Cancers

Article

27 pages, 15911 KiB

Open AccessEditor’s ChoiceArticle

Pro-Inflammatory Cytokines Transactivate Glycosylated Cytokine Receptors on Cancer Cells to Induce Epithelial–Mesenchymal Transition to the Metastatic Phenotype

by Leili Baghaie, David A. Bunsick, Emilyn B. Aucoin, Elizabeth Skapinker, Abdulrahman M. Yaish, Yunfan Li, William W. Harless and Myron R. Szewczuk

Cancers 2025, 17(7), 1234; https://doi.org/10.3390/cancers17071234 - 5 Apr 2025

Cited by 1 | Viewed by 788

Abstract

Background/Objectives: The significance of cytokine signaling on cancer progression and metastasis has raised interest in cancer research over the last few decades. Here, we analyzed the effects of three cytokines that we previously reported are significantly upregulated rapidly after the surgical removal of [...] Read more.

Background/Objectives: The significance of cytokine signaling on cancer progression and metastasis has raised interest in cancer research over the last few decades. Here, we analyzed the effects of three cytokines that we previously reported are significantly upregulated rapidly after the surgical removal of primary breast, colorectal, and prostate cancer. We also investigated the regulation of their cognate receptors. Methods: All experiments were conducted using the PANC-1, SW620, and MCF-7 cell lines, treated with three different cytokines (TGF-β1, HGF, and IL-6). The effect of these cytokines on the expression of epithelial–mesenchymal transition (EMT) cell surface markers and neuraminidase-1 activity was measured via fluorescent microscopy and image analysis software. Results: The findings show that these cytokines increase the expression of mesenchymal markers while reducing epithelial markers, corresponding to the EMT process. A strong link between cytokine receptor signaling and the Neu-1-MMP-9-GPCR crosstalk was identified, suggesting that cytokine receptor binding leads to increased Neu-1 activity and subsequent signaling pathway activation. Oseltamivir phosphate (OP) prevented sialic acid hydrolysis by neuraminidase-1 (Neu-1), leading to the downregulation of these signaling cascades. Conclusions: In concert with the previous work revealing the role of Neu-1 in regulating other glycosylated receptors implicated in cancer cell proliferation and EMT, targeting Neu-1 may provide effective treatment against a variety of malignancies. Most significantly, the treatment of patients with specific inhibitors of Neu-1 soon after primary cancer surgery may improve our ability to cure early-stage cancer by inhibiting the EMT process and disrupting the ability of any residual cancer cell population to metastasize. Full article

(This article belongs to the Special Issue Role of Cytokines in Cancer)

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17 pages, 3414 KiB

Open AccessEditor’s ChoiceArticle

TLR2-Bound Cancer-Secreted Hsp70 Induces MerTK-Mediated Immunosuppression and Tumorigenesis in Solid Tumors

by Ahmet Kaynak, Subrahmanya D. Vallabhapurapu, Harold W. Davis, Eric P. Smith, Petr Muller, Borek Vojtesek, Robert S. Franco, Wen-Hai Shao and Xiaoyang Qi

Cancers 2025, 17(3), 450; https://doi.org/10.3390/cancers17030450 - 28 Jan 2025

Cited by 2 | Viewed by 1423

Abstract

Background: A hallmark of cancer is the presence of an immunosuppressive tumor microenvironment (TME). Immunosuppressive M2 macrophages (MΦs) in the TME facilitate escape from immune surveillance and promote tumor growth; therefore, TME-induced immunosuppression is a potent immunotherapeutic approach to treating cancer. Methods [...] Read more.

Background: A hallmark of cancer is the presence of an immunosuppressive tumor microenvironment (TME). Immunosuppressive M2 macrophages (MΦs) in the TME facilitate escape from immune surveillance and promote tumor growth; therefore, TME-induced immunosuppression is a potent immunotherapeutic approach to treating cancer. Methods: Cancer cell-secreted proteins were detected by using liquid chromatography–mass spectrometry (LC-MS). Neutralizing antibodies (nAbs) were used to assess which proteins were involved in MΦs polarization and differentiation. The protein–protein interaction was characterized using co-immunoprecipitation and immunofluorescence assays. Cancer-secreted heat shock protein 70 (Hsp70) protein was quantified using an enzyme-linked immunosorbent assay (ELISA). MΦ polarization and tumor growth were assessed in vivo with subcutaneous LLC-GFP tumor models and toll-like receptor 2 (TLR2) knockout mice; in vitro assessments were conducted using TLR2 knockout and both LLC-GFP and LN227 lentiviral-mediated knockdown (KD) cells. Results: Cancer cells released a secreted form of Hsp70 that acted on MΦ TLR2 to upregulate Mer receptor tyrosine kinase (MerTK) and induce MΦ M2 polarization. Hsp70 nAbs led to a reduction in CD14 expression by 75% in THP-1 cells in response to Gli36 EMD-CM. In addition, neutralizing TLR2 nAbs resulted in a 30% and 50% reduction in CD14 expression on THP-1 cells in response to MiaPaCa-2 and Gli36 exosome/microparticle-depleted conditioned media (EMD-CMs), respectively. Hsp70, TLR2, and MerTK formed a protein complex. Tumor growth and intra-tumor M2 MΦs were significantly reduced upon cancer cell Hsp70 knockdown and in TLR2 knockout mice. Conclusions: Cancer-secreted Hsp70 interacts with TLR2, upregulates MerTK on MΦs, and induces immunosuppressive MΦ M2 polarization. This previously unreported action of secreted Hsp70 suggests that disrupting the Hsp70-TLR2-MerTK interaction could serve as a promising immunotherapeutic approach to mitigate TME immunosuppression in solid cancers. Full article

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

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12 pages, 1306 KiB

Open AccessEditor’s ChoiceArticle

Comprehensive Molecular Profiling of Metastatic Pancreatic Adenocarcinomas

by Vijay Antony, Tong Sun, Darin Dolezal and Guoping Cai

Cancers 2025, 17(3), 335; https://doi.org/10.3390/cancers17030335 - 21 Jan 2025

Cited by 1 | Viewed by 1387

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed late, with an extremely poor prognosis. Treatment options like surgery, radiation, and chemotherapy are rarely curative. Tumor progression from primary to metastatic PDAC remains poorly understood at the molecular level. Methods: In the current study, [...] Read more.

Background: Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed late, with an extremely poor prognosis. Treatment options like surgery, radiation, and chemotherapy are rarely curative. Tumor progression from primary to metastatic PDAC remains poorly understood at the molecular level. Methods: In the current study, we analyzed the molecular profiles of metastatic PDAC obtained via the Oncomine Comprehensive Assay in comparison to primary PDAC. Results: The current study cohort consisted of 115 metastatic PDAC cases, of which 71 (62%) cases succeeded in molecular testing while the remaining 44 (38%) cases contained insufficient tumor cells. Molecular profiling of 71 cases revealed a total of 239 molecular alterations, 3.4 alterations per case on average, predominantly in the form of gene mutations. The most common gene mutations included KRAS (86%) and TP53 (83%) mutations. Gene copy number alterations were also detected in 19 (27%) cases involving genes such as CCNE1 and ERBB2. Compared to the molecular profiles of primary PDAC reported in our prior study and TCGA database, there seemed to be increased rates of TP53, ARID1A, BRAF, and PIK3CA mutations in the metastatic diseases. Conclusions: These findings suggest that metastatic PDAC possesses unique genetic characteristics, offering potential therapeutic targets in advanced-stage pancreatic cancer. Full article

(This article belongs to the Special Issue Histology and Pathology of Pancreatic Cancer)

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20 pages, 2716 KiB

Open AccessEditor’s ChoiceArticle

Machine Learning and Computed Tomography Radiomics to Predict Disease Progression to Upfront Pembrolizumab Monotherapy in Advanced Non-Small-Cell Lung Cancer: A Pilot Study

by Ian Janzen, Cheryl Ho, Barbara Melosky, Qian Ye, Jessica Li, Gang Wang, Stephen Lam, Calum MacAulay and Ren Yuan

Cancers 2025, 17(1), 58; https://doi.org/10.3390/cancers17010058 - 28 Dec 2024

Cited by 2 | Viewed by 2203

Abstract

Background/Objectives: Pembrolizumab monotherapy is approved in Canada for first-line treatment of advanced NSCLC with PD-L1 ≥ 50% and no EGFR/ALK aberrations. However, approximately 55% of these patients do not respond to pembrolizumab, underscoring the need for the early intervention of non-responders to optimize [...] Read more.

Background/Objectives: Pembrolizumab monotherapy is approved in Canada for first-line treatment of advanced NSCLC with PD-L1 ≥ 50% and no EGFR/ALK aberrations. However, approximately 55% of these patients do not respond to pembrolizumab, underscoring the need for the early intervention of non-responders to optimize treatment strategies. Distinguishing the 55% sub-cohort prior to treatment is a real-world dilemma. Methods: In this retrospective study, we analyzed two patient cohorts treated with pembrolizumab monotherapy (training set: n = 97; test set: n = 17). The treatment response was assessed using baseline and follow-up CT scans via RECIST 1.1 criteria. Results: A logistic regression model, incorporating pre-treatment CT radiomic features of lung tumors and clinical variables, achieved high predictive accuracy (AUC: 0.85 in training; 0.81 in testing, 95% CI: 0.63–0.99). Notably, radiomic features from the peritumoral region were found to be independent predictors, complementing the standard CT evaluations and other clinical characteristics. Conclusions: This pragmatic model offers a valuable tool to guide first-line treatment decisions in NSCLC patients with high PD-L1 expression and has the potential to advance personalized oncology and improve timely disease management. Full article

(This article belongs to the Special Issue Advances in Oncological Imaging)

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24 pages, 1923 KiB

Open AccessEditor’s ChoiceArticle

Predictive Mortality and Gastric Cancer Risk Using Clinical and Socio-Economic Data: A Nationwide Multicenter Cohort Study

by Seong Uk Kang, Seung-Joo Nam, Oh Beom Kwon, Inhyeok Yim, Tae-Hoon Kim, Na Young Yeo, Myoung Nam Lim, Woo Jin Kim and Sang Won Park

Cancers 2025, 17(1), 30; https://doi.org/10.3390/cancers17010030 - 25 Dec 2024

Cited by 1 | Viewed by 1359

Abstract

Background/Objectives: Gastric cancer is a leading cause of cancer-related mortality, particularly in East Asia, with a notable burden in Republic of Korea. This study aimed to construct and develop machine learning models for the prediction of gastric cancer mortality and the identification of [...] Read more.

Background/Objectives: Gastric cancer is a leading cause of cancer-related mortality, particularly in East Asia, with a notable burden in Republic of Korea. This study aimed to construct and develop machine learning models for the prediction of gastric cancer mortality and the identification of risk factors. Methods: All data were acquired from the Korean Clinical Data Utilization for Research Excellence by multiple medical centers in South Korea. A total of 23,717 gastric cancer patients were divided into two groups by cause of mortality (all-cause of 2664 and disease-specific of 1620) and investigated. We used comprehensive data integrating clinical, pathological, lifestyle, and socio-economic factors. Cox proportional hazards analysis was conducted to estimate hazard ratios for mortality. Five machine learning models (random forest, gradient boosting machine, XGBoost, light GBM, and cat boosting) were developed to predict mortality. The models were interpreted by SHAP, one of the explainable AI techniques. Results: For all-cause mortality, the gradient-boosting machine learning model demonstrated the highest performance with an AUC-ROC of 0.795. For disease-specific mortality, the light GBM model outperformed others, achieving an AUC-ROC of 0.867. Significant predictors included the AJCC7 stage, tumor size, lymph node count, and lifestyle factors such as smoking, drinking, and diabetes. Conclusions: This study underscores the importance of integrating both clinical and lifestyle data to enhance mortality prediction accuracy in gastric cancer patients. The findings highlight the need for personalized treatment approaches in the Korean population and emphasize the role of demographic-specific data in predictive modeling. Full article

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

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19 pages, 2052 KiB

Open AccessEditor’s ChoiceArticle

Uterine Carcinosarcoma (UCS): A Literature Review and Survival Analysis from a Retrospective Cohort Study

by Mauro Francesco Pio Maiorano, Gennaro Cormio, Brigida Anna Maiorano and Vera Loizzi

Cancers 2024, 16(23), 3905; https://doi.org/10.3390/cancers16233905 - 21 Nov 2024

Cited by 3 | Viewed by 2168

Abstract

Background/Objectives: Uterine carcinosarcomas (UCSs) are rare and aggressive malignancies with limited epidemiological data. This study aims to evaluate the clinical and pathological features and prognostic factors of UCS in a retrospective cohort of 80 patients, contributing to improved management strategies. Methods: We conducted [...] Read more.

Background/Objectives: Uterine carcinosarcomas (UCSs) are rare and aggressive malignancies with limited epidemiological data. This study aims to evaluate the clinical and pathological features and prognostic factors of UCS in a retrospective cohort of 80 patients, contributing to improved management strategies. Methods: We conducted a retrospective analysis of UCS cases treated from 1995 to 2024 at three institutions. Data on demographics, clinical features, histopathology, treatment, and outcomes were collected. Overall survival (OS) and prognostic factors were assessed using Kaplan–Meier and Cox proportional hazards regression analyses. Results: The median age of patients was 66 years, with a median overall survival of 34.5 months. Disease recurrence occurred in 32.5% of cases, with a median disease-free interval of 17.92 months. Age, tumour stage, and size emerged as significant predictors of survival. Stage I–II patients had a significantly better prognosis than those with Stage III–IV (HR = 0.438, p = 0.008). Tumour size >4 cm was associated with increased mortality (HR = 2.154, p = 0.019). Lymphadenectomy was not independently associated with improved survival. Adjuvant chemotherapy, mainly carboplatin and paclitaxel, was administered to 67.5% of patients, achieving a complete response in 66.67%. Conclusions: Tumour stage and age are significant independent predictors of survival in UCS, underscoring the need for early diagnosis and intervention. Tumour size is also crucial in determining prognosis. The role of lymphadenectomy remains uncertain, emphasizing the importance of individualized treatment approaches. Future research should explore molecular profiling to further refine prognostication and therapeutic strategies for this challenging malignancy. Full article

(This article belongs to the Section Molecular Cancer Biology)

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16 pages, 21457 KiB

Open AccessEditor’s ChoiceArticle

Virtual Tumor Mapping: A New Standard for Surgeon–Pathologist Collaboration in Treating Oral Squamous Cell Carcinoma

by Adam Michcik, Maksym Jopek, Rafał Pęksa, Piotr Choma, Łukasz Garbacewicz, Adam Polcyn, Tomasz Wach, Maciej Sikora and Barbara Drogoszewska

Cancers 2024, 16(22), 3761; https://doi.org/10.3390/cancers16223761 - 7 Nov 2024

Cited by 1 | Viewed by 1282

Abstract

Background: The histopathological assessment is critical in the comprehensive treatment process for patients diagnosed with oral squamous cell carcinoma (OSCC). A detailed and precise specimen characterization is essential to facilitate effective surgeon–pathologist communication. Methods: In response to this need, a user-friendly virtual communication [...] Read more.

Background: The histopathological assessment is critical in the comprehensive treatment process for patients diagnosed with oral squamous cell carcinoma (OSCC). A detailed and precise specimen characterization is essential to facilitate effective surgeon–pathologist communication. Methods: In response to this need, a user-friendly virtual communication protocol utilizing a 3D scanner has been developed. This study involved 50 patients with OSCC, whose resected tumors were directly scanned in the operating room and subsequently annotated and characterized using available software. Results: The direct application of annotations and descriptions onto the virtual tumor specimens significantly enhanced the quantity and accuracy of information conveyed to the pathologist. Conclusions: The proposed solution’s repeatability and standardized approach make integration into routine clinical practice feasible, thereby establishing a potential new standard in the field. Full article

(This article belongs to the Special Issue Recent Studies on Oral Cancer: Diagnostic Technologies, Pathology, and Surgery)

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17 pages, 9029 KiB

Open AccessEditor’s ChoiceArticle

Genome-Wide CRISPR Screen Identifies Genes Involved in Metastasis of Pancreatic Ductal Adenocarcinoma

by Risky Oktriani, Anna Chiara Pirona, Lili Kalmár, Ariani S. Rahadian, Beiping Miao, Andrea S. Bauer, Jörg D. Hoheisel, Michael Boettcher and Haoqi Du

Cancers 2024, 16(21), 3684; https://doi.org/10.3390/cancers16213684 - 31 Oct 2024

Cited by 2 | Viewed by 2096

Abstract

Background/Objectives: Early and aggressive metastasis is a major feature of pancreatic ductal adenocarcinoma. Understanding the processes underlying metastasis is crucial for making a difference to disease outcome. Towards these ends, we looked in a comprehensive manner for genes that are metastasis-specific. Methods [...] Read more.

Background/Objectives: Early and aggressive metastasis is a major feature of pancreatic ductal adenocarcinoma. Understanding the processes underlying metastasis is crucial for making a difference to disease outcome. Towards these ends, we looked in a comprehensive manner for genes that are metastasis-specific. Methods: A genome-wide CRISPR-Cas9 gene knockout screen with 259,900 single guide RNA constructs was performed on pancreatic cancer cell lines with very high or very low metastatic capacity, respectively. Functional aspects of some of the identified genes were analysed in vitro. The injection of tumour cells with or without a gene knockout into mice was used to confirm the effect on metastasis. Results: The knockout of 590 genes—and, with higher analysis stringency, 67 genes—affected the viability of metastatic cells substantially, while these genes were not vital to non-metastasizing cells. Further evaluations identified different molecular processes related to this observation. One of the genes was MYBL2, encoding for a well-known transcription factor involved in the regulation of cell survival, proliferation, and differentiation in cancer tissues. In our metastasis-focussed study, no novel functional activity was detected for MYBL2, however. Instead, a metastasis-specific transformation of its genetic interaction with FOXM1 was observed. The interaction was synergistic in cells of low metastatic capacity, while there was a strong switch to a buffering mode in metastatic cells. In vivo analyses confirmed the strong effect of MYBL2 on metastasis. Conclusions: The genes found to be critical for the viability of metastatic cells form a basis for further investigations of the processes responsible for triggering and driving metastasis. As shown for MYBL2, unexpected processes of regulating metastasis might also be involved. Full article

(This article belongs to the Section Cancer Metastasis)

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15 pages, 1992 KiB

Open AccessEditor’s ChoiceArticle

Effect of Fluorescence Lymph Node Mapping on Improving Diagnostic Values of CT D3 Lymph Node Staging for Right-Sided Colon Cancer

by Gyung Mo Son, Tae Un Kim, Mi Sook Yun, ChangYeop Kim, In Young Lee, Su Bum Park, Dong-Hoon Shin and Gi Won Ha

Cancers 2024, 16(20), 3496; https://doi.org/10.3390/cancers16203496 - 16 Oct 2024

Cited by 3 | Viewed by 1376

Abstract

Background/Objectives: This study evaluated the impact of fluorescence lymph node mapping (FLNM) using indocyanine green (ICG) on the diagnostic accuracy of preoperative computed tomography (CT) in right-sided colon cancer. Methods: A total of 218 patients who underwent laparoscopic right hemicolectomy with D3 lymph [...] Read more.

Background/Objectives: This study evaluated the impact of fluorescence lymph node mapping (FLNM) using indocyanine green (ICG) on the diagnostic accuracy of preoperative computed tomography (CT) in right-sided colon cancer. Methods: A total of 218 patients who underwent laparoscopic right hemicolectomy with D3 lymph node dissection (LND) were analyzed: 86 patients in the FLNM group and 132 in the conventional surgery group. The FLNM technique allowed for enhanced intraoperative visualization of lymph node (LN) and more precise dissection, improving the identification of metastatic LNs. The diagnostic value of preoperative CT staging was assessed in both the FLNM and control groups by calculating the apparent prevalence, true prevalence, sensitivity, specificity, positive predictive value (PPV), negative predictive value, positive likelihood ratio (PLR), negative likelihood ratio, false positive and false negative proportions, and accuracy. Results: FLNM increased the accuracy of CT staging for detecting D3 LN metastasis in advanced cancer cases, with a higher PPV, PLR, and accuracy. In the FLNM group, the false-positive rate was significantly reduced, and the specificity was higher compared to the control group. Multivariate analysis identified FLNM as an independent factor associated with improved D3 LN metastasis detection. These findings suggest that incorporating FLNM into surgical procedures enhances the diagnostic value of preoperative CT by improving the precision of LND, particularly in patients with advanced colon cancer. Conclusions: The use of FLNM for D3 LND enhances the diagnostic accuracy of cN staging in right-sided colon cancer by improving surgical precision. Full article

(This article belongs to the Special Issue The Surgical Management of Colorectal Cancer)

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24 pages, 5399 KiB

Open AccessEditor’s ChoiceArticle

Whole Exome Sequencing of Intracranial Epidermoid Cysts Reveals Immune-Associated Mechanistic and Potential Targets

by Shruthi Kondaboina, Oscar Parrish, Carolina Angelica Parada and Manuel Ferreira, Jr.

Cancers 2024, 16(20), 3487; https://doi.org/10.3390/cancers16203487 - 15 Oct 2024

Cited by 2 | Viewed by 1750

Abstract

Background/Objectives: Intracranial Epidermoid Cysts (IECs) are rare intracranial tumors primarily treated through surgery. Cyst adherence complicates complete removal, leading to high rates of tumor progression after subtotal resection. The molecular drivers of IEC remain unknown. Consequently, advances in treatment have fallen short. Tumor [...] Read more.

Background/Objectives: Intracranial Epidermoid Cysts (IECs) are rare intracranial tumors primarily treated through surgery. Cyst adherence complicates complete removal, leading to high rates of tumor progression after subtotal resection. The molecular drivers of IEC remain unknown. Consequently, advances in treatment have fallen short. Tumor genetic profiling has revealed potential targets for drug development, including FDA-approved options and reshaping treatment. The genetic landscape of IECs has not been explored. We applied Whole Exome Sequencing (WES) to IECs to gain insights into the mechanisms of oncogenesis and identify potential therapeutic targets. Methods: We performed WES on tumor tissue and matched blood samples, when available. Following GATK best practices, we conducted read processing, quality control, somatic variant calling, and copy-number inference. Data analyses and visualization were conducted in R. Results: Top altered genes are associated with the immune system and tumor microenvironment, suggesting a mechanism of immune evasion. Gene and pathway enrichment revealed a high mutation burden in genes associated with Extracellular Matrix (ECM) and PI3K-AKT-mTOR cascades. Recurrent and deleterious alterations in NOTCH2 and USP8 were identified in 50% and 30% of the cohort, respectively. Frequent amplifications in deubiquitinases and beta-defensins strengthened the involvement of immune mechanisms for oncogenic transformation. Conclusions: Top altered genes and recurrent mutations may play a role in shaping the microenvironment and modulating immune evasion in IECs. USP8 and NOTCH2 may serve as clinically relevant target for IECs. Finally, we present evidence that the crosstalk between the PI3K-Akt-mTOR and ECM signaling pathways may play a role in modulating the immune escape mechanism in IECs. Full article

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

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10 pages, 1838 KiB

Open AccessEditor’s ChoiceArticle

Examination of Sarcopenia with Obesity as a Prognostic Factor in Patients with Colorectal Cancer Using the Psoas Muscle Mass Index

by Kengo Haruna, Soichiro Minami, Norikatsu Miyoshi, Shiki Fujino, Rie Mizumoto, Yuki Toyoda, Rie Hayashi, Shinya Kato, Mitsunobu Takeda, Yuki Sekido, Tsuyoshi Hata, Atsushi Hamabe, Takayuki Ogino, Hidekazu Takahashi, Mamoru Uemura, Hirofumi Yamamoto, Yuichiro Doki and Hidetoshi Eguchi

Cancers 2024, 16(19), 3429; https://doi.org/10.3390/cancers16193429 - 9 Oct 2024

Cited by 1 | Viewed by 1809

Abstract

Background: Sarcopenia, the age-related loss of muscle mass, is a negative prognostic factor in gastrointestinal cancer. Sarcopenia combined with visceral obesity (sarcopenic obesity) is associated with poor outcomes. We explored the influence of obesity and other factors on the prognosis of patients [...] Read more.

Background: Sarcopenia, the age-related loss of muscle mass, is a negative prognostic factor in gastrointestinal cancer. Sarcopenia combined with visceral obesity (sarcopenic obesity) is associated with poor outcomes. We explored the influence of obesity and other factors on the prognosis of patients with colorectal cancer diagnosed with sarcopenia. Methods: We enrolled 211 patients with colorectal cancer diagnosed with preoperative sarcopenic obesity who underwent radical resection at Osaka University Hospital between January 2009 and January 2012. Muscle mass was assessed using the psoas muscle mass index. Obesity was evaluated by measuring the visceral fat area in the umbilical region. Patients were categorized into two groups: sarcopenia with obesity (SO) and sarcopenia without obesity (non-SO). Overall survival, cancer-specific survival, and cancer-related relapse-free survival (CRRFS) were compared between the two groups. Patient characteristics, including age, sex, body mass index, serum albumin, C-reactive protein, tumor markers, prognostic nutritional index (PNI), modified Glasgow prognostic score (mGPS), and geriatric nutritional risk index (GNRI), were also analyzed. Results: CRRFS was significantly shorter in the SO group than in the non-SO group (p = 0.028). PNI, mGPS, and GNRI were not identified as significant prognostic factors for CRRFS. Multivariate analysis highlighted sarcopenic obesity, elevated carcinoembryonic antigen levels, and unfavorable histological types as significant predictors of poor CRRFS outcomes. Conclusions: Sarcopenic obesity is an independent predictor of poor prognosis in patients with CRC. Thus, interventions aimed at increasing muscle mass and reducing visceral fat could potentially improve the prognosis of these patients. Full article

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

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17 pages, 2928 KiB

Open AccessEditor’s ChoiceArticle

A Novel Chimeric Oncolytic Virus Mediates a Multifaceted Cellular Immune Response in a Syngeneic B16 Melanoma Model

by Sonja Glauß, Victoria Neumeyer, Lorenz Hanesch, Janina Marek, Nina Hartmann, Gabriela M. Wiedemann and Jennifer Altomonte

Cancers 2024, 16(19), 3405; https://doi.org/10.3390/cancers16193405 - 6 Oct 2024

Cited by 3 | Viewed by 2058

Abstract

Background/Objectives: Oncolytic virotherapy is a promising approach in cancer immunotherapy. We have previously described a recombinant hybrid oncolytic virus (OV), VSV-NDV, which has a favorable safety profile and therapeutic immunogenicity, leading to direct oncolysis, abscopal effects, and prolonged survival in syngeneic in vivo [...] Read more.

Background/Objectives: Oncolytic virotherapy is a promising approach in cancer immunotherapy. We have previously described a recombinant hybrid oncolytic virus (OV), VSV-NDV, which has a favorable safety profile and therapeutic immunogenicity, leading to direct oncolysis, abscopal effects, and prolonged survival in syngeneic in vivo tumor models. While OVs are known to mediate systemic anti-tumor immune responses, the detailed characterization of local and systemic immune responses to fusogenic oncolytic virotherapy remains unexplored. Methods and Results: We analyzed immune cell compartments in the spleen, blood, tumor-draining lymph nodes (TDLNs), and tumors over the course of VSV-NDV therapy in a bilateral syngeneic melanoma mouse model. Our results revealed significant local infiltration and activation of T lymphocytes in tumors and globally in the blood and spleen. Notably, in vivo CD8⁺ T cell depletion led to complete abrogation of the tumor response, highlighting the crucial role of T cells in promoting the therapeutic effects of oncolytic VSV-NDV. In vitro co-culture experiments enabled the interrogation of human immune cell responses to VSV-NDV-mediated oncolysis. Human peripheral blood mononuclear cells (PBMCs) were efficiently stimulated by exposure to VSV-NDV-infected cancer cells, which recapitulates the in vivo murine findings. Conclusions: Taken together, these data characterize a broad anti-tumor immune cell response to oncolytic VSV-NDV therapy and suggest that CD8⁺ T cells play a decisive role in therapeutic outcome, which supports the further development of this chimeric vector as a multimechanistic immunotherapy for solid cancers. Full article

(This article belongs to the Special Issue Oncolytic Viruses as an Emerging Aspect of Immune Oncology)

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17 pages, 1234 KiB

Open AccessEditor’s ChoiceArticle

The Prognostic Impact of HER2-Low and Menopausal Status in Triple-Negative Breast Cancer

by Woong Ki Park, Seok Jin Nam, Seok Won Kim, Jeong Eon Lee, Jonghan Yu, Se Kyung Lee, Jai Min Ryu and Byung Joo Chae

Cancers 2024, 16(14), 2566; https://doi.org/10.3390/cancers16142566 - 17 Jul 2024

Cited by 2 | Viewed by 2244

Abstract

TNBC is noted for its aggressive behavior and poor prognosis. Recently developed HER2 target agents have shown potential benefit even in HER2-low expressing breast cancers. This study retrospectively analyzed 2542 non-metastatic TNBC patients from 2008 to 2020, revealing that 26.0% were HER2-low. Data [...] Read more.

TNBC is noted for its aggressive behavior and poor prognosis. Recently developed HER2 target agents have shown potential benefit even in HER2-low expressing breast cancers. This study retrospectively analyzed 2542 non-metastatic TNBC patients from 2008 to 2020, revealing that 26.0% were HER2-low. Data on demographics, tumor characteristics, pathologic complete response (pCR) rates and disease-free survival (DFS), distant metastasis-free survival (DMFS), overall survival (OS), and breast cancer-specific survival (BCSS) were analyzed. The HER2-low group, compared to the HER2-0 group, showed significantly better DFS, DMFS, OS, BCSS (p = 0.0072, p = 0.0096, p = 0.0180, and p = 0.0001, respectively) with older age and higher rates of postmenopausal status (p < 0.0001). No significant differences in pCR rates were observed. Multivariate analyses identified HER2 status as a significant prognostic factor for DFS (p = 0.048), DMFS (p = 0.018), OS (p = 0.049), and BCSS (p = 0.008). Subgroup analysis revealed that these effects varied with menopausal status, showing more pronounced benefits in postmenopausal women. Our findings suggest that HER2-low TNBC patients exhibit a distinct clinical profile and improved survival compared to HER2-0 TNBC patients, especially in postmenopausal patients. Further research on estrogen and HER2 interaction is needed. Full article

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

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22 pages, 3817 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 3 | Viewed by 2021

Abstract

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

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

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

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17 pages, 4025 KiB

Open AccessEditor’s ChoiceArticle

CRISPR-Cas9 Knockout Screens Identify DNA Damage Response Pathways and BTK as Essential for Cisplatin Response in Diffuse Large B-Cell Lymphoma

by Issa Ismail Issa, Hanne Due, Rasmus Froberg Brøndum, Vidthdyan Veeravakaran, Hulda Haraldsdóttir, Cathrine Sylvester, Asta Brogaard, Soniya Dhanjal, Bernhard Schmierer and Karen Dybkær

Cancers 2024, 16(13), 2437; https://doi.org/10.3390/cancers16132437 - 2 Jul 2024

Cited by 4 | Viewed by 2701

Abstract

The recurrence of diffuse large B-cell lymphoma (DLBCL) has been observed in 40% of cases. The standard of care for refractory/relapsed DLBCL (RR-DLBCL) is platinum-based treatment prior to autologous stem cell transplantation; however, the prognosis for RR-DLBCL patients remains poor. Thus, to identify [...] Read more.

The recurrence of diffuse large B-cell lymphoma (DLBCL) has been observed in 40% of cases. The standard of care for refractory/relapsed DLBCL (RR-DLBCL) is platinum-based treatment prior to autologous stem cell transplantation; however, the prognosis for RR-DLBCL patients remains poor. Thus, to identify genes affecting the cisplatin response in DLBCL, cisplatin-based whole-genome CRISPR-Cas9 knockout screens were performed in this study. We discovered DNA damage response (DDR) pathways as enriched among identified sensitizing CRISPR-mediated gene knockouts. In line, the knockout of the nucleotide excision repair genes XPA and ERCC6 sensitized DLBCL cells to platinum drugs irrespective of proliferation rate, thus documenting DDR as essential for cisplatin sensitivity in DLBCL. Functional analysis revealed that the loss of XPA and ERCC6 increased DNA damage levels and altered cell cycle distribution. Interestingly, we also identified BTK, which is involved in B-cell receptor signaling, to affect cisplatin response. The knockout of BTK increased cisplatin sensitivity in DLBCL cells, and combinatory drug screens revealed a synergistic effect of the BTK inhibitor, ibrutinib, with platinum drugs at low concentrations. Applying local and external DLBCL cohorts, we addressed the clinical relevance of the genes identified in the CRISPR screens. BTK was among the most frequently mutated genes with a frequency of 3–5%, and XPA and ERCC6 were also mutated, albeit at lower frequencies. Furthermore, 27–54% of diagnostic DLBCL samples had mutations in pathways that can sensitize cells to cisplatin. In conclusion, this study shows that XPA and ERCC6, in addition to BTK, are essential for the response to platinum-based drugs in DLBCL. Full article

(This article belongs to the Section Molecular Cancer Biology)

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18 pages, 5955 KiB

Open AccessEditor’s ChoiceArticle

Inhibition of Histone Deacetylase Activity Increases Cisplatin Efficacy to Eliminate Metastatic Cells in Pediatric Liver Cancers

by Ruhi Gulati, Yasmeen Fleifil, Katherine Jennings, Alex Bondoc, Greg Tiao, James Geller, Lubov Timchenko and Nikolai Timchenko

Cancers 2024, 16(13), 2300; https://doi.org/10.3390/cancers16132300 - 22 Jun 2024

Cited by 4 | Viewed by 1664

Abstract

The pediatric liver cancers, hepatoblastoma and hepatocellular carcinoma, are dangerous cancers which often spread to the lungs. Although treatments with cisplatin significantly improve outcomes, cisplatin may not eliminate metastasis-initiating cells. Our group has recently shown that the metastatic microenvironments of hepatoblastoma contain Cancer [...] Read more.

The pediatric liver cancers, hepatoblastoma and hepatocellular carcinoma, are dangerous cancers which often spread to the lungs. Although treatments with cisplatin significantly improve outcomes, cisplatin may not eliminate metastasis-initiating cells. Our group has recently shown that the metastatic microenvironments of hepatoblastoma contain Cancer Associated Fibroblasts (CAFs) and neuron-like cells, which initiate cancer spread from liver to lungs. In this study, we found that these cells express high levels of HDAC1; therefore, we examined if histone deacetylase inhibition improves cisplatin anti-proliferative effects and reduces the formation of tumor clusters in pediatric liver cancer metastatic microenvironments. Methods: New cell lines were generated from primary hepatoblastoma liver tumors (hbl) and lung metastases (LM) of HBL patients. In addition, cell lines were generated from hepatocellular neoplasm, not otherwise specified (HCN-NOS) tumor samples, and hcc cell lines. Hbl, LM and hcc cells were treated with cisplatin, SAHA or in combination. The effect of these drugs on the number of cells, formation of tumor clusters and HDAC1-Sp5-p21 axis were examined. Results: Both HBL and HCC tissue specimens have increased HDAC1-Sp5 pathway activation, recapitulated in cell lines generated from the tumors. HDAC inhibition with vorinostat (SAHA) increases cisplatin efficacy to eliminate CAFs in hbl and in hcc cell lines. Although the neuron-like cells survive the combined treatments, proliferation was inhibited. Notably, combining SAHA with cisplatin overcame cisplatin resistance in an LM cell line from an aggressive case with multiple metastases. Underlying mechanisms of this enhanced inhibition include suppression of the HDAC1-Sp5 pathway and elevation of an inhibitor of proliferation p21. Similar findings were found with gemcitabine treatments suggesting that elimination of proliferative CAFs cells is a key event in the inhibition of mitotic microenvironment. Conclusions: Our studies demonstrate the synergistic benefits of HDAC inhibition and cisplatin to eliminate metastasis-initiating cells in pediatric liver cancers. Full article

(This article belongs to the Topic Individualized Molecular Mechanisms and Treatment in Tumor Metastasis)

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17 pages, 899 KiB

Open AccessEditor’s ChoiceArticle

Prognostic Relevance of Preoperative Immune, Inflammatory, and Nutritional Biomarkers in Patients Undergoing Gastrectomy for Resectable Gastric Adenocarcinoma: An Observational Multicentre Study

by Jaume Tur-Martínez, Joaquín Rodríguez-Santiago, Javier Osorio, Mònica Miró, Concepción Yarnoz, Mariona Jofra, Georgina Ferret, Helena Salvador-Roses, Sonia Fernández-Ananín, Arantxa Clavell, Alexis Luna, Aurora Aldeano, Carles Olona, Judith Hermoso, Mercè Güell-Farré, Mariagiulia Dal Cero, Marta Gimeno, Natàlia Pallarès and Manuel Pera

Cancers 2024, 16(12), 2188; https://doi.org/10.3390/cancers16122188 - 11 Jun 2024

Cited by 3 | Viewed by 1668

Abstract

Background: The aim of this study was to evaluate different preoperative immune, inflammatory, and nutritional scores and their best cut-off values as predictors of poorer overall survival (OS) and disease-free survival (DFS) in patients who underwent curative gastric cancer resection. Methods: This was [...] Read more.

Background: The aim of this study was to evaluate different preoperative immune, inflammatory, and nutritional scores and their best cut-off values as predictors of poorer overall survival (OS) and disease-free survival (DFS) in patients who underwent curative gastric cancer resection. Methods: This was a retrospective observational multicentre study based on data of the Spanish EURECCA Esophagogastric Cancer Registry. Time-dependent Youden index and log-rank test were used to obtain the best cut-offs of 18 preoperative biomarkers for OS and DFS. An adjusted Cox model with variables selected by bootstrapping was used to identify the best preoperative biomarkers, which were also analysed for every TNM stage. Results: High neutrophil-to-lymphocyte ratio (NLR), high monocyte systemic inflammation index (moSII), and low prognostic nutritional index (PNI) were identified as independent predictors of poor outcome: NLR > 5.91 (HR:1.73; 95%CI [1.23–2.43]), moSII >2027.12 (HR:2.26; 95%CI [1.36–3.78]), and PNI >40.31 (HR:0.75; 95%CI [0.58–0.96]) for 5-year OS and NLR > 6.81 (HR:1.75; 95%CI [1.24–2.45]), moSII > 2027.12 (HR:2.46; 95%CI [1.49–4.04]), and PNI > 40.31 (HR:0.77; 95%CI [0.60,0.97]) for 5-year DFS. These outcomes were maintained in the whole cohort for NLR and moSII (p < 0.05) but not in stage II and for PNI in all tumoral stages. The associations of NLR-PNI and moSII-PNI were also a relevant prognostic factor for OS. Conclusions: High NLR, high moSII (for stages I and III), and low PNI (regardless of tumour stage) were the most promising preoperative biomarkers to predict poor OS and DFS in gastric cancer patients treated with curative intent. Full article

(This article belongs to the Special Issue Diagnosis and Staging of Gastroesophageal Cancer)

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17 pages, 1236 KiB

Open AccessEditor’s ChoiceArticle

Implementation of HER2 Testing in Endometrial Cancer, a Summary of Real-World Initial Experience in a Large Tertiary Cancer Center

by Anna Plotkin, Ekaterina Olkhov-Mitsel, Weei-Yuarn Huang and Sharon Nofech-Mozes

Cancers 2024, 16(11), 2100; https://doi.org/10.3390/cancers16112100 - 31 May 2024

Cited by 6 | Viewed by 6958

Abstract

HER2-targeted therapies have transformed the management of advanced or recurrent serous endometrial cancer (EC), leading to an increased clinical demand for HER2 testing. Despite its adoption in select academic centers, the global extent of such tumor testing is unclear. In this study, we [...] Read more.

HER2-targeted therapies have transformed the management of advanced or recurrent serous endometrial cancer (EC), leading to an increased clinical demand for HER2 testing. Despite its adoption in select academic centers, the global extent of such tumor testing is unclear. In this study, we report on the initial two-year experience of HER2 testing at a major academic center with a reference gynecologic oncology service and biomarker reference laboratory. All patients who underwent HER2 testing based on physician discretion, reflex HER2 testing, and reference laboratory requests were included. From February 2021 to October 2023, HER2 testing was performed on 192 tumor tissue samples from 180 EC patients. Serous carcinoma constituted 52% of samples, reflecting diagnostic challenges and limited therapeutic options for advanced EC. HER2 positivity was found in 28% of all cases and 30% of p53-aberrant cases. An immunohistochemistry (IHC) score of 3+ was found in 15% of samples, while IHC 2+ was found in 45% (13% IHC 2+/ISH+ and 32% IHC 2+/ISH−). The newly identified ‘HER2-low’ category comprised 46% of the samples. Heterogeneity was noted in 42% of HER2-positive cases, with complex patterns in 3%. NGS and HER2 IHC-FISH showed a 24% discordance, attributed to intratumoral heterogeneity, tumor cellularity, a small number of amplified cells, and the HER2/CEP17 ratio near the cut-off. This study offers real-world insights into HER2 testing in EC, highlighting the challenges and underscoring the need for standardized guidelines in specimen handling, proficiency testing, and scoring criteria to enhance patient management and therapeutic decision-making. Full article

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

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17 pages, 950 KiB

Open AccessEditor’s ChoiceArticle

Acceptance of Self-Sampling by Women Not Regularly Participating in Cervical Cancer Screening in Areas with Low Medical Density: A Qualitative Study within the French CapU4 Trial

by Johane Le Goff, Anne-Sophie Le Duc-Banaszuk, Caroline Lefeuvre, Adeline Pivert, Alexandra Ducancelle, Hélène De Pauw, Marc Arbyn, Aubeline Vinay and Franck Rexand-Galais

Cancers 2024, 16(11), 2066; https://doi.org/10.3390/cancers16112066 - 30 May 2024

Cited by 2 | Viewed by 1998

Abstract

Cervical cancer (CC) was diagnosed in 3159 women in France in 2023, and 1117 died from it. Organized screening for cervical cancer is potentially very effective for participating women. However, reaching under-screened populations remains a major challenge. The present qualitative study explored women’s [...] Read more.

Cervical cancer (CC) was diagnosed in 3159 women in France in 2023, and 1117 died from it. Organized screening for cervical cancer is potentially very effective for participating women. However, reaching under-screened populations remains a major challenge. The present qualitative study explored women’s opinions on what discourages or encourages them to participate in CC screening and assessed the acceptability of two experimental strategies (urinary or vaginal self-sampling kits) to increase the screening coverage in three rural French administrative departments with low medical density and/or low screening participation rates. Forty-eight semi-structured interviews and four focus groups were conducted by a team of psychologists. Results showed that the participants accepted at-home self-sampling to reach non-participating women in medically underserved areas. However, they suggested that the type of kit sent should be adapted to the patient’s profile (embarrassment from earlier exams, cultural aspects, fear of invasiveness, etc.), and that kits should be simple to use (in understandable language taking sociocultural aspects into account). Women wished to be assured that testing on self-samples is accurate and needed information about further actions in case of a positive result. Full article

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

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21 pages, 3176 KiB

Open AccessEditor’s ChoiceArticle

Restricting Colorectal Cancer Cell Metabolism with Metformin: An Integrated Transcriptomics Study

by Ayla Orang, Shashikanth Marri, Ross A. McKinnon, Janni Petersen and Michael Z. Michael

Cancers 2024, 16(11), 2055; https://doi.org/10.3390/cancers16112055 - 29 May 2024

Cited by 4 | Viewed by 4613

Abstract

Background: Metformin is a first-line therapy for type 2 diabetes as it disrupts cellular metabolism. Despite the association between metformin and lower cancer incidence, the anti-tumour activity of the drug in colorectal cancer (CRC) is incompletely understood. This study identifies underlying molecular mechanisms [...] Read more.

Background: Metformin is a first-line therapy for type 2 diabetes as it disrupts cellular metabolism. Despite the association between metformin and lower cancer incidence, the anti-tumour activity of the drug in colorectal cancer (CRC) is incompletely understood. This study identifies underlying molecular mechanisms by which metformin slows colorectal cancer cell proliferation by investigating metformin-associated microRNA (miRNA) and target gene pairs implicated in signalling pathways. Methods: The present study analysed changes in miRNAs and the coding transcriptome in CRC cells treated with a sublethal dose of metformin, followed by the contextual validation of potential miRNA–target gene pairs. Results: Analyses of small RNA and transcriptome sequencing data revealed 104 miRNAs and 1221 mRNAs to be differentially expressed in CRC cells treated with metformin for 72 h. Interaction networks between differentially expressed miRNAs and putative target mRNAs were identified. Differentially expressed genes were mainly implicated in metabolism and signalling processes, such as the PI3K-Akt and MAPK/ERK pathways. Further validation of potential miRNA–target mRNA pairs revealed that metformin induced miR-2110 and miR-132-3p to target PIK3R3 and, consequently, regulate CRC cell proliferation, cell cycle progression and the PI3K-Akt signalling pathway. Metformin also induced miR-222-3p and miR-589-3p, which directly target STMN1 to inhibit CRC cell proliferation and cell cycle progression. Conclusions: This study identified novel changes in the coding transcriptome and small non-coding RNAs associated with metformin treatment of CRC cells. Integration of these datasets highlighted underlying mechanisms by which metformin impedes cell proliferation in CRC. Importantly, it identified the post-transcriptional regulation of specific genes that impact both metabolism and cell proliferation. Full article

(This article belongs to the Special Issue Targeting Metabolic Vulnerabilities in Cancer)

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12 pages, 911 KiB

Open AccessEditor’s ChoiceArticle

Diagnostic Accuracy of DNA-Methylation in Detection of Cervical Dysplasia: Findings from a Population-Based Screening Program

by Narcisa Muresu, Mariangela V. Puci, Giovanni Sotgiu, Illari Sechi, Manuela Usai, Andrea Cossu, Marianna Martinelli, Clementina Elvezia Cocuzza and Andrea Piana

Cancers 2024, 16(11), 1986; https://doi.org/10.3390/cancers16111986 - 23 May 2024

Cited by 5 | Viewed by 2387

Abstract

Background: Epigenetic biomarkers in cancer have emerged as promising tools for early detection, prognosis, and treatment response prediction. In cervical cells, hypermethylation of the host and viral HPV-genome increases with the severity of lesions, providing a useful biomarker in the triage of hr-HPV-positive [...] Read more.

Background: Epigenetic biomarkers in cancer have emerged as promising tools for early detection, prognosis, and treatment response prediction. In cervical cells, hypermethylation of the host and viral HPV-genome increases with the severity of lesions, providing a useful biomarker in the triage of hr-HPV-positive women and during treatment. The present study focuses on evaluating the clinical performance of the FAM19A4/miR124-2 methylation test in a population-based cervical screening program. Methods: Previously collected cervical samples, after bisulfite-converted DNA, were analyzed by PreCursor-M+ kit (distributed by Fujirebio Europe), for DNA methylation. The sensitivity, specificity, and negative/positive predictive values of DNA methylation were compared to histology, colposcopy, the HPV-DNA test, and cytology results. Results: Among the 61-sample set, the specificity of methylation vs. positive histology (≥CIN2) and colposcopy (≥G2) were 87% and 90%, whereas the sensitivity was 50% and 33.3%, respectively. The combination of methylation analysis with standard methods increases diagnostic accuracy. Conclusions: Overall, we found a good specificity of DNA methylation in comparison to currently used techniques. Further larger studies could support the use of FAM19A4/miR124-2 as reliable biomarkers in the prevention of cervical cancer as triage in the screening protocol. Full article

(This article belongs to the Special Issue Cervical Cancer: Risk Factors, Screening, and Prevention Strategies)

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25 pages, 3965 KiB

Open AccessEditor’s ChoiceArticle

Multidrug-Resistant Profiles in Non-Small Cell Lung Carcinoma Patient-Derived Cells: Implications for Personalized Approaches with Tyrosine Kinase Inhibitors

by Jelena Dinić, Miodrag Dragoj, Sofija Jovanović Stojanov, Ana Stepanović, Ema Lupšić, Milica Pajović, Thomas Mohr, Sofija Glumac, Dragana Marić, Maja Ercegovac, Ana Podolski-Renić and Milica Pešić

Cancers 2024, 16(11), 1984; https://doi.org/10.3390/cancers16111984 - 23 May 2024

Cited by 3 | Viewed by 1940

Abstract

The impact of tyrosine kinase inhibitors (TKIs) on multidrug resistance (MDR) in non-small cell lung carcinoma (NSCLC) is a critical aspect of cancer therapy. While TKIs effectively target specific signaling pathways of cancer cells, they can also act as substrates for ABC transporters, [...] Read more.

The impact of tyrosine kinase inhibitors (TKIs) on multidrug resistance (MDR) in non-small cell lung carcinoma (NSCLC) is a critical aspect of cancer therapy. While TKIs effectively target specific signaling pathways of cancer cells, they can also act as substrates for ABC transporters, potentially triggering MDR. The aim of our study was to evaluate the response of 17 patient-derived NSCLC cultures to 10 commonly prescribed TKIs and to correlate these responses with patient mutational profiles. Using an ex vivo immunofluorescence assay, we analyzed the expression of the MDR markers ABCB1, ABCC1, and ABCG2, and correlated these data with the genetic profiles of patients for a functional diagnostic approach. NSCLC cultures responded differently to TKIs, with erlotinib showing good efficacy regardless of mutation burden or EGFR status. However, the modulation of MDR mechanisms by erlotinib, such as increased ABCG2 expression, highlights the challenges associated with erlotinib treatment. Other TKIs showed limited efficacy, highlighting the variability of response in NSCLC. Genetic alterations in signaling pathways associated with drug resistance and sensitivity, including TP53 mutations, likely contributed to the variable responses to TKIs. The relationships between ABC transporter expression, gene alterations, and response to TKIs did not show consistent patterns. Our results suggest that in addition to mutational status, performing functional sensitivity screening is critical for identifying appropriate treatment strategies with TKIs. These results underscore the importance of considering drug sensitivity, off-target effects, MDR risks, and patient-specific genetic profiles when optimizing NSCLC treatment and highlight the potential for personalized approaches, especially in early stages. Full article

(This article belongs to the Special Issue Cancer Chemotherapy Resistance)

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14 pages, 1361 KiB

Open AccessEditor’s ChoiceArticle

High Serum Levels of CCL20 Are Associated with Recurrence and Unfavorable Overall Survival in Advanced Melanoma Patients Receiving Immunotherapy

by Julian Kött, Inka Lilott Hoehne, Isabel Heidrich, Noah Zimmermann, Kim-Lea Reese, Tim Zell, Glenn Geidel, Alessandra Rünger, Stefan W. Schneider, Klaus Pantel, Daniel J. Smit and Christoffer Gebhardt

Cancers 2024, 16(9), 1737; https://doi.org/10.3390/cancers16091737 - 29 Apr 2024

Cited by 4 | Viewed by 2977

Abstract

Background: Immune checkpoint inhibition has revolutionized melanoma therapy, but many patients show primary or secondary resistance. Biomarkers are, therefore, urgently required to predict response prior to the initiation of therapy and to monitor disease progression. Methods: In this prospective study, we analyzed the [...] Read more.

Background: Immune checkpoint inhibition has revolutionized melanoma therapy, but many patients show primary or secondary resistance. Biomarkers are, therefore, urgently required to predict response prior to the initiation of therapy and to monitor disease progression. Methods: In this prospective study, we analyzed the serum C-C motif chemokine ligand 20 (CCL20) concentration using an enzyme-linked immunosorbent assay. Blood was obtained at baseline before the initiation of immunotherapy with anti-PD-1 monotherapy or Nivolumab and Ipilimumab in advanced melanoma patients (stages III and IV) enrolled at the University Medical Center Hamburg-Eppendorf. The CCL20 levels were correlated with clinico-pathological parameters and disease-related outcomes. Results: An increased C-C motif chemokine ligand 20 (CCL20) concentration (≥0.34 pg/mL) at baseline was associated with a significantly impaired progression-free survival (PFS) in the high-CCL20 group (3 months (95% CI: 2–6 months) vs. 11 months (95% CI: 6–26 months)) (p = 0.0033) and could be identified as an independent negative prognostic factor for PFS in univariate (Hazard Ratio (HR): 1.98, 95% CI 1.25–3.12, p = 0.004) and multivariate (HR: 1.99, 95% CI 1.21–3.29, p = 0.007) Cox regression analysis, which was associated with a higher risk than S100 (HR: 1.74). Moreover, high CCL20 levels were associated with impaired overall survival (median OS not reached for low-CCL20 group, p = 0.042) with an HR of 1.85 (95% CI 1.02–3.37, p = 0.043) in univariate analysis similar to the established prognostic marker S100 (HR: 1.99, 95% CI: 1.02–3.88, p = 0.043). Conclusions: CCL20 may represent a novel blood-based biomarker for the prediction of resistance to immunotherapy that can be used in combination with established strong clinical predictors (e.g., ECOG performance score) and laboratory markers (e.g., S100) in advanced melanoma patients. Future prospective randomized trials are needed to establish CCL20 as a liquid biopsy-based biomarker in advanced melanoma. Full article

(This article belongs to the Special Issue Novel Developments on Skin Cancer Diagnostics and Treatment)

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16 pages, 1764 KiB

Open AccessEditor’s ChoiceArticle

Utility of Clinical Next Generation Sequencing Tests in KIT/PDGFRA/SDH Wild-Type Gastrointestinal Stromal Tumors

by Ryan A. Denu, Cissimol P. Joseph, Elizabeth S. Urquiola, Precious S. Byrd, Richard K. Yang, Ravin Ratan, Maria Alejandra Zarzour, Anthony P. Conley, Dejka M. Araujo, Vinod Ravi, Elise F. Nassif Haddad, Michael S. Nakazawa, Shreyaskumar Patel, Wei-Lien Wang, Alexander J. Lazar and Neeta Somaiah

Cancers 2024, 16(9), 1707; https://doi.org/10.3390/cancers16091707 - 27 Apr 2024

Cited by 6 | Viewed by 3623

Abstract

Objective: The vast majority of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in KIT, PDGFRA, or components of the succinate dehydrogenase (SDH) complex (SDHA, SDHB, SDHC, and SDHD genes). A small fraction of GISTs lack [...] Read more.

Objective: The vast majority of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in KIT, PDGFRA, or components of the succinate dehydrogenase (SDH) complex (SDHA, SDHB, SDHC, and SDHD genes). A small fraction of GISTs lack alterations in KIT, PDGFRA, and SDH. We aimed to further characterize the clinical and genomic characteristics of these so-called “triple-negative” GISTs. Methods: We extracted clinical and genomic data from patients seen at MD Anderson Cancer Center with a diagnosis of GIST and available clinical next generation sequencing data to identify “triple-negative” patients. Results: Of the 20 patients identified, 11 (55.0%) had gastric, 8 (40.0%) had small intestinal, and 1 (5.0%) had rectal primary sites. In total, 18 patients (90.0%) eventually developed recurrent or metastatic disease, and 8 of these presented with de novo metastatic disease. For the 13 patients with evaluable response to imatinib (e.g., neoadjuvant treatment or for recurrent/metastatic disease), the median PFS with imatinib was 4.4 months (range 0.5–191.8 months). Outcomes varied widely, as some patients rapidly developed progressive disease while others had more indolent disease. Regarding potential genomic drivers, four patients were found to have alterations in the RAS/RAF/MAPK pathway: two with a BRAF V600E mutation and two with NF1 loss-of-function (LOF) mutations (one deletion and one splice site mutation). In addition, we identified two with TP53 LOF mutations, one with NTRK3 fusion (ETV6-NTRK3), one with PTEN deletion, one with FGFR1 gain-of-function (GOF) mutation (K654E), one with CHEK2 LOF mutation (T367fs*), one with Aurora kinase A fusion (AURKA-CSTF1), and one with FANCA deletion. Patients had better responses with molecularly targeted therapies than with imatinib. Conclusions: Triple-negative GISTs comprise a diverse cohort with different driver mutations. Compared to KIT/PDGFRA-mutant GIST, limited benefit was observed with imatinib in triple-negative GIST. In depth molecular profiling can be helpful in identifying driver mutations and guiding therapy. Full article

(This article belongs to the Special Issue Genome Sequencing of Cancer: Identifying Targets and Biomarkers for Therapy)

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12 pages, 834 KiB

Open AccessEditor’s ChoiceArticle

The Current Achievements of Multi-Gene Panel Tests in Clinical Settings for Patients with Non-Small-Cell Lung Cancer

by Tadashi Sakaguchi, Akemi Iketani, Seiya Esumi, Maki Esumi, Yuta Suzuki, Kentaro Ito, Kentaro Fujiwara, Yoichi Nishii, Koji Katsuta, Hiroki Yasui, Osamu Taguchi and Osamu Hataji

Cancers 2024, 16(9), 1670; https://doi.org/10.3390/cancers16091670 - 25 Apr 2024

Cited by 6 | Viewed by 2368

Abstract

Some multi-gene panel tests have been implemented in clinical settings to guide targeted therapy in non-small-cell lung cancer (NSCLC) in Japan. The current performance of multi-gene panel tests under the condition that the Oncomine Dx Target Test (ODxTT) and Amoy Dx^® Pan [...] Read more.

Some multi-gene panel tests have been implemented in clinical settings to guide targeted therapy in non-small-cell lung cancer (NSCLC) in Japan. The current performance of multi-gene panel tests under the condition that the Oncomine Dx Target Test (ODxTT) and Amoy Dx^® Pan Lung Cancer PCR panel (AmoyDx-multi) are available remains relatively unknown. We retrospectively reviewed consecutive patients with NSCLC, whose FFPE samples were considered for genetic testing. We assessed the submission rates, the success rates, and the driver oncogene detection rates of multi-gene panel tests. A total of 225 patients were histologically newly diagnosed with NSCLC or diagnosed with a recurrence of NSCLC without a previous multi-gene panel test at our institution. Among the 225 patients, the FFPE samples of 212 patients (94.2%) were submitted for multi-gene panel testing, including 191 samples (84.9%) for the ODxTT and 21 samples (9.3%) for the AmoyDx-multi. Among the 212 samples submitted to multi-gene panel tests, the success rate was 99.5% (211/212). The detection rate of driver oncogene alterations for all histologies was 52.4% (111/212), and that for adenocarcinoma was 69.7% (106/152). A favorable submission rate and success rate of multi-gene panel tests were shown, along with a favorable detection rate in recent clinical settings. Full article

(This article belongs to the Section Cancer Biomarkers)

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14 pages, 1677 KiB

Open AccessEditor’s ChoiceArticle

tRNA-Derived Fragments as Biomarkers in Bladder Cancer

by Olaf Strømme, Kathleen A. Heck, Gaute Brede, Håvard T. Lindholm, Marit Otterlei and Carl-Jørgen Arum

Cancers 2024, 16(8), 1588; https://doi.org/10.3390/cancers16081588 - 20 Apr 2024

Cited by 5 | Viewed by 2596

Abstract

Bladder cancer (BC) diagnosis is reliant on cystoscopy, an invasive procedure associated with urinary tract infections. This has sparked interest in identifying noninvasive biomarkers in body fluids such as blood and urine. A source of biomarkers in these biofluids are extracellular vesicles (EVs), [...] Read more.

Bladder cancer (BC) diagnosis is reliant on cystoscopy, an invasive procedure associated with urinary tract infections. This has sparked interest in identifying noninvasive biomarkers in body fluids such as blood and urine. A source of biomarkers in these biofluids are extracellular vesicles (EVs), nanosized vesicles that contain a wide array of molecular cargo, including small noncoding RNA such as transfer RNA-derived fragments (tRF) and microRNA. Here, we performed small-RNA next-generation sequencing from EVs from urine and serum, as well as from serum supernatant. RNA was extracted from 15 non-cancer patients (NCPs) with benign findings in cystoscopy and 41 patients with non-muscle invasive BC. Urine and serum were collected before transurethral resection of bladder tumors (TUR-b) and at routine post-surgery check-ups. We compared levels of tRFs in pre-surgery samples to samples from NCPs and post-surgery check-ups. To further verify our findings, samples from 10 patients with stage T1 disease were resequenced. When comparing tRF expression in urine EVs between T1 stage BC patients and NCPs, 14 differentially expressed tRFs (DEtRFs) were identified. In serum supernatant, six DEtRFs were identified among stage T1 patients when comparing pre-surgery to post-surgery samples and four DEtRFs were found when comparing pre-surgery samples to NCPs. By performing a blast search, we found that sequences of DEtRFs aligned with genomic sequences pertaining to processes relevant to cancer development, such as enhancers, regulatory elements and CpG islands. Our findings display a number of tRFs that may hold potential as biomarkers for the diagnosis and recurrence-free survival of BC. Full article

(This article belongs to the Section Cancer Biomarkers)

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15 pages, 2352 KiB

Open AccessEditor’s ChoiceArticle

A Novel ceRNET Relying on the lncRNA JPX, miR-378a-3p, and Its mRNA Targets in Lung Cancer

by Nicola Mosca, Mariaceleste Pezzullo, Ilenia De Leo, Anna Truda, Giovanna Marchese, Aniello Russo and Nicoletta Potenza

Cancers 2024, 16(8), 1526; https://doi.org/10.3390/cancers16081526 - 17 Apr 2024

Cited by 3 | Viewed by 2405

Abstract

Lung cancer is the leading cause of cancer-related death worldwide. Non-coding RNAs are emerging as critical players for the onset and progression of cancer. Analyses of three different datasets revealed that the lncRNA JPX was overexpressed in adenocarcinoma tissues in comparison to normal [...] Read more.

Lung cancer is the leading cause of cancer-related death worldwide. Non-coding RNAs are emerging as critical players for the onset and progression of cancer. Analyses of three different datasets revealed that the lncRNA JPX was overexpressed in adenocarcinoma tissues in comparison to normal lungs, as expected for an oncogene. Intriguingly, the predicted binding miR-378a-3p showed a significant inverse correlation with JPX expression. The lncRNA/miRNA physical interaction was validated by reporter vectors. Then, the oncogenic activity of JPX, the tumor-suppressive role of miR-378a-3p, and the contribution of their functional interaction to cancer hallmarks were demonstrated using assays for cell proliferation, migration, invasion, and 3D-spheroid formation. Finally, molecular circuits were investigated by boosting the expression of both JPX and miR-378a-3p, singularly and in combination, demonstrating that JPX counteracted miR-378a-3p silencing activity toward its oncogenic targets GLUT1, NRP1, YY1, and Wnt5a. Overall, the data unveil a novel ceRNET (competing endogenous RNA network), wherein JPX acts as a ceRNA by binding to miR-378a-3p, thus reducing the miRNA silencing activity toward its downstream targets, and eliciting oncogenic pathways driving lung cancer. The knowledge of the network may pave the way to develop new diagnostic panels, and innovative RNA-targeted and RNA-based therapeutic strategies. Full article

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

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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 4323

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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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 1784

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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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 4279

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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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 3 | Viewed by 3257

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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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 6 | Viewed by 3635

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, 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 2091

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 2943

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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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 3449

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 3 | Viewed by 5081

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 3935

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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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 9 | Viewed by 4124

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 2389

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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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 2767

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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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 3669

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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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 10 | Viewed by 3203

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 3428

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 16 | Viewed by 13642

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 4 | Viewed by 3552

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 2919

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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13 pages, 15593 KiB

Open AccessEditor’s ChoiceArticle

The Immunomodulatory Effects of Fluorescein-Mediated Sonodynamic Treatment Lead to Systemic and Intratumoral Depletion of Myeloid-Derived Suppressor Cells in a Preclinical Malignant Glioma Model

by Serena Pellegatta, Nicoletta Corradino, Manuela Zingarelli, Edoardo Porto, Matteo Gionso, Arianna Berlendis, Gianni Durando, Martina Maffezzini, Silvia Musio, Domenico Aquino, Francesco DiMeco and Francesco Prada

Cancers 2024, 16(4), 792; https://doi.org/10.3390/cancers16040792 - 15 Feb 2024

Cited by 5 | Viewed by 2180

Abstract

Fluorescein-mediated sonodynamic therapy (FL-SDT) is an extremely promising approach for glioma treatment, resulting from the combination of low-intensity focused ultrasound (FUS) with a sonosensitizer. In the present study, we evaluated the efficacy and immunomodulation of SDT with fluorescein as the sonosensitizer in immunocompetent [...] Read more.

Fluorescein-mediated sonodynamic therapy (FL-SDT) is an extremely promising approach for glioma treatment, resulting from the combination of low-intensity focused ultrasound (FUS) with a sonosensitizer. In the present study, we evaluated the efficacy and immunomodulation of SDT with fluorescein as the sonosensitizer in immunocompetent GL261 glioma mice for the first time. In vitro studies demonstrated that the exposure of GL261 cells to FL-SDT induced immunogenic cell death and relevant upregulation of MHC class I, CD80 and CD86 expression. In vivo studies were then performed to treat GL261 glioma-bearing mice with FL-SDT, fluorescein alone, or FUS alone. Perturbation of the glioma-associated macrophage subset within the immune microenvironment was induced by all the treatments. Notably, a relevant depletion of myeloid-derived suppressor cells (MDSCs) and concomitant robust infiltration of CD8+ T cells were observed in the SDT-FL-treated mice, resulting in a significant radiological delay in glioma progression and a consequent improvement in survival. Tumor control and improved survival were also observed in mice treated with FL alone (median survival 41.5 days, p > 0.0001 compared to untreated mice), reflecting considerable modulation of the immune microenvironment. Interestingly, a high circulating lymphocyte-to-monocyte ratio and a very low proportion of MDSCs were predictive of better survival in FL- and FL-SDT-treated mice than in untreated and FUS-treated mice, in which elevated monocyte and MDSC frequencies correlated with worse survival. The immunostimulatory potential of FL-SDT treatment and the profound modulation of most immunosuppressive components within the microenvironment encouraged the exploration of the combination of FL-SDT with immunotherapeutic strategies. Full article

(This article belongs to the Special Issue Sonodynamic Cancer Therapy)

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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 2464

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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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 2 | Viewed by 3408

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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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 2 | Viewed by 2869

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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