs from CRC patients and healthy donors, which might have clinical implications. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series: The Functions of Extracellular Vesicles in Cancer)

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13 pages, 987 KiB

Open AccessArticle

International External Validation of Risk Prediction Model of 90-Day Mortality after Gastrectomy for Cancer Using Machine Learning

by Mariagiulia Dal Cero, Joan Gibert, Luis Grande, Marta Gimeno, Javier Osorio, Maria Bencivenga, Uberto Fumagalli Romario, Riccardo Rosati, Paolo Morgagni, Suzanne Gisbertz, Wojciech P. Polkowski, Lucio Lara Santos, Piotr Kołodziejczyk, Wojciech Kielan, Rossella Reddavid, Johanna W. van Sandick, Gian Luca Baiocchi, Ines Gockel, Andrew Davies, Bas P. L. Wijnhoven, Daniel Reim, Paulo Costa, William H. Allum, Guillaume Piessen, John V. Reynolds, Stefan P. Mönig, Paul M. Schneider, Elisenda Garsot, Emma Eizaguirre, Mònica Miró, Sandra Castro, Coro Miranda, Xavier Monzonis-Hernández, Manuel Pera and on behalf of the Spanish EURECCA Esophagogastric Cancer Group and the European GASTRODATA Study Group Show full author list Hide full author list

Cancers 2024, 16(13), 2463; https://doi.org/10.3390/cancers16132463 - 5 Jul 2024

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Abstract

Background: Radical gastrectomy remains the main treatment for gastric cancer, despite its high mortality. A clinical predictive model of 90-day mortality (90DM) risk after gastric cancer surgery based on the Spanish EURECCA registry database was developed using a matching learning algorithm. We performed [...] Read more.

Background: Radical gastrectomy remains the main treatment for gastric cancer, despite its high mortality. A clinical predictive model of 90-day mortality (90DM) risk after gastric cancer surgery based on the Spanish EURECCA registry database was developed using a matching learning algorithm. We performed an external validation of this model based on data from an international multicenter cohort of patients. Methods: A cohort of patients from the European GASTRODATA database was selected. Demographic, clinical, and treatment variables in the original and validation cohorts were compared. The performance of the model was evaluated using the area under the curve (AUC) for a random forest model. Results: The validation cohort included 2546 patients from 24 European hospitals. The advanced clinical T- and N-category, neoadjuvant therapy, open procedures, total gastrectomy rates, and mean volume of the centers were significantly higher in the validation cohort. The 90DM rate was also higher in the validation cohort (5.6%) vs. the original cohort (3.7%). The AUC in the validation model was 0.716. Conclusion: The externally validated model for predicting the 90DM risk in gastric cancer patients undergoing gastrectomy with curative intent continues to be as useful as the original model in clinical practice. Full article

(This article belongs to the Section Clinical Research of Cancer)

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Cancers, Volume 16, Issue 13 (July-1 2024) – 204 articles

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