Cancers

19 pages, 4940 KiB

Open AccessEditor’s ChoiceArticle

Proteomic Analysis of Spatial Heterogeneity Identifies HMGB2 as Putative Biomarker of Tumor Progression in Adult-Type Diffuse Astrocytomas

by Aline P. Becker, Valesio Becker, Joseph McElroy, Amy Webb, Chunhua Han, Yingshi Guo, Erica H. Bell, Jessica Fleming, Ilinca Popp, Ori Staszewski, Marco Prinz, Jose J. Otero, Saikh Jaharul Haque, Anca-Ligia Grosu and Arnab Chakravarti

Cancers 2024, 16(8), 1516; https://doi.org/10.3390/cancers16081516 - 16 Apr 2024

Cited by 1 | Viewed by 1582

Abstract

Although grading is defined by the highest histological grade observed in a glioma, most high-grade gliomas retain areas with histology reminiscent of their low-grade counterparts. We sought to achieve the following: (i) identify proteins and molecular pathways involved in glioma evolution; and (ii) [...] Read more.

Although grading is defined by the highest histological grade observed in a glioma, most high-grade gliomas retain areas with histology reminiscent of their low-grade counterparts. We sought to achieve the following: (i) identify proteins and molecular pathways involved in glioma evolution; and (ii) validate the high mobility group protein B2 (HMGB2) as a key player in tumor progression and as a prognostic/predictive biomarker for diffuse astrocytomas. We performed liquid chromatography tandem mass spectrometry (LC-MS/MS) in multiple areas of adult-type astrocytomas and validated our finding in multiplatform-omics studies and high-throughput IHC analysis. LC-MS/MSdetected proteomic signatures characterizing glioma evolution towards higher grades associated with, but not completely dependent, on IDH status. Spatial heterogeneity of diffuse astrocytomas was associated with dysregulation of specific molecular pathways, and HMGB2 was identified as a putative driver of tumor progression, and an early marker of worse overall survival in grades 2 and 3 diffuse gliomas, at least in part regulated by DNA methylation. In grade 4 astrocytomas, HMGB2 expression was strongly associated with proliferative activity and microvascular proliferation. Grounded in proteomic findings, our results showed that HMGB2 expression assessed by IHC detected early signs of tumor progression in grades 2 and 3 astrocytomas, as well as identified GBMs that had a better response to the standard chemoradiation with temozolomide. Full article

(This article belongs to the Section Cancer Biomarkers)

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17 pages, 13335 KiB

Open AccessEditor’s ChoiceArticle

Time-Restricted Feeding Attenuates Metabolic Dysfunction-Associated Steatohepatitis and Hepatocellular Carcinoma in Obese Male Mice

by Manasi Das, Deepak Kumar, Consuelo Sauceda, Alexis Oberg, Lesley G. Ellies, Liping Zeng, Lily J. Jih, Isabel G. Newton and Nicholas J. G. Webster

Cancers 2024, 16(8), 1513; https://doi.org/10.3390/cancers16081513 - 16 Apr 2024

Cited by 4 | Viewed by 3571

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) has surpassed the hepatitis B virus and hepatitis C virus as the leading cause of chronic liver disease in most parts of the Western world. MASLD (formerly known as NAFLD) encompasses both simple steatosis and more aggressive [...] Read more.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has surpassed the hepatitis B virus and hepatitis C virus as the leading cause of chronic liver disease in most parts of the Western world. MASLD (formerly known as NAFLD) encompasses both simple steatosis and more aggressive metabolic dysfunction-associated steatohepatitis (MASH), which is accompanied by inflammation, fibrosis, and cirrhosis, and ultimately can lead to hepatocellular carcinoma (HCC). There are currently very few approved therapies for MASH. Weight loss strategies such as caloric restriction can ameliorate the harmful metabolic effect of MASH and inhibit HCC; however, it is difficult to implement and maintain in daily life, especially in individuals diagnosed with HCC. In this study, we tested a time-restricted feeding (TRF) nutritional intervention in mouse models of MASH and HCC. We show that TRF abrogated metabolic dysregulation induced by a Western diet without any calorie restriction or weight loss. TRF improved insulin sensitivity and reduced hyperinsulinemia, liver steatosis, inflammation, and fibrosis. Importantly, TRF inhibited liver tumors in two mouse models of obesity-driven HCC. Our data suggest that TRF is likely to be effective in abrogating MASH and HCC and warrant further studies of time-restricted eating in humans with MASH who are at higher risk of developing HCC. Full article

(This article belongs to the Special Issue Circadian Rhythms, Cancers and Chronotherapy)

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38 pages, 1732 KiB

Open AccessEditor’s ChoiceReview

Heat Shock Proteins, a Double-Edged Sword: Significance in Cancer Progression, Chemotherapy Resistance and Novel Therapeutic Perspectives

by Dominika Kunachowicz, Magdalena Król-Kulikowska, Wiktoria Raczycka, Jakub Sleziak, Marta Błażejewska and Julita Kulbacka

Cancers 2024, 16(8), 1500; https://doi.org/10.3390/cancers16081500 - 14 Apr 2024

Cited by 8 | Viewed by 4302

Abstract

Heat shock proteins (Hsps) are involved in one of the adaptive mechanisms protecting cells against environmental and metabolic stress. Moreover, the large role of these proteins in the carcinogenesis process, as well as in chemoresistance, was noticed. This review aims to draw attention [...] Read more.

Heat shock proteins (Hsps) are involved in one of the adaptive mechanisms protecting cells against environmental and metabolic stress. Moreover, the large role of these proteins in the carcinogenesis process, as well as in chemoresistance, was noticed. This review aims to draw attention to the possibilities of using Hsps in developing new cancer therapy methods, as well as to indicate directions for future research on this topic. In order to discuss this matter, a thorough review of the latest scientific literature was carried out, taking into account the importance of selected proteins from the Hsp family, including Hsp27, Hsp40, Hsp60, Hsp70, Hsp90 and Hsp110. One of the more characteristic features of all Hsps is that they play a multifaceted role in cancer progression, which makes them an obvious target for modern anticancer therapy. Some researchers emphasize the importance of directly inhibiting the action of these proteins. In turn, others point to their possible use in the design of cancer vaccines, which would work by inducing an immune response in various types of cancer. Due to these possibilities, it is believed that the use of Hsps may contribute to the progress of oncoimmunology, and thus help in the development of modern anticancer therapies, which would be characterized by higher effectiveness and lower toxicity to the patients. Full article

(This article belongs to the Special Issue Heat Shock Proteins in Cancers)

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16 pages, 4375 KiB

Open AccessEditor’s ChoiceArticle

Induction of the Inflammasome Pathway by Tyrosine Kinase Inhibitors Provides an Actionable Therapeutic Target for Hepatocellular Carcinoma

by Anna Tutusaus, Marco Sanduzzi-Zamparelli, Loreto Boix, Patricia Rider, Silvia Subías, Pablo García de Frutos, Anna Colell, Montserrat Marí, María Reig and Albert Morales

Cancers 2024, 16(8), 1491; https://doi.org/10.3390/cancers16081491 - 13 Apr 2024

Cited by 4 | Viewed by 3936

Abstract

During the last decade, tyrosine kinase inhibitors (TKIs) sorafenib and regorafenib have been standard systemic treatments for advanced hepatocellular carcinoma (HCC). Previous data associated sorafenib with inflammasome activation. However, the role of the inflammasome in sorafenib and regorafenib signaling has not been described [...] Read more.

During the last decade, tyrosine kinase inhibitors (TKIs) sorafenib and regorafenib have been standard systemic treatments for advanced hepatocellular carcinoma (HCC). Previous data associated sorafenib with inflammasome activation. However, the role of the inflammasome in sorafenib and regorafenib signaling has not been described in liver cancer patients. For this purpose, we analyzed inflammasome-related transcriptomic changes in a murine HCC model. Our data confirmed inflammasome activation after both TKI treatments, sharing a similar pattern of increased gene expression. According to human database results, transcriptional increase of inflammasome genes is associated with poorer prognosis for male liver cancer patients, suggesting a sex-dependent role for inflammasome activation in HCC therapy. In biopsies of HCC and its surrounding tissue, we detected durable increases in the inflammasome activation pattern after sorafenib or regorafenib treatment in male patients. Further supporting its involvement in sorafenib action, inflammasome inhibition (MCC950) enhanced sorafenib anticancer activity in experimental HCC models, while no direct in vitro effect was observed in HCC cell lines. Moreover, activated human THP-1 macrophages released IL-1β after sorafenib administration, while 3D Hep3B spheres displayed increased tumor growth after IL-1β addition, pointing to the liver microenvironment as a key player in inflammasome action. In summary, our results unveil the inflammasome pathway as an actionable target in sorafenib or regorafenib therapy and associate an inflammasome signature in HCC and surrounding tissue with TKI administration. Therefore, targeting inflammasome activation, principally in male patients, could help to overcome sorafenib or regorafenib resistance and enhance the efficacy of TKI treatments in HCC. Full article

(This article belongs to the Special Issue Immunotherapy for Hepatocellular Carcinoma: Novel Experimental Approaches and Biomarkers)

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15 pages, 1087 KiB

Open AccessEditor’s ChoiceArticle

Early-Stage Non-Small Cell Lung Cancer: Prevalence of Actionable Alterations in a Monocentric Consecutive Cohort

by Rossella Bruno, Anello Marcello Poma, Martina Panozzi, Alessandra Lenzini, Gianmarco Elia, Carmelina Cristina Zirafa, Vittorio Aprile, Marcello Carlo Ambrogi, Editta Baldini, Marco Lucchi, Franca Melfi, Antonio Chella, Andrea Sbrana and Greta Alì

Cancers 2024, 16(7), 1410; https://doi.org/10.3390/cancers16071410 - 3 Apr 2024

Cited by 5 | Viewed by 3147

Abstract

Early-stage (ES) non-small cell lung cancer (NSCLC) is diagnosed in about 30% of cases. The preferred treatment is surgery, but a significant proportion of patients experience recurrence. Neoadjuvant and adjuvant chemotherapy has a limited clinical benefit. EGFR tyrosine kinase inhibitors and immunotherapy have [...] Read more.

Early-stage (ES) non-small cell lung cancer (NSCLC) is diagnosed in about 30% of cases. The preferred treatment is surgery, but a significant proportion of patients experience recurrence. Neoadjuvant and adjuvant chemotherapy has a limited clinical benefit. EGFR tyrosine kinase inhibitors and immunotherapy have recently opened new therapeutic scenarios. However, only a few data are available about the ES-NSCLC molecular landscape and the impact of oncogene addiction on therapy definition. Here, we determined the prevalence of the main lung cancer driver alterations in a monocentric consecutive cohort. Molecular analysis was performed on 1122 cases, including 368 ES and 754 advanced NSCLC. The prevalence of actionable alterations was similar between early and advanced stages. ES-NSCLC was significantly enriched for MET exon-14 skipping alterations and presented a lower prevalence of BRAF p.(V600E) mutation. PD-L1 expression levels, evaluated according to actionable alterations, were higher in advanced than early tumors harboring EGFR, KRAS, MET alterations and gene fusions. Taken together, these results confirm the value of biomarker testing in ES-NSCLC. Although approved targeted therapies for ES-NSCLC are still limited, the identification of actionable alterations could improve patients’ selection for immunotherapy, favoring the enrollment in clinical trials and allowing a faster treatment start at disease recurrence. Full article

(This article belongs to the Section Cancer Biomarkers)

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11 pages, 760 KiB

Open AccessEditor’s ChoiceArticle

Clinical Outcome of Nivolumab Plus Ipilimumab in Patients with Locally Advanced Non-Small-Cell Lung Cancer with Relapse after Concurrent Chemoradiotherapy followed by Durvalumab

by Atsuto Mouri, Satoshi Watanabe, Takaaki Tokito, Yoshiaki Nagai, Yu Saida, Hisao Imai, Ou Yamaguchi, Kunihiko Kobayashi, Kyoichi Kaira and Hiroshi Kagamu

Cancers 2024, 16(7), 1409; https://doi.org/10.3390/cancers16071409 - 3 Apr 2024

Cited by 2 | Viewed by 2943

Abstract

Nivolumab plus ipilimumab showed promising efficacy in patients with metastatic non-small-cell lung cancer (NSCLC). The efficacy of the nivolumab plus ipilimumab combination regimen in NSCLC patients who relapse after durvalumab consolidation following concurrent chemoradiotherapy (CCRT) has not been determined. Between January 2021 and [...] Read more.

Nivolumab plus ipilimumab showed promising efficacy in patients with metastatic non-small-cell lung cancer (NSCLC). The efficacy of the nivolumab plus ipilimumab combination regimen in NSCLC patients who relapse after durvalumab consolidation following concurrent chemoradiotherapy (CCRT) has not been determined. Between January 2021 and June 2022, clinical data were retrospectively extracted from the medical records of patients with NSCLC who received nivolumab plus ipilimumab after CCRT and durvalumab consolidation. A total of 30 patients were included in this analysis. The median number of durvalumab treatment cycles was 11. Median PFS and OS with nivolumab plus ipilimumab were 4.2 months (95% confidence interval [CI]: 0.7–7.7) and 18.5 months (95% CI: 3.5–33.5), respectively. The 6-month and 12-month PFS rates were 46.7% (95% CI: 28.8–64.5) and 36.4% (95% CI: 19.0–53.7). In multivariate analysis, a significant correlation was observed between a durvalumab treatment duration of 6 months or more and PFS (p = 0.04) as well as OS (p = 0.001). Grade 3 adverse events, including pneumonitis, dermatitis, and colitis, occurred in 10% of the patients. This study suggests that nivolumab plus ipilimumab is effective, especially in patients who have received durvalumab for 6 months or more, and tolerable for patients who relapsed after durvalumab following CCRT. Full article

(This article belongs to the Special Issue Pulmonary Oncology Research)

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16 pages, 1638 KiB

Open AccessEditor’s ChoiceReview

Role of the Atypical MAPK ERK3 in Cancer Growth and Progression

by Lobna Elkhadragy, Amanda Myers and Weiwen Long

Cancers 2024, 16(7), 1381; https://doi.org/10.3390/cancers16071381 - 31 Mar 2024

Cited by 1 | Viewed by 2502

Abstract

Extracellular signal-regulated kinase 3 (ERK3) is an atypical mitogen-activated protein kinase (MAPK) whose structural and regulatory features are distinct from those of conventional MAPKs, such as ERK1/2. Since its identification in 1991, the regulation, substrates and functions of ERK3 have remained largely unknown. [...] Read more.

Extracellular signal-regulated kinase 3 (ERK3) is an atypical mitogen-activated protein kinase (MAPK) whose structural and regulatory features are distinct from those of conventional MAPKs, such as ERK1/2. Since its identification in 1991, the regulation, substrates and functions of ERK3 have remained largely unknown. However, recent years have witnessed a wealth of new findings about ERK3 signaling. Several important biological functions for ERK3 have been revealed, including its role in neuronal morphogenesis, inflammation, metabolism, endothelial cell tube formation and epithelial architecture. In addition, ERK3 has been recently shown to play important roles in cancer cell proliferation, migration, invasion and chemoresistance in multiple types of cancers. Furthermore, accumulating studies have uncovered various molecular mechanisms by which the expression level, protein stability and activity of ERK3 are regulated. In particular, several post-translational modifications (PTMs), including ubiquitination, hydroxylation and phosphorylation, have been shown to regulate the stability and activity of ERK3 protein. In this review, we discuss recent findings regarding biochemical and cellular functions of ERK3, with a main focus on its roles in cancers, as well as the molecular mechanisms of regulating its expression and activity. Full article

(This article belongs to the Special Issue Genetic and Epigenetic Regulation of Cancer Metastasis)

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21 pages, 321 KiB

Open AccessEditor’s ChoiceReview

The Role of Circulating Tumor Cells as a Liquid Biopsy for Cancer: Advances, Biology, Technical Challenges, and Clinical Relevance

by Tyler A. Allen

Cancers 2024, 16(7), 1377; https://doi.org/10.3390/cancers16071377 - 31 Mar 2024

Cited by 18 | Viewed by 3748

Abstract

Cancer remains a leading cause of mortality worldwide, with metastasis significantly contributing to its lethality. The metastatic spread of tumor cells, primarily through the bloodstream, underscores the importance of circulating tumor cells (CTCs) in oncological research. As a critical component of liquid biopsies, [...] Read more.

Cancer remains a leading cause of mortality worldwide, with metastasis significantly contributing to its lethality. The metastatic spread of tumor cells, primarily through the bloodstream, underscores the importance of circulating tumor cells (CTCs) in oncological research. As a critical component of liquid biopsies, CTCs offer a non-invasive and dynamic window into tumor biology, providing invaluable insights into cancer dissemination, disease progression, and response to treatment. This review article delves into the recent advancements in CTC research, highlighting their emerging role as a biomarker in various cancer types. We explore the latest technologies and methods for CTC isolation and detection, alongside novel approaches to characterizing their biology through genomics, transcriptomics, proteomics, and epigenetic profiling. Additionally, we examine the clinical implementation of these findings, assessing how CTCs are transforming the landscape of cancer diagnosis, prognosis, and management. By offering a comprehensive overview of current developments and potential future directions, this review underscores the significance of CTCs in enhancing our understanding of cancer and in shaping personalized therapeutic strategies, particularly for patients with metastatic disease. Full article

(This article belongs to the Special Issue Advances in Circulating Tumor Cells as a Liquid Biopsy for Cancers)

17 pages, 1340 KiB

Open AccessEditor’s ChoiceReview

Prediction of Response to Anti-Angiogenic Treatment for Advanced Colorectal Cancer Patients: From Biological Factors to Functional Imaging

by Giuseppe Corrias, Eleonora Lai, Pina Ziranu, Stefano Mariani, Clelia Donisi, Nicole Liscia, Giorgio Saba, Andrea Pretta, Mara Persano, Daniela Fanni, Dario Spanu, Francesca Balconi, Francesco Loi, Simona Deidda, Angelo Restivo, Valeria Pusceddu, Marco Puzzoni, Cinzia Solinas, Elena Massa, Clelia Madeddu, Clara Gerosa, Luigi Zorcolo, Gavino Faa, Luca Saba and Mario Scartozzi Show full author list Hide full author list

Cancers 2024, 16(7), 1364; https://doi.org/10.3390/cancers16071364 - 30 Mar 2024

Cited by 4 | Viewed by 2213

Abstract

Colorectal cancer (CRC) is a leading tumor worldwide. In CRC, the angiogenic pathway plays a crucial role in cancer development and the process of metastasis. Thus, anti-angiogenic drugs represent a milestone for metastatic CRC (mCRC) treatment and lead to significant improvement of clinical [...] Read more.

Colorectal cancer (CRC) is a leading tumor worldwide. In CRC, the angiogenic pathway plays a crucial role in cancer development and the process of metastasis. Thus, anti-angiogenic drugs represent a milestone for metastatic CRC (mCRC) treatment and lead to significant improvement of clinical outcomes. Nevertheless, not all patients respond to treatment and some develop resistance. Therefore, the identification of predictive factors able to predict response to angiogenesis pathway blockade is required in order to identify the best candidates to receive these agents. Unfortunately, no predictive biomarkers have been prospectively validated to date. Over the years, research has focused on biologic factors such as genetic polymorphisms, circulating biomarkers, circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and microRNA. Moreover, research efforts have evaluated the potential correlation of molecular biomarkers with imaging techniques used for tumor assessment as well as the application of imaging tools in clinical practice. In addition to functional imaging, radiomics, a relatively newer technique, shows real promise in the setting of correlating molecular medicine to radiological phenotypes. Full article

(This article belongs to the Special Issue Predictive Biomarkers for Colorectal Cancer)

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14 pages, 277 KiB

Open AccessEditor’s ChoiceReview

Revolutionizing Treatment: Breakthrough Approaches for BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer

by Maciej Jaromin, Tomasz Konecki and Piotr Kutwin

Cancers 2024, 16(7), 1366; https://doi.org/10.3390/cancers16071366 - 30 Mar 2024

Cited by 9 | Viewed by 3421

Abstract

Bladder cancer is the 10th most popular cancer in the world, and non-muscle-invasive bladder cancer (NMIBC) is diagnosed in ~80% of all cases. Treatments for NMIBC include transurethral resection of the bladder tumor (TURBT) and intravesical instillations of Bacillus Calmette-Guérin (BCG). Treatment of [...] Read more.

Bladder cancer is the 10th most popular cancer in the world, and non-muscle-invasive bladder cancer (NMIBC) is diagnosed in ~80% of all cases. Treatments for NMIBC include transurethral resection of the bladder tumor (TURBT) and intravesical instillations of Bacillus Calmette-Guérin (BCG). Treatment of BCG-unresponsive tumors is scarce and usually leads to Radical Cystectomy. In this paper, we review recent advancements in conservative treatment of BCG-unresponsive tumors. The main focus of the paper is FDA-approved medications: Pembrolizumab and Nadofaragene Firadenovec (Adstiladrin). Other, less researched therapeutic possibilities are also included, namely: N-803 immunotherapy, TAR-200 and TAR-210 intravesical delivery systems and combined Cabazitaxel, Gemcitabine and Cisplatin chemotherapy. Conservative treatment and delaying radical cystectomy would greatly benefit patients’ quality of life; it is undoubtedly the future of BCG-unresponsive NMIBC. Full article

(This article belongs to the Special Issue Time for a Paradigm Shift in Non-muscle-invasive Bladder Cancer (Volume II))

11 pages, 1189 KiB

Open AccessEditor’s ChoiceArticle

Early Serum Markers for Immune Checkpoint Inhibitor Induced Hypophysitis in Melanoma Patients

by Fouad Mitri, Devayani Machiraju, Christina Naoum and Jessica C. Hassel

Cancers 2024, 16(7), 1340; https://doi.org/10.3390/cancers16071340 - 29 Mar 2024

Cited by 1 | Viewed by 1890

Abstract

Background: Immune checkpoint inhibitors (ICIs) have shown promising anti-tumor activities and are widely used for the treatment of advanced cancers. However, they may lead to immune-related adverse events (irAEs) and some of them, such as hypophysitis, can be life-threatening. Here, early diagnosis is [...] Read more.

Background: Immune checkpoint inhibitors (ICIs) have shown promising anti-tumor activities and are widely used for the treatment of advanced cancers. However, they may lead to immune-related adverse events (irAEs) and some of them, such as hypophysitis, can be life-threatening. Here, early diagnosis is critical. Methods: We retrospectively analyzed 40 melanoma patients who developed hypophysitis during ICI treatment with either ipilimumab and/or anti-PD1 therapy and compared them to 40 control patients who did not develop hypophysitis during the ICI treatment, matched for age, gender, type of immunotherapy, and stage. Clinical data and blood values such as LDH, CRP, TSH, T3, T4, and absolute immune cell counts were retrieved from the medical records. Patient characteristics, laboratory values, progression-free survival, and overall survival were compared between the two groups. Results: Patients with ir-hypophysitis had a median age of 59 years, and most of them were male. Clinically, frequent symptoms were fatigue, headache, dizziness, and gastrointestinal symptoms such as nausea or abdominal pain. The onset of ir-hypophysitis differed much between ipilimumab- (median 8 weeks) and anti-PD1 (median 40 weeks)-induced hypophysitis (p < 0.001). At baseline, besides a slightly increased CRP level (p = 0.06), no differences were observed in patients who later developed hypophysitis compared to the control. After treatment started, hypophysitis patients showed a constant and significant decline in T4 levels from the start of therapy until diagnosis (p < 0.05), independent of the ICI treatment regime. However, a decline in T3 and TSH was only noted in patients with ipilimumab-induced ir-hypophysitis. Furthermore, serum sodium levels declined rapidly at the diagnosis of hypophysitis (p < 0.001). In addition, there was a constant increase in the absolute counts of eosinophils and lymphocytes from baseline in hypophysitis patients (p < 0.05). Conclusion: Ir-hypophysitis reveals different clinical pictures and onset times depending on the ICI regime used. Whereas a drop in T4 levels was indicative of developing hypophysitis independent of the ICI regime, TSH levels only declined in patients under ipilimumab-based ICI regimes. To best monitor our patients, it is important to recognize these differences. Full article

(This article belongs to the Special Issue Oncology: State-of-the-Art Research in Germany)

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18 pages, 2523 KiB

Open AccessEditor’s ChoiceArticle

Synergy between BRD9- and IKZF3-Targeting as a Therapeutic Strategy for Multiple Myeloma

by Basudev Chowdhury, Swati Garg, Wei Ni, Martin Sattler, Dana Sanchez, Chengcheng Meng, Taisei Akatsu, Richard Stone, William Forrester, Edmund Harrington, Sara J. Buhrlage, James D. Griffin and Ellen Weisberg

Cancers 2024, 16(7), 1319; https://doi.org/10.3390/cancers16071319 - 28 Mar 2024

Cited by 3 | Viewed by 2705

Abstract

Progress in the treatment of multiple myeloma (MM) has resulted in improvement in the survival rate. However, there is still a need for more efficacious and tolerated therapies. We and others have shown that bromodomain-containing protein 9 (BRD9), a member of the non-canonical [...] Read more.

Progress in the treatment of multiple myeloma (MM) has resulted in improvement in the survival rate. However, there is still a need for more efficacious and tolerated therapies. We and others have shown that bromodomain-containing protein 9 (BRD9), a member of the non-canonical SWI/SNF chromatin remodeling complex, plays a role in MM cell survival, and targeting BRD9 selectively blocks MM cell proliferation and synergizes with IMiDs. We found that synergy in vitro is associated with the downregulation of MYC and Ikaros proteins, including IKZF3, and overexpression of IKZF3 or MYC could partially reverse synergy. RNA-seq analysis revealed synergy to be associated with the suppression of pathways associated with MYC and E2F target genes and pathways, including cell cycle, cell division, and DNA replication. Stimulated pathways included cell adhesion and immune and inflammatory response. Importantly, combining IMiD treatment and BRD9 targeting, which leads to the downregulation of MYC protein and upregulation of CRBN protein, was able to override IMiD resistance of cells exposed to iberdomide in long-term culture. Taken together, our results support the notion that combination therapy based on agents targeting BRD9 and IKZF3, two established dependencies in MM, represents a promising novel therapeutic strategy for MM and IMiD-resistant disease. Full article

(This article belongs to the Special Issue Signaling Pathways in Multiple Myeloma)

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24 pages, 879 KiB

Open AccessEditor’s ChoiceReview

An Updated Review of Management of Resectable Stage III NSCLC in the Era of Neoadjuvant Immunotherapy

by Saurav Verma, Daniel Breadner, Abhenil Mittal, David A. Palma, Rahul Nayak, Jacques Raphael and Mark Vincent

Cancers 2024, 16(7), 1302; https://doi.org/10.3390/cancers16071302 - 27 Mar 2024

Cited by 5 | Viewed by 5881

Abstract

Immune-checkpoint inhibitors (ICIs) have an established role in the treatment of locally advanced and metastatic non-small cell lung cancer (NSCLC). ICIs have now entered the paradigm of early-stage NSCLC. The recent evidence shows that the addition of ICI to neoadjuvant chemotherapy improves the [...] Read more.

Immune-checkpoint inhibitors (ICIs) have an established role in the treatment of locally advanced and metastatic non-small cell lung cancer (NSCLC). ICIs have now entered the paradigm of early-stage NSCLC. The recent evidence shows that the addition of ICI to neoadjuvant chemotherapy improves the pathological complete response (pCR) rate and survival rate in early-stage resectable NSCLC and is now a standard of care option in this setting. In this regard, stage III NSCLC merits special consideration, as it is heterogenous and requires a multidisciplinary approach to management. As the neoadjuvant approach is being adopted widely, new challenges have emerged and the boundaries for resectability are being re-examined. Consequently, it is ever more important to carefully individualize the treatment strategy for each patient with resectable stage III NSCLC. In this review, we discuss the recent literature in this field with particular focus on evolving definitions of resectability, T4 disease, N2 disease (single and multi-station), and nodal downstaging. We also highlight the controversy around adjuvant treatment in this setting and discuss the selection of patients for adjuvant treatment, options of salvage, and next line treatment in cases of progression on/after neoadjuvant treatment or after R2 resection. We will conclude with a brief discussion of predictive biomarkers, predictive models, ongoing studies, and directions for future research in this space. Full article

(This article belongs to the Special Issue Treatment of Lung Cancer)

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12 pages, 852 KiB

Open AccessEditor’s ChoiceArticle

Perioperative Chemotherapy for Gastro-Esophageal or Gastric Cancer: Anthracyclin Triplets versus FLOT

by Julie F. M. Geerts, Charlène J. van der Zijden, Pieter C. van der Sluis, Manon C. W. Spaander, Grard A. P. Nieuwenhuijzen, Camiel Rosman, Hanneke W. M. van Laarhoven, Rob H. A. Verhoeven, Bas P. L. Wijnhoven, Sjoerd M. Lagarde and Bianca Mostert

Cancers 2024, 16(7), 1291; https://doi.org/10.3390/cancers16071291 - 26 Mar 2024

Cited by 6 | Viewed by 2813

Abstract

Background: The FLOT4-AIO trial (2019) showed improved survival with perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) compared to anthracyclin triplets in gastric cancer treatment. It is unclear whether these results extend to real-world scenarios in the Netherlands. This study aimed to compare outcomes [...] Read more.

Background: The FLOT4-AIO trial (2019) showed improved survival with perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) compared to anthracyclin triplets in gastric cancer treatment. It is unclear whether these results extend to real-world scenarios in the Netherlands. This study aimed to compare outcomes of perioperative FLOT to anthracyclin triplets in a real-world Dutch gastric cancer population. Methods: Patients diagnosed with resectable (cT2-4a/cTxN0-3/NxM0) gastric or gastro-esophageal junction carcinoma between 2015–2021 who received neoadjuvant FLOT or anthracyclin triplets were selected from the Netherlands Cancer Registry. The primary outcome was overall survival (OS), analyzed through multivariable Cox regression. Secondary outcomes included pathological complete response (pCR), neoadjuvant chemotherapy cycle completion, surgical resection rates, and adjuvant therapy. Results: Adjusted OS showed no significant survival benefit (HR = 0.88, 95% CI 0.77–1.01, p = 0.07), even though the median OS was numerically improved by 8 months with FLOT compared to anthracyclin triplets (48.1 vs. 39.9 months, p = 0.16). FLOT patients were more likely to undergo diagnostic staging laparoscopies (74.2% vs. 44.1%, p < 0.001), had higher rates of completing neoadjuvant chemotherapy (OR = 1.35, 95% CI 1.09–1.68, p = 0.007), receiving adjuvant therapy (OR = 1.34, 95% CI 1.08–1.66, p = 0.08), and achieving pCR (OR = 1.52, 95% CI 1.05–2.20, p = 0.03). No significant differences were observed in (radical) resection rates. Conclusion(s): Real-world data showed no significant OS improvement for FLOT-treated patients compared to anthracyclin triplets, despite more staging laparoscopies. However, FLOT patients demonstrated higher rates of neoadjuvant therapy completion, proceeding to adjuvant therapy, and increased pCR rates. Therefore, we recommend the continued use of neoadjuvant FLOT therapy in the current clinical setting. Full article

(This article belongs to the Special Issue Clinical Trials in Gastroesophageal Cancer)

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12 pages, 473 KiB

Open AccessEditor’s ChoiceArticle

Comparing R-Bendamustine vs. R-CHOP Plus Maintenance Therapy as First-Line Systemic Treatment in Follicular Lymphoma: A Multicenter Retrospective GELTAMO Study

by Mariana Bastos-Oreiro, Antonio Gutierrez, Almudena Cabero, Javier López, Paola Villafuerte, Ana Jiménez-Ubieto, Raquel de Oña, Adolfo De la Fuente, Belén Navarro, Javier Peñalver, Pilar Martínez, Carmen Alonso, María Infante, Raúl Córdoba, Blanca Perez-Montero, Jaime Pérez de Oteyza, Sonia González de Villambrosio, Paula Fernández-Caldas, Raquel del Campo, Daniel García Belmonte, Javier Diaz-Gálvez, Antonio Salar and Juan-Manuel Sancho Show full author list Hide full author list

Cancers 2024, 16(7), 1285; https://doi.org/10.3390/cancers16071285 - 26 Mar 2024

Cited by 2 | Viewed by 4360

Abstract

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and R-bendamustine (R-B) are the most common frontline treatment strategies for advanced-stage follicular lymphoma (FL). After R-CHOP induction therapy, using rituximab for maintenance therapy notably improves outcomes; however, whether this can be achieved by using the [...] Read more.

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and R-bendamustine (R-B) are the most common frontline treatment strategies for advanced-stage follicular lymphoma (FL). After R-CHOP induction therapy, using rituximab for maintenance therapy notably improves outcomes; however, whether this can be achieved by using the same approach after R-B therapy is still being determined. This retrospective analysis compared 476 FL patients from 17 GELTAMO centers who received R-based regimens followed by rituximab maintenance therapy for untreated advanced-stage FL. The complete response rate at the end of induction was higher with R-B and relapses were more frequent with R-CHOP. During induction, cytopenias were significantly more frequent with R-CHOP and so was the use of colony-stimulating factors. During maintenance therapy, R-B showed more neutropenia and infectious toxicity. After a median follow-up of 81 months (95% CI: 77–86), the 6-year rates of progression-free survival (PFS) were 79% (95% CI: 72–86) for R-bendamustine vs. 67% (95% CI: 61–73) for R-CHOP (p = 0.046), and 6-year overall survival (OS) values were 91% (95% CI: 86–96) for R-B vs. 91% (95% CI: 87–94) for R-CHOP (p = 0.49). In conclusion, R-B followed by rituximab maintenance therapy in patients with previously untreated FL resulted in significantly longer PFS than R-CHOP, with older patients also benefiting from this treatment without further toxicity. Adverse events during maintenance were more frequent with R-B without impacting mortality. Full article

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

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28 pages, 6424 KiB

Open AccessEditor’s ChoiceArticle

Transforming Growth Factor Beta 2 (TGFB2) mRNA Levels, in Conjunction with Interferon-Gamma Receptor Activation of Interferon Regulatory Factor 5 (IRF5) and Expression of CD276/B7-H3, Are Therapeutically Targetable Negative Prognostic Markers in Low-Grade Gliomas

by Vuong Trieu, Anthony E. Maida and Sanjive Qazi

Cancers 2024, 16(6), 1202; https://doi.org/10.3390/cancers16061202 - 19 Mar 2024

Cited by 2 | Viewed by 3672

Abstract

LGG tumors are characterized by a low infiltration of immune cells, requiring therapeutic interventions to boost the immune response. We conducted a study analyzing mRNA expression datasets from the UCSC Xena web platform. To screen for upregulated genes, we sought to compare normal [...] Read more.

LGG tumors are characterized by a low infiltration of immune cells, requiring therapeutic interventions to boost the immune response. We conducted a study analyzing mRNA expression datasets from the UCSC Xena web platform. To screen for upregulated genes, we sought to compare normal brain tissue with LGG tumor samples. We also used cBioportal to determine the relationship between mRNA expression levels of 513 LGG patients and their overall survival (OS) outcomes. Three tumor-associated macrophage (TAM) markers, MSR1/CD204, CD86, and CD68, exhibited a 6-fold (p < 0.0001), 8.9-fold (p < 0.0001), and 15.6-fold increase in mRNA expression levels, respectively, in LGG tumors. In addition, both TGFB1 (4.1-fold increase, p < 0.0001) and TGFB2 (2.2-fold increase, p < 0.0001) ligands were also upregulated in these tumors compared to normal brain tissue, suggesting that TGFB ligands are pivotal in establishing an immunosuppressive, angiogenic, and pro-tumorigenic TME in gliomas mediated through TAMs. In addition, mRNA upregulation of interferon-gamma receptors, IFNGR1 and IFNGR2, and the downstream signaling molecules STAT1, IRF1, and IRF5, pointed to an essential role for IFN-γ mediated remodeling of the TME. Interestingly, the mRNA expression of a tumor-associated antigen, CD276/B7-H3, showed a significant (p < 0.0001) 4.03-fold increase in tumor tissue, giving further insights into the roles of macrophages and tumor cells in supporting the immunosuppressive TME. Multivariate Cox proportional hazards models investigating the interaction of TGFB2 and activation of IFNGR2, STAT1, IRF1, or IRF5 showed that the prognostic impact of high mRNA levels (25th percentile cut-off) of TGFB2 was independent of IFNGR2, STAT1, IRF1, or IRF5 mRNA levels (TGFB2^high HR (95% CI) = 4.07 (2.35–7.06), 6 (3.62–10.11), 4.38 (2.67–7.17), and 4.48 (2.82–7.12) for models with IFNGR2, STAT1, IRF1, or IRF5, respectively) and age at diagnosis. Patients with high levels of TGFB2 and IFNGR2 were over-represented by LGG patients with isocitrate dehydrogenase wild-type (IDHwt) mutation status. The prognostic impact of high levels of TGFB2 and IDH wild-type observed by the increases in hazard ratios for TGFB2 (HR (95% CI range) = 2.02 (1.05–3.89)) and IDH wild-type (HR (95% CI range) = 4.44 (1.9–10.4)) were independent predictors of survival, suggesting that risk stratification of patients identifies LGG patients with IDH wild-type and high levels of TGFB2 in the design of clinical trials. Furthermore, we have additional IRF5 and CD276/B7-H3 as prognostic markers that can also be targeted for combination therapies with TGFB2 inhibitors. In support of these findings, we demonstrated that low levels of gene methylation in TGFB2, IFNGR2, IRF1, IRF5, STAT1, and CD276 were associated with significantly worse overall survival (OS) outcomes. This suggests that potential mechanisms to increase the expression of these prognostic markers occur via the action of demethylation enzymes. Full article

(This article belongs to the Special Issue Past, Present, and Future Strategies in the Treatment and Management of Gliomas)

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20 pages, 3034 KiB

Open AccessEditor’s ChoiceReview

Enhancing Leukemia Treatment: The Role of Combined Therapies Based on Amino Acid Starvation

by Can Chen and Ji Zhang

Cancers 2024, 16(6), 1171; https://doi.org/10.3390/cancers16061171 - 16 Mar 2024

Cited by 5 | Viewed by 2984

Abstract

Cancer cells demand amino acids beyond their usage as “building blocks” for protein synthesis. As a result, targeting amino acid acquisition and utilization has emerged as a pivotal strategy in cancer treatment. In the setting of leukemia therapy, compelling examples of targeting amino [...] Read more.

Cancer cells demand amino acids beyond their usage as “building blocks” for protein synthesis. As a result, targeting amino acid acquisition and utilization has emerged as a pivotal strategy in cancer treatment. In the setting of leukemia therapy, compelling examples of targeting amino acid metabolism exist at both pre-clinical and clinical stages. This review focuses on summarizing novel insights into the metabolism of glutamine, asparagine, arginine, and tryptophan in leukemias, and providing a comprehensive discussion of perturbing their metabolism to improve the therapeutic outcomes. Certain amino acids, such as glutamine, play a vital role in the energy metabolism of cancer cells and the maintenance of redox balance, while others, such as arginine and tryptophan, contribute significantly to the immune microenvironment. Therefore, assessing the efficacy of targeting amino acid metabolism requires comprehensive strategies. Combining traditional chemotherapeutics with novel strategies to perturb amino acid metabolism is another way to improve the outcome in leukemia patients via overcoming chemo-resistance or promoting immunotherapy. In this review, we also discuss several ongoing or complete clinical trials, in which targeting amino acid metabolism is combined with other chemotherapeutics in treating leukemia. Full article

(This article belongs to the Special Issue Novel Combination Therapies for Acute Leukemia)

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22 pages, 1410 KiB

Open AccessEditor’s ChoiceReview

Triple-Negative Breast Cancer and Emerging Therapeutic Strategies: ATR and CHK1/2 as Promising Targets

by Amalia Sofianidi, Ecaterina E. Dumbrava, Konstantinos N. Syrigos and Azadeh Nasrazadani

Cancers 2024, 16(6), 1139; https://doi.org/10.3390/cancers16061139 - 13 Mar 2024

Cited by 8 | Viewed by 5509

Abstract

Worldwide, breast cancer is the most frequently diagnosed malignancy in women, with triple-negative breast cancer (TNBC) being the most aggressive molecular subtype. Due to the dearth of effective therapeutic options for TNBC, novel agents targeting key mechanisms and pathways in cancer cells are [...] Read more.

Worldwide, breast cancer is the most frequently diagnosed malignancy in women, with triple-negative breast cancer (TNBC) being the most aggressive molecular subtype. Due to the dearth of effective therapeutic options for TNBC, novel agents targeting key mechanisms and pathways in cancer cells are continuously explored; these include ATR inhibitors, which target the ATR kinase involved in the DNA damage response (DDR) pathway, and CHK1/2 inhibitors, which target the Checkpoint Kinase 1/2 (CHK1/2) involved in cell cycle arrest and DNA repair. ATR and CHK1/2 inhibitors show potential as prospective treatments for TNBC by focusing on the DDR and interfering with cell cycle regulation in cancer cells. Preliminary preclinical and clinical findings suggest that when combined with chemotherapy, ATR and CHK1/2 inhibitors demonstrate significant anti-proliferative efficacy against TNBC. In this article, we introduce ATR and CHK1/2 inhibitors as promising therapeutic approaches for the management of TNBC. Preclinical and clinical studies performed evaluating ATR and CHK1/2 inhibitors for the treatment of TNBC and associated challenges encountered in this context to date are reviewed. Full article

(This article belongs to the Special Issue Women’s Health and Gynaecological Cancers: From Nutrition and Environmental Factors to Novel Diagnostics and Therapies)

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12 pages, 761 KiB

Open AccessEditor’s ChoiceReview

Low-Volume Metastases in Cervical Cancer: Does Size Matter?

by Tommaso Bianchi, Tommaso Grassi, Giampaolo Di Martino, Serena Negri, Gaetano Trezzi, Robert Fruscio and Fabio Landoni

Cancers 2024, 16(6), 1107; https://doi.org/10.3390/cancers16061107 - 9 Mar 2024

Cited by 2 | Viewed by 2141

Abstract

The implementation of sentinel lymph node (SLN) biopsy is changing the scenario in the surgical treatment of early-stage cervical cancer, and the oncologic safety of replacing bilateral pelvic lymphadenectomy with SLN biopsy is currently under investigation. Part of the undisputed value of SLN [...] Read more.

The implementation of sentinel lymph node (SLN) biopsy is changing the scenario in the surgical treatment of early-stage cervical cancer, and the oncologic safety of replacing bilateral pelvic lymphadenectomy with SLN biopsy is currently under investigation. Part of the undisputed value of SLN biopsy is its diagnostic accuracy in detecting low-volume metastases (LVM) via pathologic ultrastaging. In early-stage cervical cancer, the reported incidence of LVM ranges from 4 to 20%. The prognostic impact and the role of adjuvant treatment in patients with LVM is still unclear. Some non-prespecified analyses in prospective studies showed no impact on the oncologic outcomes compared to node-negative disease. However, the heterogeneity of the studies, the differences in the disease stage and the use of adjuvant treatment, and the concomitant pelvic lymphadenectomy (PLND) make reaching any conclusions on this topic hard. Current guidelines suggest considering micrometastases (MIC) as a node-positive disease, while considering isolated tumor cells (ITC) as a node-negative disease with a low level of evidence. This review aims to highlight the unanswered questions about the definition, identification, and prognostic and therapeutic roles of LVM and to underline the present and future challenges we are facing. We hope that this review will guide further research, giving robust evidence on LVM and their impacts on clinical practice. Full article

(This article belongs to the Special Issue Lymph Node Dissection for Gynecologic Cancers)

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26 pages, 1847 KiB

Open AccessEditor’s ChoiceReview

Stereotactic Radiosurgery and Stereotactic Fractionated Radiotherapy in the Management of Brain Metastases

by Sofian Benkhaled, Luis Schiappacasse, Ali Awde and Remy Kinj

Cancers 2024, 16(6), 1093; https://doi.org/10.3390/cancers16061093 - 8 Mar 2024

Cited by 9 | Viewed by 3222

Abstract

The management of brain metastases (BM) remains an important and complex issue in the treatment of cancer-related neurological complications. BM are particularly common in patients diagnosed with lung, melanoma, or breast cancer. Over the past decade, therapeutic approaches for the majority of BM [...] Read more.

The management of brain metastases (BM) remains an important and complex issue in the treatment of cancer-related neurological complications. BM are particularly common in patients diagnosed with lung, melanoma, or breast cancer. Over the past decade, therapeutic approaches for the majority of BM patients have changed. Considering and addressing the fact that patients with BM are living longer, the need to provide effective local control while preserving quality of life and neurocognition is fundamental. Over the past decade, SRS and SRT have become a more commonly chosen treatment option for BM. Despite significant advances in the treatment of BM, numerous questions remain regarding patient selection and optimal treatment sequencing. Clinical trials are critical to advancing our understanding of BM, especially as more therapeutic alternatives become available. Therefore, it is imperative for interdisciplinary teams to improve their understanding of the latest advances in SRS-SRT. This review aims to comprehensively explore SRS and SRT as treatments for BM, covering clinical considerations in their application (e.g., patient selection and eligibility), managing limited and multiple intact BM, addressing brainstem metastases, exploring combination therapies with systemic treatments, and considering the health economic perspective. Full article

(This article belongs to the Special Issue Stereotactic Radiotherapy in Tumor Ablation)

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15 pages, 2164 KiB

Open AccessEditor’s ChoiceArticle

High HER2 Intratumoral Heterogeneity Is a Predictive Factor for Poor Prognosis in Early-Stage and Locally Advanced HER2-Positive Breast Cancer

by Tomonori Tanei, Shigeto Seno, Yoshiaki Sota, Takaaki Hatano, Yuri Kitahara, Kaori Abe, Nanae Masunaga, Masami Tsukabe, Tetsuhiro Yoshinami, Tomohiro Miyake, Masafumi Shimoda, Hideo Matsuda and Kenzo Shimazu

Cancers 2024, 16(5), 1062; https://doi.org/10.3390/cancers16051062 - 5 Mar 2024

Cited by 5 | Viewed by 3574

Abstract

Purpose: Breast cancer tumors frequently have intratumoral heterogeneity (ITH). Tumors with high ITH cause therapeutic resistance and have human epidermal growth factor receptor 2 (HER2) heterogeneity in response to HER2-targeted therapies. This study aimed to investigate whether high HER2 heterogeneity levels were clinically [...] Read more.

Purpose: Breast cancer tumors frequently have intratumoral heterogeneity (ITH). Tumors with high ITH cause therapeutic resistance and have human epidermal growth factor receptor 2 (HER2) heterogeneity in response to HER2-targeted therapies. This study aimed to investigate whether high HER2 heterogeneity levels were clinically related to a poor prognosis for HER2-targeted adjuvant therapy resistance in primary breast cancers. Methods: This study included patients with primary breast cancer (n = 251) treated with adjuvant HER2-targeted therapies. HER2 heterogeneity was manifested by the shape of HER2 fluorescence in situ hybridization amplification (FISH) distributed histograms with the HER2 gene copy number within a tumor sample. Each tumor was classified into a biphasic grade graph (high heterogeneity [HH]) group or a monophasic grade graph (low heterogeneity [LH]) group based on heterogeneity. Both groups were evaluated for disease-free survival (DFS) and overall survival (OS) for a median of ten years of annual follow-up. Results: Of 251 patients with HER2-positive breast cancer, 46 (18.3%) and 205 (81.7%) were classified into the HH and LH groups, respectively. The HH group had more distant metastases and a poorer prognosis than the LH group (DFS: p < 0.001 (HH:63% vs. LH:91% at 10 years) and for the OS: p = 0.012 (HH:78% vs. LH:95% at 10 years). Conclusions: High HER2 heterogeneity is a poor prognostic factor in patients with HER2-positive breast cancer. A novel approach to heterogeneity, which is manifested by the shape of HER2 FISH distributions, might be clinically useful in the prognosis prediction of patients after HER2 adjuvant therapy. Full article

(This article belongs to the Section Molecular Cancer Biology)

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15 pages, 3594 KiB

Open AccessEditor’s ChoiceArticle

Identification of GB3 as a Novel Biomarker of Tumor-Derived Vasculature in Neuroblastoma Using a Stiffness-Based Model

by Aranzazu Villasante, Josep Corominas, Clara Alcon, Andrea Garcia-Lizarribar, Jaume Mora, Monica Lopez-Fanarraga and Josep Samitier

Cancers 2024, 16(5), 1060; https://doi.org/10.3390/cancers16051060 - 5 Mar 2024

Cited by 1 | Viewed by 2188

Abstract

Neuroblastoma (NB) is a childhood cancer in sympathetic nervous system cells. NB exhibits cellular heterogeneity, with adrenergic and mesenchymal states displaying distinct tumorigenic potentials. NB is highly vascularized, and blood vessels can form through various mechanisms, including endothelial transdifferentiation, leading to the development [...] Read more.

Neuroblastoma (NB) is a childhood cancer in sympathetic nervous system cells. NB exhibits cellular heterogeneity, with adrenergic and mesenchymal states displaying distinct tumorigenic potentials. NB is highly vascularized, and blood vessels can form through various mechanisms, including endothelial transdifferentiation, leading to the development of tumor-derived endothelial cells (TECs) associated with chemoresistance. We lack specific biomarkers for TECs. Therefore, identifying new TEC biomarkers is vital for effective NB therapies. A stiffness-based platform simulating human arterial and venous stiffness was developed to study NB TECs in vitro. Adrenergic cells cultured on arterial-like stiffness transdifferentiated into TECs, while mesenchymal state cells did not. The TECs derived from adrenergic cells served as a model to explore new biomarkers, with a particular focus on GB3, a glycosphingolipid receptor implicated in angiogenesis, metastasis, and drug resistance. Notably, the TECs unequivocally expressed GB3, validating its novelty as a marker. To explore targeted therapeutic interventions, nanoparticles functionalized with the non-toxic subunit B of the Shiga toxin were generated, because they demonstrated a robust affinity for GB3-positive cells. Our results demonstrate the value of the stiffness-based platform as a predictive tool for assessing NB aggressiveness, the discovery of new biomarkers, and the evaluation of the effectiveness of targeted therapeutic strategies. Full article

(This article belongs to the Section Cancer Biomarkers)

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19 pages, 1200 KiB

Open AccessEditor’s ChoiceReview

Recent Advances in Therapeutic Strategies to Improve Colorectal Cancer Treatment

by William H. Gmeiner

Cancers 2024, 16(5), 1029; https://doi.org/10.3390/cancers16051029 - 2 Mar 2024

Cited by 19 | Viewed by 10697

Abstract

Colorectal cancer (CRC) is the second-leading cause of cancer-related mortality worldwide. CRC mortality results almost exclusively from metastatic disease (mCRC) for which systemic chemotherapy is often a preferred therapeutic option. Biomarker-based stratification of mCRC enables the use of precision therapy based on individual [...] Read more.

Colorectal cancer (CRC) is the second-leading cause of cancer-related mortality worldwide. CRC mortality results almost exclusively from metastatic disease (mCRC) for which systemic chemotherapy is often a preferred therapeutic option. Biomarker-based stratification of mCRC enables the use of precision therapy based on individual tumor mutational profiles. Activating mutations in the RAS/RAF/MAPK pathway downstream of EGFR signaling have, until recently, limited the use of EGFR-targeted therapies for mCRC; however, the development of anti-RAS and anti-RAF therapies together with improved strategies to limit compensatory signaling pathways is resulting in improved survival rates in several highly lethal mCRC sub-types (e.g., BRAF-mutant). The use of fluoropyrimidine (FP)-based chemotherapy regimens to treat mCRC continues to evolve contributing to improved long-term survival. Future advances in chemotherapy for mCRC will need to position development relative to the advances made in precision oncology. Full article

(This article belongs to the Special Issue Novel Strategies in the Prevention/Treatment of Colorectal Cancer)

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28 pages, 2428 KiB

Open AccessEditor’s ChoiceReview

Epigenetic Mechanisms in Latent Epstein-Barr Virus Infection and Associated Cancers

by Atharva S. Torne and Erle S. Robertson

Cancers 2024, 16(5), 991; https://doi.org/10.3390/cancers16050991 - 29 Feb 2024

Cited by 11 | Viewed by 5238

Abstract

The Epstein–Barr Virus (EBV) is a double-stranded DNA-based human tumor virus that was first isolated in 1964 from lymphoma biopsies. Since its initial discovery, EBV has been identified as a major contributor to numerous cancers and chronic autoimmune disorders. The virus is particularly [...] Read more.

The Epstein–Barr Virus (EBV) is a double-stranded DNA-based human tumor virus that was first isolated in 1964 from lymphoma biopsies. Since its initial discovery, EBV has been identified as a major contributor to numerous cancers and chronic autoimmune disorders. The virus is particularly efficient at infecting B-cells but can also infect epithelial cells, utilizing an array of epigenetic strategies to establish long-term latent infection. The association with histone modifications, alteration of DNA methylation patterns in host and viral genomes, and microRNA targeting of host cell factors are core epigenetic strategies that drive interactions between host and virus, which are necessary for viral persistence and progression of EBV-associated diseases. Therefore, understanding epigenetic regulation and its role in post-entry viral dynamics is an elusive area of EBV research. Here, we present current outlooks of EBV epigenetic regulation as it pertains to viral interactions with its host during latent infection and its propensity to induce tumorigenesis. We review the important epigenetic regulators of EBV latency and explore how the strategies involved during latent infection drive differential epigenetic profiles and host-virus interactions in EBV-associated cancers. Full article

(This article belongs to the Special Issue Epstein–Barr Virus (EBV) Associated Cancers)

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24 pages, 404 KiB

Open AccessEditor’s ChoiceReview

Risk Factors and Innovations in Risk Assessment for Melanoma, Basal Cell Carcinoma, and Squamous Cell Carcinoma

by K. Wunderlich, M. Suppa, S. Gandini, J. Lipski, J. M. White and V. Del Marmol

Cancers 2024, 16(5), 1016; https://doi.org/10.3390/cancers16051016 - 29 Feb 2024

Cited by 23 | Viewed by 4996

Abstract

Skin cancer is the most frequently diagnosed cancer globally and is preventable. Various risk factors contribute to different types of skin cancer, including melanoma, basal cell carcinoma, and squamous cell carcinoma. These risk factors encompass both extrinsic, such as UV exposure and behavioral [...] Read more.

Skin cancer is the most frequently diagnosed cancer globally and is preventable. Various risk factors contribute to different types of skin cancer, including melanoma, basal cell carcinoma, and squamous cell carcinoma. These risk factors encompass both extrinsic, such as UV exposure and behavioral components, and intrinsic factors, especially involving genetic predisposition. However, the specific risk factors vary among the skin cancer types, highlighting the importance of precise knowledge to facilitate appropriate early diagnosis and treatment for at-risk individuals. Better understanding of the individual risk factors has led to the development of risk scores, allowing the identification of individuals at particularly high risk. These advances contribute to improved prevention strategies, emphasizing the commitment to mitigating the impact of skin cancer. Full article

(This article belongs to the Special Issue Skin Cancer: Recent Advances in Diagnosis, Treatment, and Prevention)

14 pages, 2047 KiB

Open AccessEditor’s ChoiceArticle

Anti-PD-1 Therapy in Advanced Pediatric Malignancies in Nationwide Study: Good Outcome in Skin Melanoma and Hodgkin Lymphoma

by Agata Marjańska, Katarzyna Pawińska-Wąsikowska, Aleksandra Wieczorek, Monika Drogosiewicz, Bożenna Dembowska-Bagińska, Katarzyna Bobeff, Wojciech Młynarski, Katarzyna Adamczewska-Wawrzynowicz, Jacek Wachowiak, Małgorzata A. Krawczyk, Ninela Irga-Jaworska, Jadwiga Węcławek-Tompol, Krzysztof Kałwak, Małgorzata Sawicka-Żukowska, Maryna Krawczuk-Rybak, Anna Raciborska, Agnieszka Mizia-Malarz, Agata Sobocińska-Mirska, Paweł Łaguna, Walentyna Balwierz and Jan Styczyński Show full author list Hide full author list

Cancers 2024, 16(5), 968; https://doi.org/10.3390/cancers16050968 - 28 Feb 2024

Cited by 3 | Viewed by 2539

Abstract

Background/aim: The role of immune checkpoint inhibitors (ICIs; anti-PD1) in the treatment of childhood cancers is still evolving. The aim of this nationwide retrospective study was to assess the safety and effectiveness of ICIs used in a group of 42 patients, with a [...] Read more.

Background/aim: The role of immune checkpoint inhibitors (ICIs; anti-PD1) in the treatment of childhood cancers is still evolving. The aim of this nationwide retrospective study was to assess the safety and effectiveness of ICIs used in a group of 42 patients, with a median age of 13.6 years, with various types of advanced malignancies treated in pediatric oncology centers in Poland between 2015 and 2023. Results: The indications for treatment with anti-PD1 were as follows: Hodgkin lymphoma (11); malignant skin melanoma (9); neuroblastoma (8); and other malignancies (14). At the end of follow-up, complete remission (CR) was observed in 37.7% (15/42) of children and disease stabilization in 9.5% (4/42), with a mean survival 3.6 (95% CI = 2.6–4.6) years. The best survival (OS = 1.0) was observed in the group of patients with Hodgkin lymphoma. For malignant melanoma of the skin, neuroblastoma, and other rare malignancies, the estimated 3-year OS values were, respectively, 0.78, 0.33, and 0.25 (p = 0.002). The best progression-free survival value (0.78) was observed in the group with malignant melanoma. Significantly better effects of immunotherapy were confirmed in patients ≥ 14 years of age and good overall performance ECOG status. Severe adverse events were observed in 30.9% (13/42) patients. Full article

(This article belongs to the Special Issue Targeted Therapy of Pediatric Cancer)

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30 pages, 2609 KiB

Open AccessEditor’s ChoiceReview

Impact of Complex Apoptotic Signaling Pathways on Cancer Cell Sensitivity to Therapy

by Ryungsa Kim, Takanori Kin and William T. Beck

Cancers 2024, 16(5), 984; https://doi.org/10.3390/cancers16050984 - 28 Feb 2024

Cited by 21 | Viewed by 6330

Abstract

Anticancer drugs induce apoptotic and non-apoptotic cell death in various cancer types. The signaling pathways for anticancer drug-induced apoptotic cell death have been shown to differ between drug-sensitive and drug-resistant cells. In atypical multidrug-resistant leukemia cells, the c-Jun/activator protein 1 (AP-1)/p53 [...] Read more.

Anticancer drugs induce apoptotic and non-apoptotic cell death in various cancer types. The signaling pathways for anticancer drug-induced apoptotic cell death have been shown to differ between drug-sensitive and drug-resistant cells. In atypical multidrug-resistant leukemia cells, the c-Jun/activator protein 1 (AP-1)/p53 signaling pathway leading to apoptotic death is altered. Cancer cells treated with anticancer drugs undergo c-Jun/AP-1–mediated apoptotic death and are involved in c-Jun N-terminal kinase activation and growth arrest- and DNA damage-inducible gene 153 (Gadd153)/CCAAT/enhancer-binding protein homologous protein pathway induction, regardless of the p53 genotype. Gadd153 induction is associated with mitochondrial membrane permeabilization after anticancer drug treatment and involves a coupled endoplasmic reticulum stress response. The induction of apoptosis by anticancer drugs is mediated by the intrinsic pathway (cytochrome c, Cyt c) and subsequent activation of the caspase cascade via proapoptotic genes (e.g., Bax and Bcl-xS) and their interactions. Anticancer drug-induced apoptosis involves caspase-dependent and caspase-independent pathways and occurs via intrinsic and extrinsic pathways. The targeting of antiapoptotic genes such as Bcl-2 enhances anticancer drug efficacy. The modulation of apoptotic signaling by Bcl-xS transduction increases the sensitivity of multidrug resistance-related protein-overexpressing epidermoid carcinoma cells to anticancer drugs. The significance of autophagy in cancer therapy remains to be elucidated. In this review, we summarize current knowledge of cancer cell death-related signaling pathways and their alterations during anticancer drug treatment and discuss potential strategies to enhance treatment efficacy. Full article

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

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13 pages, 2431 KiB

Open AccessEditor’s ChoiceArticle

Assessing the New 2020 ESGO/ESTRO/ESP Endometrial Cancer Risk Molecular Categorization System for Predicting Survival and Recurrence

by Yung-Taek Ouh, Yoonji Oh, Jinwon Joo, Joo Hyun Woo, Hye Jin Han, Hyun Woong Cho, Jae Kwan Lee, Yikyeong Chun, Myoung-nam Lim and Jin Hwa Hong

Cancers 2024, 16(5), 965; https://doi.org/10.3390/cancers16050965 - 27 Feb 2024

Cited by 4 | Viewed by 2966

Abstract

This study aimed to evaluate the efficacy of the 2020 European Society of Gynecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology (ESGO/ESTRO/ESP) guidelines for endometrial cancer (EC). Additionally, a novel risk category incorporating clinicopathological and molecular factors was introduced. The predictive [...] Read more.

This study aimed to evaluate the efficacy of the 2020 European Society of Gynecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology (ESGO/ESTRO/ESP) guidelines for endometrial cancer (EC). Additionally, a novel risk category incorporating clinicopathological and molecular factors was introduced. The predictive value of this new category for recurrence and survival in Korean patients with EC was assessed, and comparisons were made with the 2013 and 2016 European Society of Medical Oncology (ESMO) risk classifications. Patients with EC were categorized into the POLE-mutated (POLEmut), mismatch repair-deficient (MMRd), p53-aberrant (P53abn), and nonspecific molecular profile (NSMP) subtypes. Recurrence, survival, and adjuvant therapy were assessed according to each classification. Notably, patients with the POLEmut subtype showed no relapse, while patients with the P53abn subtype exhibited higher recurrence (31.8%) and mortality rates (31.8%). Regarding adjuvant therapy, 33.3% of low-risk patients were overtreated according to the 2020 ESGO/ESTRO/ESP guidelines. Overall and progression-free survival differed significantly across molecular classifications, with the POLEmut subtype showing the best and the P53abn subtype showing the worst outcomes. The 2020 ESGO molecular classification system demonstrated practical utility and significantly influenced survival outcomes. Immunohistochemistry for TP53 and MMR, along with POLE sequencing, facilitated substantial patient reclassification, underscoring the clinical relevance of molecular risk categories in EC management. Full article

(This article belongs to the Special Issue Endometrial Cancer: Old Questions and New Perspectives (Volume II))

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17 pages, 3156 KiB

Open AccessEditor’s ChoiceSystematic Review

The Efficacy and Safety of Immune Checkpoint Inhibitors in Adrenocortical Carcinoma: A Systematic Review and Meta-Analysis

by Obada Ababneh, Alina Ghazou, Mohmmad Alawajneh, Saleh Alhaj Mohammad, Abdullah Bani-Hani, Nasr Alrabadi and Aditya Shreenivas

Cancers 2024, 16(5), 900; https://doi.org/10.3390/cancers16050900 - 23 Feb 2024

Cited by 6 | Viewed by 3534

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of different malignancies. However, their efficacy in advanced adrenocortical carcinoma (ACC) remains uncertain. Thus, we conducted a systematic review and meta-analysis to summarize the efficacy and tolerability of ICIs in patients with advanced ACC. We [...] Read more.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of different malignancies. However, their efficacy in advanced adrenocortical carcinoma (ACC) remains uncertain. Thus, we conducted a systematic review and meta-analysis to summarize the efficacy and tolerability of ICIs in patients with advanced ACC. We searched PubMed, Scopus, and CENTRAL for studies that used ICIs in ACC. Studies with more than five patients were included in the meta-analysis of the objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and grade 3/4 adverse events. Twenty studies with 23 treatment arms and 250 patients were included. Single-agent anti-PD1 or anti-PD-L1 treatment was utilized in 13 treatment arms, whereas an anti-PD1 or anti-PD-L1 and anti-CTLA4 combination was used in 4 treatment arms. Other anti-PD1- or anti-PD-L1-based combinations were used in five treatment arms. The ORR was 14% (95% CI = 10–19%, I² = 0%), and the DCR was 43% (95% CI = 37–50%, I² = 13%). The combination anti-PD1- or anti-PD-L1-based treatment strategies did not correlate with higher responses compared with monotherapy. The median OS was 13.9 months (95% CI = 7.85–23.05), and the median PFS was 2.8 months (95% CI = 1.8–5.4). ICIs have a modest efficacy in advanced ACC but a good OS. Further studies are needed to investigate predictive biomarkers for ICI response and to compare ICI-based strategies with the current standard of care. Full article

(This article belongs to the Special Issue Immune Checkpoint Inhibitors for Urologic Cancers)

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11 pages, 468 KiB

Open AccessEditor’s ChoiceArticle

Fear of Recurrence in Advanced Cancer Patients: Sociodemographic, Clinical, and Psychological Correlates

by Caterina Calderon, Marina Gustems, Rocio Galán-Moral, Maria M. Muñoz-Sánchez, Lorena Ostios-García and Paula Jiménez-Fonseca

Cancers 2024, 16(5), 909; https://doi.org/10.3390/cancers16050909 - 23 Feb 2024

Cited by 8 | Viewed by 2600

Abstract

Fear of cancer recurrence significantly impacts advanced cancer patients, prompting emotional distress and increased healthcare utilization. This present study aims to analyze the fear of recurrence among patients with advanced cancer undergoing systemic treatment and its relationship with sociodemographic, clinical, and psychological factors. [...] Read more.

Fear of cancer recurrence significantly impacts advanced cancer patients, prompting emotional distress and increased healthcare utilization. This present study aims to analyze the fear of recurrence among patients with advanced cancer undergoing systemic treatment and its relationship with sociodemographic, clinical, and psychological factors. A multicenter cross-sectional study was conducted in 15 oncology departments across Spain, involving patients with locally advanced, unresectable, or metastatic cancer eligible for systemic treatment. Participants provided demographic information and completed instruments such as the Cancer Worry Scale, Brief Symptom Inventory, Mishel Uncertainty in Illness Scale, and the Duke–UNC-11 Functional Social Support Questionnaire (DUFSSQ). A total of 1195 participants participated: median age 66, 56% male, mostly metastatic cancers (80%), and common tumor sites. Two fear groups emerged: 28% low and 72% high levels of fear. High fear was associated with being female, being younger, lower levels of education, and worse survival estimates. High fear correlated with more depression, anxiety, somatic symptoms, uncertainty, and stronger social support. Multivariate analyses indicated that younger patients, those with shorter survival estimates, higher depression and anxiety scores, more uncertainty, and stronger social support had a greater likelihood of experiencing fear of recurrence, while the opposite was true for older patients. This study underscores distinct fear of recurrence profiles in advanced cancer patients, emphasizing the need for targeted interventions and support. Future research should delve deeper into understanding their repercussions for improving patient care and well-being. Full article

(This article belongs to the Special Issue Integrating Palliative Care in Oncology)

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24 pages, 11226 KiB

Open AccessEditor’s ChoiceArticle

Identification of a Gene Signature That Predicts Dependence upon YAP/TAZ-TEAD

by Ryan Kanai, Emily Norton, Patrick Stern, Richard O. Hynes and John M. Lamar

Cancers 2024, 16(5), 852; https://doi.org/10.3390/cancers16050852 - 20 Feb 2024

Cited by 2 | Viewed by 2914

Abstract

Targeted therapies are effective cancer treatments when accompanied by accurate diagnostic tests that can help identify patients that will respond to those therapies. The YAP/TAZ-TEAD axis is activated and plays a causal role in several cancer types, and TEAD inhibitors are currently in [...] Read more.

Targeted therapies are effective cancer treatments when accompanied by accurate diagnostic tests that can help identify patients that will respond to those therapies. The YAP/TAZ-TEAD axis is activated and plays a causal role in several cancer types, and TEAD inhibitors are currently in early-phase clinical trials in cancer patients. However, a lack of a reliable way to identify tumors with YAP/TAZ-TEAD activation for most cancer types makes it difficult to determine which tumors will be susceptible to TEAD inhibitors. Here, we used a combination of RNA-seq and bioinformatic analysis of metastatic melanoma cells to develop a YAP/TAZ gene signature. We found that the genes in this signature are TEAD-dependent in several melanoma cell lines, and that their expression strongly correlates with YAP/TAZ activation in human melanomas. Using DepMap dependency data, we found that this YAP/TAZ signature was predictive of melanoma cell dependence upon YAP/TAZ or TEADs. Importantly, this was not limited to melanoma because this signature was also predictive when tested on a panel of over 1000 cancer cell lines representing numerous distinct cancer types. Our results suggest that YAP/TAZ gene signatures like ours may be effective tools to predict tumor cell dependence upon YAP/TAZ-TEAD, and thus potentially provide a means to identify patients likely to benefit from TEAD inhibitors. Full article

(This article belongs to the Special Issue New Insights on the Hippo-YAP/TAZ-TEAD Pathway and Its Roles in Cancer)

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23 pages, 25758 KiB

Open AccessEditor’s ChoiceArticle

Molecular, Metabolic, and Subcellular Mapping of the Tumor Immune Microenvironment via 3D Targeted and Non-Targeted Multiplex Multi-Omics Analyses

by Sammy Ferri-Borgogno, Jared K. Burks, Erin H. Seeley, Trevor D. McKee, Danielle L. Stolley, Akshay V. Basi, Javier A. Gomez, Basant T. Gamal, Shamini Ayyadhury, Barrett C. Lawson, Melinda S. Yates, Michael J. Birrer, Karen H. Lu and Samuel C. Mok

Cancers 2024, 16(5), 846; https://doi.org/10.3390/cancers16050846 - 20 Feb 2024

Cited by 10 | Viewed by 12540

Abstract

Most platforms used for the molecular reconstruction of the tumor–immune microenvironment (TIME) of a solid tumor fail to explore the spatial context of the three-dimensional (3D) space of the tumor at a single-cell resolution, and thus lack information about cell–cell or cell–extracellular matrix [...] Read more.

Most platforms used for the molecular reconstruction of the tumor–immune microenvironment (TIME) of a solid tumor fail to explore the spatial context of the three-dimensional (3D) space of the tumor at a single-cell resolution, and thus lack information about cell–cell or cell–extracellular matrix (ECM) interactions. To address this issue, a pipeline which integrated multiplex spatially resolved multi-omics platforms was developed to identify crosstalk signaling networks among various cell types and the ECM in the 3D TIME of two FFPE (formalin-fixed paraffin embedded) gynecologic tumor samples. These platforms include non-targeted mass spectrometry imaging (glycans, metabolites, and peptides) and Stereo-seq (spatial transcriptomics) and targeted seqIF (IHC proteomics). The spatially resolved imaging data in a two- and three-dimensional space demonstrated various cellular neighborhoods in both samples. The collection of spatially resolved analytes in a voxel (3D pixel) across serial sections of the tissue was also demonstrated. Data collected from this analytical pipeline were used to construct spatial 3D maps with single-cell resolution, which revealed cell identity, activation, and energized status. These maps will provide not only insights into the molecular basis of spatial cell heterogeneity in the TIME, but also novel predictive biomarkers and therapeutic targets, which can improve patient survival rates. Full article

(This article belongs to the Section Tumor Microenvironment)

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21 pages, 3530 KiB

Open AccessEditor’s ChoiceArticle

Identification of Tissue miRNA Signatures for Pancreatic Ductal Adenocarcinoma

by Carlo Caputo, Michela Falco, Anna Grimaldi, Angela Lombardi, Chiara Carmen Miceli, Mariateresa Cocule, Marco Montella, Luca Pompella, Giuseppe Tirino, Severo Campione, Chiara Tammaro, Antonio Cossu, Grazia Fenu Pintori, Margherita Maioli, Donatella Coradduzza, Giovanni Savarese, Antonio Fico, Alessandro Ottaiano, Giovanni Conzo, Madhura S. Tathode, Fortunato Ciardiello, Michele Caraglia, Ferdinando De Vita and Gabriella Misso Show full author list Hide full author list

Cancers 2024, 16(4), 824; https://doi.org/10.3390/cancers16040824 - 18 Feb 2024

Cited by 2 | Viewed by 3320

Abstract

Pancreatic ductal adenocarcinoma (PDAC), a neoplasm of the gastrointestinal tract, is the most common pancreatic malignancy (90%) and the fourth highest cause of cancer mortality worldwide. Surgery intervention is currently the only strategy able to offer an advantage in terms of overall survival, [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC), a neoplasm of the gastrointestinal tract, is the most common pancreatic malignancy (90%) and the fourth highest cause of cancer mortality worldwide. Surgery intervention is currently the only strategy able to offer an advantage in terms of overall survival, but prognosis remains poor even for operated patients. Therefore, the development of robust biomarkers for early diagnosis and prognostic stratification in clinical practice is urgently needed. In this work, we investigated deregulated microRNAs (miRNAs) in tissues from PDAC patients with high (G3) or low (G2) histological grade and with (N+) or without (N−) lymph node metastases. miRNA expression profiling was performed by a comprehensive PCR array and subsequent validation by RT-qPCR. The results showed a significant increase in miR-1-3p, miR-31-5p, and miR-205-5p expression in G3 compared to G2 patients (** p < 0.01; *** p < 0.001; *** p < 0.001). miR-518d-3p upregulation and miR-215-5p downregulation were observed in N+ compared to N− patients. A statistical analysis performed using OncomiR program showed the significant involvement (p < 0.05) of two miRNAs (miR-31 and miR-205) in the histological grade of PDAC patients. Also, an expression analysis in PDAC patients showed that miR-31 and miR-205 had the highest expression at grade 3 compared with normal and other tumor grades. Overall, survival plots confirmed that the overexpression of miR-31 and miR-205 was significantly correlated with decreased survival in TCGA PDAC clinical samples. A KEGG pathway analysis showed that all three miRNAs are involved in the regulation of multiple pathways, including the Hippo signaling, adherens junction and microRNAs in cancer, along with several target genes. Based on in silico analysis and experimental validation, our study suggests the potential role of miR-1-3p, miR-31-5p, and miR-205-5p as useful clinical biomarkers and putative therapeutic targets in PDAC, which should be further investigated to determine the specific molecular processes affected by their aberrant expression. Full article

(This article belongs to the Special Issue Hallmark Properties and Behind-the-Scenes Role of Non-coding RNAs in Gastrointestinal Cancers’ Onset, Progression and Metastasis)

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23 pages, 5097 KiB

Open AccessEditor’s ChoiceArticle

Transduction Efficiency of Zika Virus E Protein Pseudotyped HIV-1gfp and Its Oncolytic Activity Tested in Primary Glioblastoma Cell Cultures

by Jan Patrick Formanski, Hai Dang Ngo, Vivien Grunwald, Celine Pöhlking, Jana Sue Jonas, Dominik Wohlers, Birco Schwalbe and Michael Schreiber

Cancers 2024, 16(4), 814; https://doi.org/10.3390/cancers16040814 - 17 Feb 2024

Viewed by 2651

Abstract

The development of new tools against glioblastoma multiforme (GBM), the most aggressive and common cancer originating in the brain, remains of utmost importance. Lentiviral vectors (LVs) are among the tools of future concepts, and pseudotyping offers the possibility of tailoring LVs to efficiently [...] Read more.

The development of new tools against glioblastoma multiforme (GBM), the most aggressive and common cancer originating in the brain, remains of utmost importance. Lentiviral vectors (LVs) are among the tools of future concepts, and pseudotyping offers the possibility of tailoring LVs to efficiently transduce and inactivate GBM tumor cells. Zika virus (ZIKV) has a specificity for GBM cells, leaving healthy brain cells unharmed, which makes it a prime candidate for the development of LVs with a ZIKV coat. Here, primary GBM cell cultures were transduced with different LVs encased with ZIKV envelope variants. LVs were generated by using the pNLgfpAM plasmid, which produces the lentiviral, HIV-1-based, core particle with GFP (green fluorescent protein) as a reporter (HIVgfp). Using five different GBM primary cell cultures and three laboratory-adapted GBM cell lines, we showed that ZIKV/HIVgfp achieved a 4–6 times higher transduction efficiency compared to the commonly used VSV/HIVgfp. Transduced GBM cell cultures were monitored over a period of 9 days to identify GFP+ cells to study the oncolytic effect due to ZIKV/HIVgfp entry. Tests of GBM tumor specificity by transduction of GBM tumor and normal brain cells showed a high specificity for GBM cells. Full article

(This article belongs to the Special Issue Feature Papers in Section "Methods and Technologies Development")

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22 pages, 5602 KiB

Open AccessEditor’s ChoiceReview

Tissue-Based Diagnostic Biomarkers of Aggressive Variant Prostate Cancer: A Narrative Review

by Olga Kouroukli, Vasiliki Bravou, Konstantinos Giannitsas and Vasiliki Tzelepi

Cancers 2024, 16(4), 805; https://doi.org/10.3390/cancers16040805 - 16 Feb 2024

Viewed by 2312

Abstract

Prostate cancer (PC) is a common malignancy among elderly men, characterized by great heterogeneity in its clinical course, ranging from an indolent to a highly aggressive disease. The aggressive variant of prostate cancer (AVPC) clinically shows an atypical pattern of disease progression, similar [...] Read more.

Prostate cancer (PC) is a common malignancy among elderly men, characterized by great heterogeneity in its clinical course, ranging from an indolent to a highly aggressive disease. The aggressive variant of prostate cancer (AVPC) clinically shows an atypical pattern of disease progression, similar to that of small cell PC (SCPC), and also shares the chemo-responsiveness of SCPC. The term AVPC does not describe a specific histologic subtype of PC but rather the group of tumors that, irrespective of morphology, show an aggressive clinical course, dictated by androgen receptor (AR) indifference. AR indifference represents an adaptive response to androgen deprivation therapy (ADT), driven by epithelial plasticity, an inherent ability of tumor cells to adapt to their environment by changing their phenotypic characteristics in a bi-directional way. The molecular profile of AVPC entails combined alterations in the tumor suppressor genes retinoblastoma protein 1 (RB1), tumor protein 53 (TP53), and phosphatase and tensin homolog (PTEN). The understanding of the biologic heterogeneity of castration-resistant PC (CRPC) and the need to identify the subset of patients that would potentially benefit from specific therapies necessitate the development of prognostic and predictive biomarkers. This review aims to discuss the possible pathophysiologic mechanisms of AVPC development and the potential use of emerging tissue-based biomarkers in clinical practice. Full article

(This article belongs to the Section Cancer Pathophysiology)

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21 pages, 10757 KiB

Open AccessEditor’s ChoiceReview

Next-Generation HER2-Targeted Antibody–Drug Conjugates in Breast Cancer

by Brittney S. Zimmerman and Francisco J. Esteva

Cancers 2024, 16(4), 800; https://doi.org/10.3390/cancers16040800 - 16 Feb 2024

Cited by 11 | Viewed by 14317

Abstract

Human epidermal growth factor receptor 2 (HER2) tyrosine kinase is overexpressed in 20% of breast cancers and associated with a less favorable prognosis compared to HER2-negative disease. Patients have traditionally been treated with a combination of chemotherapy and HER2-targeted monoclonal antibodies such as [...] Read more.

Human epidermal growth factor receptor 2 (HER2) tyrosine kinase is overexpressed in 20% of breast cancers and associated with a less favorable prognosis compared to HER2-negative disease. Patients have traditionally been treated with a combination of chemotherapy and HER2-targeted monoclonal antibodies such as trastuzumab and pertuzumab. The HER2-targeted antibody–drug conjugates (ADCs) trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) represent a novel class of therapeutics in breast cancer. These drugs augment monoclonal antibodies with a cytotoxic payload, which is attached by a linker, forming the basic structure of an ADC. Novel combinations and sequential approaches are under investigation to overcome resistance to T-DM1 and T-DXd. Furthermore, the landscape of HER2-targeted therapy is rapidly advancing with the development of ADCs designed to attack cancer cells with greater precision and reduced toxicity. This review provides an updated summary of the current state of HER2-targeted ADCs as well as a detailed review of investigational agents on the horizon. Clinical trials are crucial in determining the optimal dosing regimens, understanding resistance mechanisms, and identifying patient populations that would derive the most benefit from these treatments. These novel ADCs are at the forefront of a new era in targeted cancer therapy, holding the potential to improve outcomes for patients with HER2-positive and HER2-Low breast cancer. Full article

(This article belongs to the Special Issue Her2-Positive Cancers and Antibody-Based Treatment: State of the Art and Future Developments (Volume II))

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21 pages, 3137 KiB

Open AccessEditor’s ChoiceArticle

Evaluation of Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration (EBUS-TBNA) Samples from Advanced Non-Small Cell Lung Cancer for Whole Genome, Whole Exome and Comprehensive Panel Sequencing

by David Fielding, Vanessa Lakis, Andrew J. Dalley, Haarika Chittoory, Felicity Newell, Lambros T. Koufariotis, Ann-Marie Patch, Stephen Kazakoff, Farzad Bashirzadeh, Jung Hwa Son, Kimberley Ryan, Daniel Steinfort, Jonathan P. Williamson, Michael Bint, Carl Pahoff, Phan Tien Nguyen, Scott Twaddell, David Arnold, Christopher Grainge, Andrew Pattison, David Fairbairn, Shailendra Gune, Jemma Christie, Oliver Holmes, Conrad Leonard, Scott Wood, John V. Pearson, Sunil R. Lakhani, Nicola Waddell, Peter T. Simpson and Katia Nones Show full author list Hide full author list

Cancers 2024, 16(4), 785; https://doi.org/10.3390/cancers16040785 - 15 Feb 2024

Cited by 1 | Viewed by 2710

Abstract

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is often the only source of tumor tissue from patients with advanced, inoperable lung cancer. EBUS-TBNA aspirates are used for the diagnosis, staging, and genomic testing to inform therapy options. Here we extracted DNA and RNA from [...] Read more.

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is often the only source of tumor tissue from patients with advanced, inoperable lung cancer. EBUS-TBNA aspirates are used for the diagnosis, staging, and genomic testing to inform therapy options. Here we extracted DNA and RNA from 220 EBUS-TBNA aspirates to evaluate their suitability for whole genome (WGS), whole exome (WES), and comprehensive panel sequencing. For a subset of 40 cases, the same nucleic acid extraction was sequenced using WGS, WES, and the TruSight Oncology 500 assay. Genomic features were compared between sequencing platforms and compared with those reported by clinical testing. A total of 204 aspirates (92.7%) had sufficient DNA (100 ng) for comprehensive panel sequencing, and 109 aspirates (49.5%) had sufficient material for WGS. Comprehensive sequencing platforms detected all seven clinically reported tier 1 actionable mutations, an additional three (7%) tier 1 mutations, six (15%) tier 2–3 mutations, and biomarkers of potential immunotherapy benefit (tumor mutation burden and microsatellite instability). As expected, WGS was more suited for the detection and discovery of emerging novel biomarkers of treatment response. WGS could be performed in half of all EBUS-TBNA aspirates, which points to the enormous potential of EBUS-TBNA as source material for large, well-curated discovery-based studies for novel and more effective predictors of treatment response. Comprehensive panel sequencing is possible in the vast majority of fresh EBUS-TBNA aspirates and enhances the detection of actionable mutations over current clinical testing. Full article

(This article belongs to the Special Issue Genetic, Epigenetic, and Epitranscriptomic Changes in Lung Cancer)

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11 pages, 1915 KiB

Open AccessEditor’s ChoiceArticle

ATOH1, TFAP2B, and CEACAM6 as Immunohistochemical Markers to Distinguish Merkel Cell Carcinoma and Small Cell Lung Cancer

by Serena M. Vilasi, Jannett Nguyen, Catherine J. Wang, Lingling Miao, Kenneth Daily, Mary Eid, Joon Seon Song, Hong Jiang, Kris Ylaya, Klaus J. Busam, Maria R. Gaiser, Stephen M. Hewitt and Isaac Brownell

Cancers 2024, 16(4), 788; https://doi.org/10.3390/cancers16040788 - 15 Feb 2024

Cited by 3 | Viewed by 2275

Abstract

Merkel cell carcinoma (MCC) and small cell lung cancer (SCLC) can be histologically similar. Immunohistochemistry (IHC) for cytokeratin 20 (CK20) and thyroid transcription factor 1 (TTF-1) are commonly used to differentiate MCC from SCLC; however, these markers have limited sensitivity and specificity. To [...] Read more.

Merkel cell carcinoma (MCC) and small cell lung cancer (SCLC) can be histologically similar. Immunohistochemistry (IHC) for cytokeratin 20 (CK20) and thyroid transcription factor 1 (TTF-1) are commonly used to differentiate MCC from SCLC; however, these markers have limited sensitivity and specificity. To identify new diagnostic markers, we performed differential gene expression analysis on transcriptome data from MCC and SCLC tumors. Candidate markers included atonal BHLH transcription factor 1 (ATOH1) and transcription factor AP-2β (TFAP2B) for MCC, as well as carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) for SCLC. Immunostaining for CK20, TTF-1, and new candidate markers was performed on 43 MCC and 59 SCLC samples. All three MCC markers were sensitive and specific, with CK20 and ATOH1 staining 43/43 (100%) MCC and 0/59 (0%) SCLC cases and TFAP2B staining 40/43 (93%) MCC and 0/59 (0%) SCLC cases. TTF-1 stained 47/59 (80%) SCLC and 1/43 (2%) MCC cases. CEACAM6 stained 49/59 (83%) SCLC and 0/43 (0%) MCC cases. Combining CEACAM6 and TTF-1 increased SCLC detection sensitivity to 93% and specificity to 98%. These data suggest that ATOH1, TFAP2B, and CEACAM6 should be explored as markers to differentiate MCC and SCLC. Full article

(This article belongs to the Special Issue Skin Cancer: Recent Advances in Diagnosis, Treatment, and Prevention)

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17 pages, 4839 KiB

Open AccessEditor’s ChoiceArticle

Drug Response of Patient-Derived Lung Cancer Cells Predicts Clinical Outcomes of Targeted Therapy

by Sunshin Kim, Youngjoo Lee, Bo Ram Song, Hanna Sim, Eun Hye Kang, Mihwa Hwang, Namhee Yu, Sehwa Hong, Charny Park, Beung-Chul Ahn, Eun Jin Lim, Kum Hui Hwang, Seog-Yun Park, Jin-Ho Choi, Geon Kook Lee and Ji-Youn Han

Cancers 2024, 16(4), 778; https://doi.org/10.3390/cancers16040778 - 14 Feb 2024

Cited by 1 | Viewed by 2514

Abstract

Intratumor heterogeneity leads to different responses to targeted therapies, even within patients whose tumors harbor identical driver oncogenes. This study examined clinical outcomes according to a patient-derived cell (PDC)-based drug sensitivity test in lung cancer patients treated with targeted therapies. From 487 lung [...] Read more.

Intratumor heterogeneity leads to different responses to targeted therapies, even within patients whose tumors harbor identical driver oncogenes. This study examined clinical outcomes according to a patient-derived cell (PDC)-based drug sensitivity test in lung cancer patients treated with targeted therapies. From 487 lung cancers, 397 PDCs were established with a success rate of 82%. In 139 PDCs from advanced non-small-cell lung cancer (NSCLC) patients receiving targeted therapies, the standardized area under the curve (AUC) values for the drugs was significantly correlated with their tumor response (p = 0.002). Among 59 chemo-naive EGFR/ALK-positive NSCLC patients, the PDC non-responders showed a significantly inferior response rate (RR) and progression-free survival (PFS) for the targeted drugs than the PDC responders (RR, 25% vs. 78%, p = 0.011; median PFS, 3.4 months [95% confidence interval (CI), 2.8–4.1] vs. 11.8 months [95% CI, 6.5–17.0], p < 0.001). Of 25 EGFR-positive NSCLC patients re-challenged with EGFR inhibitors, the PDC responder showed a higher RR than the PDC non-responder (42% vs. 15%). Four patients with wild-type EGFR or uncommon EGFR-mutant NSCLC were treated with EGFR inhibitors based on their favorable PDC response to EGFR inhibitors, and two patients showed dramatic responses. Therefore, the PDC-based drug sensitivity test results were significantly associated with clinical outcomes in patients with EGFR- or ALK-positive NSCLC. It may be helpful for predicting individual heterogenous clinical outcomes beyond genomic alterations. Full article

(This article belongs to the Special Issue Tumor Models and Drug Targeting In Vitro (Volume II))

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21 pages, 855 KiB

Open AccessEditor’s ChoiceReview

The Microbiome Modulates the Immune System to Influence Cancer Therapy

by Ruchi Roy and Sunil Kumar Singh

Cancers 2024, 16(4), 779; https://doi.org/10.3390/cancers16040779 - 14 Feb 2024

Cited by 7 | Viewed by 5361

Abstract

The gut microbiota composition can affect the tumor microenvironment and its interaction with the immune system, thereby having implications for treatment predictions. This article reviews the studies available to better understand how the gut microbiome helps the immune system fight cancer. To describe [...] Read more.

The gut microbiota composition can affect the tumor microenvironment and its interaction with the immune system, thereby having implications for treatment predictions. This article reviews the studies available to better understand how the gut microbiome helps the immune system fight cancer. To describe this fact, different mechanisms and approaches utilizing probiotics to improve advancements in cancer treatment will be discussed. Moreover, not only calorie intake but also the variety and quality of diet can influence cancer patients’ immunotherapy treatment because dietary patterns can impair immunological activities either by stimulating or suppressing innate and adaptive immunity. Therefore, it is interesting and critical to understand gut microbiome composition as a biomarker to predict cancer immunotherapy outcomes and responses. Here, more emphasis will be given to the recent development in immunotherapies utilizing microbiota to improve cancer therapies, which is beneficial for cancer patients. Full article

(This article belongs to the Special Issue Cancer Therapy: Where We Are and Where We Need to Go)

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17 pages, 704 KiB

Open AccessEditor’s ChoiceReview

Variant Allele Frequency Analysis of Circulating Tumor DNA as a Promising Tool in Assessing the Effectiveness of Treatment in Non-Small Cell Lung Carcinoma Patients

by Natalia Galant, Marcin Nicoś, Barbara Kuźnar-Kamińska and Paweł Krawczyk

Cancers 2024, 16(4), 782; https://doi.org/10.3390/cancers16040782 - 14 Feb 2024

Cited by 2 | Viewed by 7460

Abstract

Despite the different possible paths of treatment, lung cancer remains one of the leading causes of death in oncological patients. New tools guiding the therapeutic process are under scientific investigation, and one of the promising indicators of the effectiveness of therapy in patients [...] Read more.

Despite the different possible paths of treatment, lung cancer remains one of the leading causes of death in oncological patients. New tools guiding the therapeutic process are under scientific investigation, and one of the promising indicators of the effectiveness of therapy in patients with NSCLC is variant allele frequency (VAF) analysis. VAF is a metric characterized as the measurement of the specific variant allele proportion within a genomic locus, and it can be determined using methods based on NGS or PCR. It can be assessed using not only tissue samples but also ctDNA (circulating tumor DNA) isolated from liquid biopsy. The non-invasive characteristic of liquid biopsy enables a more frequent collection of material and increases the potential of VAF analysis in monitoring therapy. Several studies have been performed on patients with NSCLC to evaluate the possibility of VAF usage. The research carried out so far demonstrates that the evaluation of VAF dynamics may be useful in monitoring tumor progression, remission, and recurrence during or after treatment. Moreover, the use of VAF analysis appears to be beneficial in making treatment decisions. However, several issues require better understanding and standardization before VAF testing can be implemented in clinical practice. In this review, we discuss the difficulties in the application of ctDNA VAF analysis in clinical routine, discussing the diagnostic and methodological challenges in VAF measurement in liquid biopsy. We highlight the possible applications of VAF-based measurements that are under consideration in clinical trials in the monitoring of personalized treatments for patients with NSCLC. Full article

(This article belongs to the Special Issue Novel Biomarkers in Non-Small Cell Lung Cancer (NSCLC))

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12 pages, 1197 KiB

Open AccessEditor’s ChoiceArticle

Improved Accuracy and Sensitivity in Diagnosis and Staging of Lung Cancer with Systematic and Combined Endobronchial and Endoscopic Ultrasound (EBUS-EUS): Experience from a Tertiary Center

by Abdenor Badaoui, Marion De Wergifosse, Benoit Rondelet, Pierre H. Deprez, Claudia Stanciu-Pop, Laurent Bairy, Philippe Eucher, Monique Delos, Sebahat Ocak, Cédric Gillain, Fabrice Duplaquet and Lionel Pirard

Cancers 2024, 16(4), 728; https://doi.org/10.3390/cancers16040728 - 9 Feb 2024

Cited by 3 | Viewed by 3398

Abstract

Background: Combined endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound-guided tissue acquisition (EUS-TA) are accurate procedures for the diagnosis and staging of mediastinal lymph nodes (MLNs) in lung cancer. However, the respective contribution of separate and combined procedures in diagnosis and staging [...] Read more.

Background: Combined endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound-guided tissue acquisition (EUS-TA) are accurate procedures for the diagnosis and staging of mediastinal lymph nodes (MLNs) in lung cancer. However, the respective contribution of separate and combined procedures in diagnosis and staging has not been fully studied. The aim of this study was to assess their respective performances. Methods: Patients with suspected malignant MLNs in lung cancer or recurrence identified by PET-CT who underwent combined EBUS-TBNA and EUS-TA were retrospectively reviewed. Results: A total of 141 patients underwent both procedures. Correct diagnosis was obtained in 82% with EBUS-TBNA, 91% with EUS-TA, and 94% with the combined procedure. The overall sensitivity, specificity, and positive and negative predictive values (PPV and NPV) of EBUS-TBNA, EUS-TA, and the combined procedure for diagnosing malignancy were [75%, 100%, 100%, 58%], [87%, 100%, 100%, 75%], and [93%, 100%, 100%, 80%], respectively, with a significantly better sensitivity of the combined procedure (p < 0.0001). Staging (82/141 patients) was correctly assessed in 74% with EBUS-TBNA, 68% with EUS-TA, and 85% with the combined procedure. The overall sensitivity, specificity, PPV, and NPV of EBUS-TBNA, EUS-TA, and the combined procedure for lung cancer staging were [62%, 100%, 100%, 55%], [54%, 100%, 100%, 50%], and [79%, 100%, 100%, 68%], respectively, significantly better in terms of sensitivity for the combined procedure (p < 0.001). Conclusion: The combined EBUS-EUS approach in lung cancer patients showed better accuracy and sensitivity in diagnosis and staging when compared with EBUS-TBNA and EUS-TA alone. Full article

(This article belongs to the Special Issue Pulmonary Oncology Research)

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14 pages, 1677 KiB

Open AccessEditor’s ChoiceArticle

Comprehensive Landscape of BRAF Variant Classes, Clonalities, and Co-Mutations in Metastatic Colorectal Cancer Using ctDNA Profiling

by Benny Johnson, Van Morris, Xuemei Wang, Arvind Dasari, Kanwal Raghav, John Paul Shen, Michael S. Lee, Ryan Huey, Christine Parseghian, Jason Willis, Robert Wolff, Leylah M. Drusbosky, Michael J. Overman and Scott Kopetz

Cancers 2024, 16(4), 737; https://doi.org/10.3390/cancers16040737 - 9 Feb 2024

Cited by 1 | Viewed by 2616

Abstract

Although V600E accounts for the majority of the BRAF mutations in metastatic colorectal cancer (mCRC), non-V600 BRAF variants have been shown in recent years to represent a distinct molecular subtype. This study provides a comprehensive profile of BRAF variants in mCRC using a [...] Read more.

Although V600E accounts for the majority of the BRAF mutations in metastatic colorectal cancer (mCRC), non-V600 BRAF variants have been shown in recent years to represent a distinct molecular subtype. This study provides a comprehensive profile of BRAF variants in mCRC using a large genomic database of circulating tumor DNA (ctDNA) and analyzing clinical outcomes in a cohort of patients with atypical (non-V600) BRAF variants (aBRAF; class II, class III, unclassified). Overall, 1733 out of 14,742 mCRC patients in the ctDNA cohort had at least one BRAF variant. Patients with atypical BRAF variants tended to be younger and male. In contrast to BRAF^V600E, BRAF class II and III variants and their co-occurrence with KRAS/NRAS mutations were increased at baseline and especially with those patients predicted to have prior anti-EGFR exposure. Our clinical cohort included 38 patients with atypical BRAF mCRC treated at a large academic referral center. While there were no survival differences between atypical BRAF classes, concurrent RAS mutations or liver involvement was associated with poorer prognosis. Notably, patients younger than 50 years of age had extremely poor survival. In these patients, the high-frequency KRAS/NRAS co-mutation and its correlation with poorer prognosis underlines the urgent need for novel therapeutic strategies. This study represents one of the most comprehensive characterizations to date of atypical BRAF variants, utilizing both ctDNA and clinical cohorts. Full article

(This article belongs to the Collection Factors Regulating Cancer Cell Growth, Migration, Invasion, and Apoptosis)

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18 pages, 4831 KiB

Open AccessEditor’s ChoiceArticle

Global Burden of Pancreatic Cancer Attributable to High Body-Mass Index in 204 Countries and Territories, 1990–2019

by Irena Ilic and Milena Ilic

Cancers 2024, 16(4), 719; https://doi.org/10.3390/cancers16040719 - 8 Feb 2024

Cited by 3 | Viewed by 2814

Abstract

(1) Background: This study aimed to assess the global burden of pancreatic cancer attributable to a high BMI in 1990–2019. (2) Methods: An ecological study was carried out. Data about deaths and Disability-Adjusted Life Years (DALYs) for pancreatic cancer were extracted from the [...] Read more.

(1) Background: This study aimed to assess the global burden of pancreatic cancer attributable to a high BMI in 1990–2019. (2) Methods: An ecological study was carried out. Data about deaths and Disability-Adjusted Life Years (DALYs) for pancreatic cancer were extracted from the Global Burden of Disease (GBD) study. The age-standardized rates (ASRs, per 100,000) were presented. In order to determine trends of pancreatic cancer burden, joinpoint regression analysis was used to calculate the average annual percent change (AAPC). (3) Results: The highest ASRs of DALYs of pancreatic cancer were found in the United Arab Emirates (47.5 per 100,000), followed by countries with about 25.0 per 100,000 (such as Hungary, Czechia, and Montenegro). From 1990 to 2019, the ASRs of deaths and DALYs of pancreatic cancer attributable to a high BMI significantly increased (p < 0.001) for both sexes in all ages, and across all SDI quintiles and all GBD regions. The highest fraction of DALYs attributable to a high BMI was found in the United States of America and China (equally about 15.0%), followed by the Russian Federation, India, Germany, and Brazil (about 5.0%, equally). (4) Conclusions: Further analytical epidemiological studies are necessary to elucidate the relationship between pancreatic cancer and a high BMI. Full article

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

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12 pages, 243 KiB

Open AccessEditor’s ChoiceArticle

Extrahepatic Malignancies Are the Leading Cause of Death in Patients with Chronic Hepatitis B without Cirrhosis: A Large Population-Based Cohort Study

by Young Eun Chon, Sung Jun Park, Man Young Park, Yeonjung Ha, Joo Ho Lee, Kwan Sik Lee, Eileen L. Yoon and Dae Won Jun

Cancers 2024, 16(4), 711; https://doi.org/10.3390/cancers16040711 - 7 Feb 2024

Cited by 2 | Viewed by 1734

Abstract

(1) Background: Accurate statistics on the causes of death in patients with chronic hepatitis B (CHB) are lacking. We investigated mortality rates and causes of death over time. (2) Methods: Data on patients newly diagnosed with CHB from 2007 to 2010 (cohort 1, [...] Read more.

(1) Background: Accurate statistics on the causes of death in patients with chronic hepatitis B (CHB) are lacking. We investigated mortality rates and causes of death over time. (2) Methods: Data on patients newly diagnosed with CHB from 2007 to 2010 (cohort 1, n = 223,424) and 2012 to 2015 (cohort 2, n = 177,966) were retrieved from the Korean National Health Insurance Service. Mortality data were obtained from Statistics Korea. The causes of death were classified as liver-related (hepatic decompensation or hepatocellular carcinoma [HCC]) or extrahepatic (cardiovascular-related, cerebrovascular-related, or extrahepatic malignancy-related). (3) Results: Over a 10-year follow-up period of 223,424 patients (cohort 1) with CHB, the overall mortality was 1.54 per 100 person-years. The mortality associated with HCC was the highest (0.65 per 100 person-years), followed by mortality related to extrahepatic malignancies (0.26 per 100 person-years), and cardio/cerebrovascular diseases (0.18 per 100 person-years). In the non-cirrhotic CHB (87.4%), 70% (11,198/15,996) of patients died due to non-liver-related causes over ten years. The 10-year overall mortality was 0.86 per 100 person-years. Among these, mortality due to extrahepatic malignancies had the highest rate (0.23 per 100 person-years), followed by mortality related to HCC (0.20 per 100 person-years), and cardio/cerebrovascular diseases (0.16 per 100 person-years). The 5-year mortality associated with extrahepatic malignancies increased from 0.36 per 100 person-years (cohort 1) to 0.40 per 100 person-years (cohort 2). (4) Conclusions: Mortality related to HCC decreased, whereas mortality related to extrahepatic malignancies increased in the antiviral era. Extrahepatic malignancies were the leading cause of death among patients with CHB without cirrhosis. Full article

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

12 pages, 2196 KiB

Open AccessEditor’s ChoiceArticle

Hepatoblastoma Relapse—Findings from the German HB99 Trial and the German Liver Tumor Registry

by Rebecca Maxwell, Beate Häberle, Roland Kappler, Dietrich von Schweinitz, Mark Rassner, Julia von Frowein and Irene Schmid

Cancers 2024, 16(4), 696; https://doi.org/10.3390/cancers16040696 - 6 Feb 2024

Cited by 1 | Viewed by 2010

Abstract

Survival rates for HB patients have improved; however, outcomes for patients who relapse remain poor. A retrospective review of information gathered for the HB99 study and the German Liver Tumor Registry identified 25 relapse patients (6.9%, 25/362). The median time from initial diagnosis [...] Read more.

Survival rates for HB patients have improved; however, outcomes for patients who relapse remain poor. A retrospective review of information gathered for the HB99 study and the German Liver Tumor Registry identified 25 relapse patients (6.9%, 25/362). The median time from initial diagnosis to first relapse was 13 months (range: 5–66 months). Two patients relapsed >36 months after initial diagnosis. A total of 68% (17/25) of relapses were metastatic, 24% local, and 8% combined. 67% of local relapses were alive at the last follow-up, in contrast to 53% of metastatic and 0% of combined relapses. At the last follow-up, 73% (8/11) of patients with lung relapses were still alive (0/4 with peritoneal, 1/2 with CNS involvement). A total of 20% of the patients had AFP-negative relapses, 64% of the relapse patients achieved a second complete remission, 69% were still in complete second remission at the last follow-up (median FU of 66 months), and 83% (5/6) of irinotecan-naïve patients who received relapse treatment including irinotecan were in second complete remission at the last follow-up. The 3-year overall survival/event-free survival from relapse was 63%/48% respectively. There is a good chance that HB patients will achieve a second remission despite a first relapse. However, patients who suffer further relapses tend to have a poorer prognosis. Full article

(This article belongs to the Special Issue Hepatoblastoma and Pediatric Liver Tumors (Volume II))

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12 pages, 248 KiB

Open AccessEditor’s ChoiceReview

Oligometastasis of Gastric Cancer: A Review

by Itaru Yasufuku, Hiroshi Tsuchiya, Seito Fujibayashi, Naoki Okumura, Yuki Sengoku, Masahiro Fukada, Ryuichi Asai, Yuta Sato, Jesse Yu Tajima, Shigeru Kiyama, Takazumi Kato, Yoshihiro Tanaka, Katsutoshi Murase and Nobuhisa Matsuhashi

Cancers 2024, 16(3), 673; https://doi.org/10.3390/cancers16030673 - 5 Feb 2024

Cited by 7 | Viewed by 4235

Abstract

The concept of oligometastasis is not yet fully established in the field of gastric cancer. However, metastatic lesions that are localized, technically resectable at diagnosis, present a certain response to preoperative chemotherapy, and present favorable survival outcomes with local treatments, sometimes in combination [...] Read more.

The concept of oligometastasis is not yet fully established in the field of gastric cancer. However, metastatic lesions that are localized, technically resectable at diagnosis, present a certain response to preoperative chemotherapy, and present favorable survival outcomes with local treatments, sometimes in combination with chemotherapy, are recognized as oligometastasis in the field of gastric cancer. Oligometastasis is noted in European Society for Medical Oncology guidelines and Japanese gastric cancer treatment guidelines, and local treatment is mentioned as one of the pivotal treatment options for oligometastasis. Solitary liver metastasis or a small number of liver metastases; retroperitoneal lymph node metastasis, especially localized para-aortic lymph node metastasis; localized peritoneal dissemination; and Krukenberg tumor are representative types of oligometastasis in gastric cancer. The AIO-FLOT3 trial prospectively evaluated the efficacy of multimodal treatments for gastric cancer with oligometastasis, including surgical resection of primary and metastatic lesions combined with chemotherapy, confirming favorable survival outcomes. Two phase 3 studies are ongoing to investigate the efficacy of surgical resection combined with perioperative chemotherapy compared with palliative chemotherapy. Thus far, the evidence suggests that multimodal treatment for oligometastasis of gastric cancer is promising. Full article

(This article belongs to the Special Issue New Insights into Oligo-Recurrence of Various Cancers)

23 pages, 1652 KiB

Open AccessEditor’s ChoiceReview

Management of Hepatocellular Carcinoma in 2024: The Multidisciplinary Paradigm in an Evolving Treatment Landscape

by Emily Kinsey and Hannah M. Lee

Cancers 2024, 16(3), 666; https://doi.org/10.3390/cancers16030666 - 4 Feb 2024

Cited by 35 | Viewed by 10798

Abstract

Liver cancer is the third most common cause of cancer-related deaths worldwide, and hepatocellular carcinoma (HCC) makes up the majority of liver cancer cases. Despite the stabilization of incidence rates in recent years due to effective viral hepatitis treatments, as well as improved [...] Read more.

Liver cancer is the third most common cause of cancer-related deaths worldwide, and hepatocellular carcinoma (HCC) makes up the majority of liver cancer cases. Despite the stabilization of incidence rates in recent years due to effective viral hepatitis treatments, as well as improved outcomes from early detection and treatment advances, the burden of HCC is anticipated to rise again due to increasing rates of metabolic dysfunction-associated steatotic liver disease and alcohol-related liver disease. The treatment landscape is evolving and requires a multidisciplinary approach, often involving multi-modal treatments that include surgical resection, transplantation, local regional therapies, and systemic treatments. The optimal approach to the care of the HCC patient requires a multidisciplinary team involving hepatology, medical oncology, diagnostic and interventional radiology, radiation oncology, and surgery. In order to determine which approach is best, an individualized treatment plan should consider the patient’s liver function, functional status, comorbidities, cancer stage, and preferences. In this review, we provide an overview of the current treatment options and key trials that have revolutionized the management of HCC. We also discuss evolving treatment paradigms for the future. Full article

(This article belongs to the Special Issue New Insights on Therapy in Hepatocellular Carcinoma)

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29 pages, 3322 KiB

Open AccessEditor’s ChoiceReview

Chimeric Antigen Receptor T Cell and Chimeric Antigen Receptor NK Cell Therapy in Pediatric and Adult High-Grade Glioma—Recent Advances

by Adrian Kowalczyk, Julia Zarychta, Anna Marszołek, Joanna Zawitkowska and Monika Lejman

Cancers 2024, 16(3), 623; https://doi.org/10.3390/cancers16030623 - 31 Jan 2024

Cited by 7 | Viewed by 3313

Abstract

High-grade gliomas (HGG) account for approximately 10% of central nervous system (CNS) tumors in children and 25% of CNS tumors in adults. Despite their rare occurrence, HGG are a significant clinical problem. The standard therapeutic procedure in both pediatric and adult patients with [...] Read more.

High-grade gliomas (HGG) account for approximately 10% of central nervous system (CNS) tumors in children and 25% of CNS tumors in adults. Despite their rare occurrence, HGG are a significant clinical problem. The standard therapeutic procedure in both pediatric and adult patients with HGG is the surgical resection of the tumor combined with chemotherapy and radiotherapy. Despite intensive treatment, the 5-year overall survival in pediatric patients is below 20–30%. This rate is even lower for the most common HGG in adults (glioblastoma), at less than 5%. It is, therefore, essential to search for new therapeutic methods that can extend the survival rate. One of the therapeutic options is the use of immune cells (T lymphocytes/natural killer (NK) cells) expressing a chimeric antigen receptor (CAR). The objective of the following review is to present the latest results of preclinical and clinical studies evaluating the efficacy of CAR-T and CAR-NK cells in HGG therapy. Full article

(This article belongs to the Special Issue Targeting the Tumor Microenvironment (Volume II))

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15 pages, 1017 KiB

Open AccessEditor’s ChoiceArticle

Severe Acute Kidney Injury in Hospitalized Cancer Patients: Epidemiology and Predictive Model of Renal Replacement Therapy and In-Hospital Mortality

by Roberto Calças Marques, Marina Reis, Gonçalo Pimenta, Inês Sala, Teresa Chuva, Inês Coelho, Hugo Ferreira, Ana Paiva and José Maximino Costa

Cancers 2024, 16(3), 561; https://doi.org/10.3390/cancers16030561 - 28 Jan 2024

Cited by 5 | Viewed by 2588

Abstract

Background: Acute kidney injury (AKI) is a common complication among cancer patients, often leading to longer hospital stays, discontinuation of cancer treatment, and a poor prognosis. This study aims to provide insight into the incidence of severe AKI in this population and identify [...] Read more.

Background: Acute kidney injury (AKI) is a common complication among cancer patients, often leading to longer hospital stays, discontinuation of cancer treatment, and a poor prognosis. This study aims to provide insight into the incidence of severe AKI in this population and identify the risk factors associated with renal replacement therapy (RRT) and in-hospital mortality. Methods: This retrospective cohort study included 3201 patients with cancer and severe AKI admitted to a Comprehensive Cancer Center between January 1995 and July 2023. Severe AKI was defined according to the KDIGO guidelines as grade ≥ 2 AKI with nephrological in-hospital follow-up. Data were analyzed in two timelines: Period A (1995–2010) and Period B (2011–2023). Results: A total of 3201 patients (1% of all hospitalized cases) were included, with a mean age of 62.5 ± 17.2 years. Solid tumors represented 75% of all neoplasms, showing an increasing tendency, while hematological cancer decreased. Obstructive AKI declined, whereas the incidence of sepsis-associated, prerenal, and drug-induced AKI increased. Overall, 20% of patients required RRT, and 26.4% died during hospitalization. A predictive model for RRT (AUC 0.833 [95% CI 0.817–0.848]) identified sepsis and hematological cancer as risk factors and prerenal and obstructive AKI as protective factors. A similar model for overall in-hospital mortality (AUC 0.731 [95% CI 0.71–0.752]) revealed invasive mechanical ventilation (IMV), sepsis, and RRT as risk factors and obstructive AKI as a protective factor. The model for hemato-oncological patients’ mortality (AUC 0.832 [95% CI 0.803–0.861]) included IMV, sepsis, hematopoietic stem cell transplantation, and drug-induced AKI. Mortality risk point score models were derived from these analyses. Conclusions: This study addresses the demographic and clinical features of cancer patients with severe AKI. The development of predictive models for RRT and in-hospital mortality, along with risk point scores, may play a role in the management of this population. Full article

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

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