Cancers

11 pages, 266 KiB

Open AccessArticle

Early Age of Onset Is an Independent Predictor for a Worse Response to Neoadjuvant Therapies in Sporadic Rectal Cancer Patients

by Caterina Foppa, Annalisa Maroli, Antonio Luberto, Carlotta La Raja, Paola Spaggiari, Cristiana Bonifacio, Stefano De Zanet, Marco Montorsi, Salvatore Piscuoglio, Luigi Maria Terracciano, Armando Santoro and Antonino Spinelli

Cancers 2023, 15(14), 3750; https://doi.org/10.3390/cancers15143750 - 24 Jul 2023

Cited by 3 | Viewed by 1493

Abstract

The incidence of rectal cancer (RC) is increasing in the population aged ≤ 49 (early-onset RC-EORC). EORC patients are more likely to present with locally advanced disease at diagnosis than late-onset RC (LORC; aged ≥ 50) patients. As a consequence, more EORC patients [...] Read more.

The incidence of rectal cancer (RC) is increasing in the population aged ≤ 49 (early-onset RC-EORC). EORC patients are more likely to present with locally advanced disease at diagnosis than late-onset RC (LORC; aged ≥ 50) patients. As a consequence, more EORC patients undergo neoadjuvant therapies. The response to treatment in EORC patients is still unknown. This study aims to explore the effect of age of onset on the pathological response to neoadjuvant therapies in sporadic locally advanced RC (LARC) patients. Based on an institutional prospectively maintained database, LARC patients undergoing neoadjuvant therapies and radical surgery between January 2010 and December 2022 were allocated to the EORC and LORC groups. The primary endpoint was the rate of incomplete response (Dworak 0–2). A total of 326 LORC and 79 EORC patients were included. Pre-neoadjuvant tumor features were comparable. A significantly higher rate of incomplete response was observed in EORC patients (49% vs. 35%; p = 0.028). From multivariable analysis, early age of onset, smoking and extramural invasion presented as independent risk factors for a worse response. This study demonstrates that an early age of onset is related to a worse response and calls for different multimodal strategies in this group of patients. Full article

(This article belongs to the Special Issue Innovations in Diagnosis and Treatment of Colon and Rectal Cancer: Preoperative Optimisation, Multidisciplinary Management, and Surgical Technology Advancement)

12 pages, 2097 KiB

Open AccessArticle

Machine Learning Identifies a Signature of Nine Exosomal RNAs That Predicts Hepatocellular Carcinoma

by Josephine Yu Yan Yap, Laura Shih Hui Goh, Ashley Jun Wei Lim, Samuel S. Chong, Lee Jin Lim and Caroline G. Lee

Cancers 2023, 15(14), 3749; https://doi.org/10.3390/cancers15143749 - 24 Jul 2023

Cited by 3 | Viewed by 1844

Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Although alpha fetoprotein (AFP) remains a commonly used serological marker of HCC, the sensitivity and specificity of AFP in detecting HCC is often limited. Exosomal RNA has emerged as a promising [...] Read more.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Although alpha fetoprotein (AFP) remains a commonly used serological marker of HCC, the sensitivity and specificity of AFP in detecting HCC is often limited. Exosomal RNA has emerged as a promising diagnostic tool for various cancers, but its use in HCC detection has yet to be fully explored. Here, we employed Machine Learning on 114,602 exosomal RNAs to identify a signature that can predict HCC. The exosomal expression data of 118 HCC patients and 112 healthy individuals were stratified split into Training, Validation and Unseen Test datasets. Feature selection was then performed on the initial training dataset using permutation importance, and the predictive performance of the selected features were tested on the validation dataset using Support Vector Machine (SVM) Classifier. A minimum of nine features were identified to be predictive of HCC and these nine features were then evaluated across six different models in an unseen test set. These features, mainly in the immune, platelet/neutrophil and cytoskeletal pathways, exhibited good predictive performance with ROC-AUC from 0.79–0.88 in the unseen test set. Hence, these nine exosomal RNAs have potential to be clinically useful minimally invasive biomarkers for HCC. Full article

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

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19 pages, 4589 KiB

Open AccessArticle

Intratumoural Delivery of mRNA Loaded on a Cationic Hyper-Branched Cyclodextrin-Based Polymer Induced an Anti-Tumour Immunological Response in Melanoma

by Yousef Khazaei Monfared, Mohammad Mahmoudian, Parvin Zakeri-Milani, Claudio Cecone, Tomoya Hayashi, Ken J. Ishii, João Conde, Adrián Matencio and Francesco Trotta

Cancers 2023, 15(14), 3748; https://doi.org/10.3390/cancers15143748 - 24 Jul 2023

Cited by 1 | Viewed by 2229

Abstract

mRNA technology has demonstrated potential for use as an effective cancer immunotherapy. However, inefficient in vivo mRNA delivery and the requirements for immune co-stimulation present major hurdles to achieving anti-tumour therapeutic efficacy. Therefore, we used a cationic hyper-branched cyclodextrin-based polymer to increase mRNA [...] Read more.

mRNA technology has demonstrated potential for use as an effective cancer immunotherapy. However, inefficient in vivo mRNA delivery and the requirements for immune co-stimulation present major hurdles to achieving anti-tumour therapeutic efficacy. Therefore, we used a cationic hyper-branched cyclodextrin-based polymer to increase mRNA delivery in both in vitro and in vivo melanoma cancer. We found that the transfection efficacy of the mRNA-EGFP-loaded Ppoly system was significantly higher than that of lipofectamine and free mRNA in both 2D and 3D melanoma cancer cells; also, this delivery system did not show cytotoxicity. In addition, the biodistribution results revealed time-dependent and significantly higher mEGFP expression in complexes with Ppoly compared to free mRNA. We then checked the anti-tumour effect of intratumourally injected free mRNA–OVA, a foreign antigen, and loaded Ppoly; the results showed a considerable decrease in both tumour size and weight in the group treated with OVA-mRNA in loaded Ppoly compared to other formulations with an efficient adaptive immune response by dramatically increasing most leukocyte subtypes and OVA-specific CD8+ T cells in both the spleen and tumour tissues. Collectively, our findings suggest that the local delivery of cationic cyclodextrin-based polymer complexes containing foreign mRNA antigens might be a good and reliable concept for cancer immunotherapy. Full article

(This article belongs to the Collection Mechanism of Immunotherapy in Cancers)

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13 pages, 283 KiB

Open AccessReview

Immunonutrition in Radical Cystectomy: State of the Art and Perspectives

by Amanda Casirati, Valentina Da Prat, Arianna Bettiga, Lucia Aretano, Francesco Trevisani, Emanuele Cereda, Alberto Briganti, Elisa Colombo, Giorgia Preziati, Francesca De Simeis, Andrea Salonia, Francesco Montorsi, Riccardo Caccialanza and Richard Naspro

Cancers 2023, 15(14), 3747; https://doi.org/10.3390/cancers15143747 - 24 Jul 2023

Cited by 3 | Viewed by 1818

Abstract

Preoperative nutritional status is a pivotal aspect to consider in patients with cancer undergoing radical cystectomy (RC), as those at risk of malnutrition or already malnourished are more prone to post-surgical complications. The loss of muscle mass is a major consequence of cancer-related [...] Read more.

Preoperative nutritional status is a pivotal aspect to consider in patients with cancer undergoing radical cystectomy (RC), as those at risk of malnutrition or already malnourished are more prone to post-surgical complications. The loss of muscle mass is a major consequence of cancer-related malnutrition. It is associated with increased risk of hospital readmission, longer hospitalization, and higher mortality. Nowadays, the close relationship between nutritional and immunological aspects under stressful conditions, such as surgery, represents an emerging scientific and clinical issue. Indeed, the synergistic action of reduced food intake and systemic inflammation generates metabolic derangements with tissue catabolism, including skeletal muscle breakdown, which is, in turn, associated with immune system dysfunction. In order to offer an additional immune-nutritional boost to the post-surgical phase, particularly in malnourished patients, nutritional support may include oral nutritional supplements and/or enteral formulas enriched with specific nutrients such as omega-3 fatty acids, arginine, glutamine, and nucleotides, with acknowledged immune-modulating effects. In the present narrative review, we addressed the state of the art of the available scientific literature on the benefit of immunonutrition in patients undergoing RC for cancer and suggest possible future perspectives to be explored. Although the role of immunonutrition was found to be little explored in the context of urologic oncology, the preliminary available data on radical cystectomy, summarized in the present paper, are promising and suggest that it may improve postoperative outcomes through immunomodulation, regardless of nutritional status before surgery. Full article

(This article belongs to the Special Issue Cancer and Nutrients)

13 pages, 887 KiB

Open AccessArticle

Diminished Short-Term Efficacy of Reduced-Dose Induction BCG in the Treatment of Non-Muscle Invasive Bladder Cancer

by David A. Ostrowski, Raju R. Chelluri, Matthew Herzig, Leilei Xia, Brian D. Cortese, Daniel S. Roberson, Thomas J. Guzzo, Daniel J. Lee and S. Bruce Malkowicz

Cancers 2023, 15(14), 3746; https://doi.org/10.3390/cancers15143746 - 24 Jul 2023

Cited by 1 | Viewed by 1758

Abstract

The ongoing Bacillus Calmette-Guérin (BCG) shortage has created challenges for the treatment of non-muscle invasive bladder cancer (NMIBCa). Our objective was to evaluate the efficacy of reduced-dose induction BCG (RD-iBCG) compared to full-dose induction BCG (FD-iBCG) regarding recurrence rates. We hypothesized that patients [...] Read more.

The ongoing Bacillus Calmette-Guérin (BCG) shortage has created challenges for the treatment of non-muscle invasive bladder cancer (NMIBCa). Our objective was to evaluate the efficacy of reduced-dose induction BCG (RD-iBCG) compared to full-dose induction BCG (FD-iBCG) regarding recurrence rates. We hypothesized that patients receiving RD-iBCG may recur at a higher rate compared to those who received FD-iBCG therapy. A retrospective review of all patients with NMIBCa treated with intravesical therapy at our institution between 2015–2020 was conducted. Inclusion criteria consisted of having a diagnosis of AUA intermediate or high-risk NMIBCa with an indication for a six-week induction course of FD or RD-BCG with at least 1 year of documented follow up. The data were censored at one year. Propensity score matching for age, sex, tumor pathology, and initial vs. recurrent disease was performed. The primary endpoint was bladder cancer recurrence, reported as recurrence-free survival. A total of 254 patients were reviewed for this study. Our final cohort was 139 patients after exclusion. Thirty-nine percent of patients had HGT1 disease. 38.6% of patients receiving RD-BCG developed a recurrence of bladder cancer within a one-year follow-up as compared to 33.7% of patients receiving FD therapy. After propensity matching, this value remained statistically significant (p = 0.03). In conclusion, RD-iBCG for NMIBCa is associated with a significantly greater risk of recurrence than full-dose induction therapy, suggesting that RD-iBCG may not be equivalent or non-inferior to full-dose administration in the short term. Full article

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9 pages, 1232 KiB

Open AccessArticle

Diagnostic Yield of Repeat Endoscopic Ultrasound-Guided Fine Needle Biopsy for Solid Pancreatic Lesions

by Baptiste Camus, Anna Pellat, Alexandre Rouquette, Ugo Marchese, Anthony Dohan, Arthur Belle, Einas Abou Ali, Stanislas Chaussade, Romain Coriat and Maximilien Barret

Cancers 2023, 15(14), 3745; https://doi.org/10.3390/cancers15143745 - 24 Jul 2023

Cited by 4 | Viewed by 1625

Abstract

Patients and methods: we performed a retrospective case-control study, including cases with repeat EUS FNB for a solid pancreatic lesion, matched on a 1:2 ratio on age, sex, tumor location and presence of chronic pancreatitis with cases diagnosed on the first EUS FNB. [...] Read more.

Patients and methods: we performed a retrospective case-control study, including cases with repeat EUS FNB for a solid pancreatic lesion, matched on a 1:2 ratio on age, sex, tumor location and presence of chronic pancreatitis with cases diagnosed on the first EUS FNB. Results: thirty-four cases and 68 controls were included in the analysis. Diagnostic accuracies were 80% and 88% in the repeat and single EUS FNB groups, respectively (p = 0.824). The second EUS FNB had a sensitivity of 80%, a specificity of 75%, a positive predictive value of 96%, and a negative predictive value of 33%. Of the 34 patients in the repeat EUS FNB group, 25 (74%) had a positive diagnosis with the second EUS FNB, 4 (12%) after surgery due to a second negative EUS FNB, 4 (12%) during clinical follow-up, and 1 (3%) after a third EUS FNB. Of the 25 patients diagnosed on the repeat EUS FNB, 17 (68%) had pancreatic adenocarcinomas, 2 (8%) neuroendocrine tumors, 2 (8%) other autoimmune pancreatitis, 2 (8%) chronic pancreatitis nodules, 1 (4%) renal cancer metastasis, and 1 (4%) other malignant diagnostic. There were no complications reported after the second EUS FNB in this study. Conclusion: repeat EUS FNB made a diagnosis in three fourths of patients with solid pancreatic lesions and a first negative EUS FNB, with 26% of benign lesions. This supports the repetition of EUS FNB sampling in this clinical situation. Full article

(This article belongs to the Special Issue Advances in Treatment for Hepatobiliary and Pancreatic Cancers: Multi-Disciplinary Strategies and Outcome Evaluation)

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15 pages, 3990 KiB

Open AccessArticle

Establishment of Novel Mouse Model of Dietary NASH Rapidly Progressing into Liver Cirrhosis and Tumors

by Qianqian Zheng, Masaya Kawaguchi, Hayato Mikami, Pan Diao, Xuguang Zhang, Zhe Zhang, Takero Nakajima, Takanobu Iwadare, Takefumi Kimura, Jun Nakayama and Naoki Tanaka

Cancers 2023, 15(14), 3744; https://doi.org/10.3390/cancers15143744 - 24 Jul 2023

Cited by 1 | Viewed by 2221

Abstract

Non-alcoholic steatohepatitis (NASH), which is the most severe manifestation of non-alcoholic fatty liver disease (NAFLD), has been recognized as a major hepatocellular carcinoma (HCC) catalyst. However, the molecular mechanism of NASH-liver fibrosis-HCC sequence remains unclear and a specific and effective treatment for NASH [...] Read more.

Non-alcoholic steatohepatitis (NASH), which is the most severe manifestation of non-alcoholic fatty liver disease (NAFLD), has been recognized as a major hepatocellular carcinoma (HCC) catalyst. However, the molecular mechanism of NASH-liver fibrosis-HCC sequence remains unclear and a specific and effective treatment for NASH has not yet been established. The progress in this field depends on the availability of reliable preclinical models which show the steady progression to NASH, liver cirrhosis, and HCC. However, most of the NASH mouse models that have been described to date develop NASH generally for more than 24 weeks and there is an uncertainty of HCC development. To overcome such shortcomings of experimental NASH studies, we established a novel NASH-HCC mouse model with very high reproducibility, generality, and convenience. We treated male C57BL/6J mice with a newly developed choline-deficient and methionine-restricted high-fat diet, named OYC-NASH2 diet, for 60 weeks. Treatment of OYC-NASH2 diet for 3 weeks revealed marked steatosis, lobular inflammation, and fibrosis, histologically diagnosed as NASH. Liver cirrhosis was observed in all mice with 48-week treatment. Liver nodules emerged at 12 weeks of the treatment, > 2 mm diameter liver tumors developed in all mice at 24 weeks of the treatment and HCC appeared after 36-week treatment. In conclusion, our rapidly progressive and highly reproducible NASH-liver cirrhosis-HCC model is helpful for preclinical development and research on the pathogenesis of human NAFLD-NASH-HCC. Our mouse model would be useful for the development of novel chemicals for NASH-HCC-targeted therapies. Full article

(This article belongs to the Special Issue Hepatocellular Carcinoma: Current Treatment Strategies for Advanced Disease and Recurrence)

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3 pages, 192 KiB

Open AccessEditorial

Surgical Treatment of Gastrointestinal Cancers

by Ulrich Ronellenfitsch

Cancers 2023, 15(14), 3743; https://doi.org/10.3390/cancers15143743 - 24 Jul 2023

Cited by 1 | Viewed by 1309

Abstract

Even though there have been remarkable advances in systemic treatment of gastrointestinal malignancies over the last few decades, in the vast majority of instances, surgery remains the sole therapeutic approach offering a chance for a definite cure [...] Full article

(This article belongs to the Special Issue Surgical Treatment of Gastrointestinal Cancers)

16 pages, 2191 KiB

Open AccessArticle

Applied Molecular-Based Quality Control of Biobanked Samples for Multi-Omics Approach

by Anna Michalska-Falkowska, Jacek Niklinski, Hartmut Juhl, Anetta Sulewska, Joanna Kisluk, Radoslaw Charkiewicz, Michal Ciborowski, Rodryg Ramlau, Robert Gryczka, Cezary Piwkowski, Miroslaw Kozlowski, Borys Miskiewicz, Przemyslaw Biecek, Karolina Wnorowska, Zofia Dzieciol-Anikiej, Karine Sargsyan, Wojciech Naumnik, Robert Mroz and Joanna Reszec-Gielazyn

Cancers 2023, 15(14), 3742; https://doi.org/10.3390/cancers15143742 - 24 Jul 2023

Cited by 8 | Viewed by 2699

Abstract

Biobanks are vital for high-throughput translational research, but the rapid development of novel molecular techniques, especially in omics assays, poses challenges to traditional practices and recommendations. In our study, we used biospecimens from oncological patients in Polish clinics and collaborated with the Indivumed [...] Read more.

Biobanks are vital for high-throughput translational research, but the rapid development of novel molecular techniques, especially in omics assays, poses challenges to traditional practices and recommendations. In our study, we used biospecimens from oncological patients in Polish clinics and collaborated with the Indivumed Group. For serum/plasma samples, we monitored hemolysis, controlled RNA extraction, assessed cDNA library quality and quantity, and verified NGS raw data. Tissue samples underwent pathologic evaluation to confirm histology and determine tumor content. Molecular quality control measures included evaluating the RNA integrity number, assessing cDNA library quality and quantity, and analyzing NGS raw data. Our study yielded the creation of distinct workflows for conducting preanalytical quality control of serum/plasma and fresh-frozen tissue samples. These workflows offer customization options to suit the capabilities of different biobanking entities. In order to ensure the appropriateness of biospecimens for advanced research applications, we introduced molecular-based quality control methods that align with the demands of high-throughput assays. The novelty of proposed workflows, rooted in innovative molecular techniques, lies in the integration of these QC methods into a comprehensive schema specifically designed for high-throughput research applications. Full article

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21 pages, 2271 KiB

Open AccessArticle

Optimization of a Luteolin-Loaded TPGS/Poloxamer 407 Nanomicelle: The Effects of Copolymers, Hydration Temperature and Duration, and Freezing Temperature on Encapsulation Efficiency, Particle Size, and Solubility

by Muhammad Redza Fahmi Mod Razif, Siok Yee Chan, Riyanto Teguh Widodo, Yik-Ling Chew, Masriana Hassan, Shairyzah Ahmad Hisham, Shamima Abdul Rahman, Long Chiau Ming, Ching Siang Tan, Siew-Keah Lee and Kai Bin Liew

Cancers 2023, 15(14), 3741; https://doi.org/10.3390/cancers15143741 - 24 Jul 2023

Cited by 5 | Viewed by 2076

Abstract

Background: Luteolin is a flavonoid compound that has been widely studied for its various anti-cancer properties and sensitization to multidrug-resistant cells. However, the limited solubility and bioavailability of Lut hindered its potential clinical use. Theoretically, the combination of this compound with vitamin E [...] Read more.

Background: Luteolin is a flavonoid compound that has been widely studied for its various anti-cancer properties and sensitization to multidrug-resistant cells. However, the limited solubility and bioavailability of Lut hindered its potential clinical use. Theoretically, the combination of this compound with vitamin E TPGS and poloxamer 407 can produce a synergistic effect to enhance tumor apoptosis and P-glycoprotein inhibition. This study aimed to develop and optimize vitamin E TPGS/Poloxamer 407 micelles loaded with luteolin through investigating certain factors that can affect the encapsulation efficiency and particle size of the micelle. Methods: A micelle was prepared using the film hydration method, and the micellar solution was lyophilized. The cake formed was analyzed. The factors investigated include the concentrations of the surfactants, ratio of vitamin E TPGS/Poloxamer 407, temperature of the hydrating solution, duration of hydration, and freezing temperature before lyophilization. The effects of these factors on the encapsulation efficiency and particle size of the micelle were also studied. The encapsulation efficiency was measured using a UV-Vis spectrophotometer, while particle size was measured using dynamic light scattering. Results: The optimized micelle was found to have 90% encapsulation efficiency with a particle size of less than 40 nm, which was achieved using a 10% concentration of surfactants at a vitamin E TPGS/Poloxamer 407 ratio of 3:1. The optimized temperature for hydrating the micellar film was 40 °C, the optimized mixing time was 1 h, and the optimized freezing temperature was −80 °C. The solubility of the luteolin-loaded micelles increased 459-fold compared to pure Lut in water. The critical micelle concentration of the vitamin E TPGS/Poloxamer 407 micelle was 0.001 mg/mL, and the release study showed that luteolin-loaded micelles exhibited sustained release behavior. The release of luteolin from a micelle was found to be higher in pH 6.8 compared to pH 7.4, which signified that luteolin could be accumulated more in a tumor microenvironment compared to blood. Conclusion: This study demonstrated that several factors need to be considered when developing such nanoparticles in order to obtain a well-optimized micelle. Full article

(This article belongs to the Special Issue Advances in Anticancer Drugs and Pharmacotherapy of Cancer)

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11 pages, 1182 KiB

Open AccessArticle

High OCT4 Expression Might Be Associated with an Aggressive Phenotype in Rectal Cancer

by Lina Lambis-Anaya, Mashiel Fernández-Ruiz, Yamil Liscano and Amileth Suarez-Causado

Cancers 2023, 15(14), 3740; https://doi.org/10.3390/cancers15143740 - 23 Jul 2023

Cited by 4 | Viewed by 1559

Abstract

Rectal cancer (RC) is one of the most common malignant neoplasms, and cancer stem cells (CSCs) of the intestinal tract have been implicated in its origin. The oncofetal protein OCT4 has been linked to neoplastic processes, but its role and clinical significance in [...] Read more.

Rectal cancer (RC) is one of the most common malignant neoplasms, and cancer stem cells (CSCs) of the intestinal tract have been implicated in its origin. The oncofetal protein OCT4 has been linked to neoplastic processes, but its role and clinical significance in RC are unknown. This study investigates the expression of the stem cell marker OCT4 related to clinical-pathological characteristics and its clinical significance in RC patients. The expression level of stem cell marker OCT4 was analyzed in 22 primary rectal tumors by western blot. The association between OCT4 protein expression and the clinical-pathological features of tumors was evaluated by χ² test and Fisher’s exact test. We demonstrated that the expression of the stem cell marker OCT4 was observed in tumor tissue but not adjacent non-tumor tissue. High expression of the stem cell marker OCT4 was significantly associated with histological differentiation grade (p = 0.039), tumor invasion level (p = 0.004), lymph node involvement (p = 0.044), tumor-node-metastasis (TNM) stage (p = 0.002), and clinical stage (p = 0.021). These findings suggest that high OCT4 expression is associated with a more aggressive RC phenotype, with a greater likelihood of progression and metastasis. These results shed light on the importance of targeting this CSC marker to attenuate RC progression. Full article

(This article belongs to the Special Issue Molecular Biology of Colorectal Cancers)

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17 pages, 1034 KiB

Open AccessReview

The Use of Targeted Cytokines as Cancer Therapeutics in Glioblastoma

by Moloud Sooreshjani, Shashwat Tripathi, Corey Dussold, Hinda Najem, John de Groot, Rimas V. Lukas and Amy B. Heimberger

Cancers 2023, 15(14), 3739; https://doi.org/10.3390/cancers15143739 - 23 Jul 2023

Cited by 2 | Viewed by 2460

Abstract

Cytokines play an important role in regulating the immune response. Although there is great interest in exploiting cytokines for cancer immunotherapy, their clinical potential is limited by their pleiotropic properties and instability. A variety of cancer cell-intrinsic and extrinsic characteristics pose a barrier [...] Read more.

Cytokines play an important role in regulating the immune response. Although there is great interest in exploiting cytokines for cancer immunotherapy, their clinical potential is limited by their pleiotropic properties and instability. A variety of cancer cell-intrinsic and extrinsic characteristics pose a barrier to effective treatments including cytokines. Recent studies using gene and cell therapy offer new opportunities for targeting cytokines or their receptors, demonstrating that they are actionable targets. Current efforts such as virotherapy, systemic cytokine therapy, and cellular and gene therapy have provided novel strategies that incorporate cytokines as potential therapeutic strategies for glioblastoma. Ongoing research on characterizing the tumor microenvironment will be informative for prioritization and combinatorial strategies of cytokines for future clinical trials. Unique therapeutic opportunities exist at the convergence of cytokines that play a dual role in tumorigenesis and immune modulation. Here, we discuss the underlying strategies in pre- and clinical trials aiming to enhance treatment outcomes in glioblastoma patients. Full article

(This article belongs to the Special Issue The Use of Targeted Cytokine for Novel Cancer Therapeutics)

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27 pages, 18187 KiB

Open AccessArticle

Histology-Validated Dielectric Characterisation of Lung Carcinoma Tissue for Microwave Thermal Ablation Applications

by Laura Farina, Giuseppe Ruvio, Ramadan Shatwan, Aliaa Shalaby, Martin O’Halloran, Alexandra White, Alan Soo, David Breen, Aoife Lowery and Anne Marie Quinn

Cancers 2023, 15(14), 3738; https://doi.org/10.3390/cancers15143738 - 23 Jul 2023

Cited by 6 | Viewed by 1516

Abstract

Microwave thermal ablation is a promising emerging treatment for early-stage lung cancer. Applicator design optimisation and treatment planning rely on accurate knowledge of dielectric tissue properties. Limited dielectric data are available in the literature for human lung tissue and pulmonary tumours. In this [...] Read more.

Microwave thermal ablation is a promising emerging treatment for early-stage lung cancer. Applicator design optimisation and treatment planning rely on accurate knowledge of dielectric tissue properties. Limited dielectric data are available in the literature for human lung tissue and pulmonary tumours. In this work, neoplastic and non-neoplastic lung dielectric properties are characterised and correlated with gross and histological morphology. Fifty-six surgical specimens were obtained from twelve patients undergoing lung resection for lung cancer in University Hospital of Galway, Ireland. Dielectric spectroscopy in the microwave frequency range (500 MHz–8.5 GHz) was performed on the ex vivo lung specimens with the open-ended coaxial probe technique (in the Department of Pathology). Dielectric data were analysed and correlated with the tissue histology. The dielectric properties of twelve lung tumours (67% non-small cell carcinoma (NSCC)) and uninvolved lung parenchyma were obtained. The values obtained from the neoplastic lung specimens (relative permittivity: 52.0 ± 5.4, effective conductivity: 1.9 ± 0.2 S/m, at 2.45 GHz) were on average twice the value of the non-neoplastic lung specimens (relative permittivity: 28.3 ± 6.7, effective conductivity: 1.0 ± 0.3 S/m, at 2.45 GHz). Dense fibrosis was comparable with tumour tissue (relative permittivity 49.3 ± 4.6, effective conductivity: 1.8 ± 0.1 S/m, at 2.45 GHz). Full article

(This article belongs to the Special Issue Novel Strategy and Technologies in Local and Locoregional Treatment for Lung Cancer)

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16 pages, 947 KiB

Open AccessReview

Advancements in the Treatment of CLL: The Rise of Zanubrutinib as a Preferred Therapeutic Option

by Stefano Molica, Constantine Tam, David Allsup and Aaron Polliack

Cancers 2023, 15(14), 3737; https://doi.org/10.3390/cancers15143737 - 23 Jul 2023

Cited by 7 | Viewed by 3754

Abstract

Ibrutinib, the first-in-class Bruton’s tyrosine kinase inhibitor (BTKi), is a commonly deployed therapeutic option for previously untreated and relapsed/refractory (R/R) patients with chronic lymphocytic leukemia (CLL). The use of ibrutinib is, however, partially limited by off-target side effects. Zanubrutinib (zanu) is a second-generation [...] Read more.

Ibrutinib, the first-in-class Bruton’s tyrosine kinase inhibitor (BTKi), is a commonly deployed therapeutic option for previously untreated and relapsed/refractory (R/R) patients with chronic lymphocytic leukemia (CLL). The use of ibrutinib is, however, partially limited by off-target side effects. Zanubrutinib (zanu) is a second-generation BTKi with enhanced target selectivity and occupancy of the kinase binding site. The SEQUOIA study showed that zanu significantly prolonged progression-free survival (PFS) when compared to bendamustine–rituximab (BR) in treatment-naive CLL patients. More recently, data from the phase III ALPINE trial, which directly compared zanu with ibrutinib, demonstrated that zanu’s advantages include an improved safety profile as well as enhanced clinical efficacy. Based on the results of the SEQUOIA and ALPINE pivotal trials, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) licensed zanu for the treatment of patients with CLL or small lymphocytic lymphoma (SLL) in January 2023. The updated (v2.2023) National Comprehensive Cancer Network (NCCN) guidelines and the most recent German CLL algorithm suggest that zanu may replace first-generation BTKis as a preferred therapeutic option for patients with CLL/SLL due to its increased selectivity for the kinase binding site, improved therapeutic efficacy, and favorable toxicity profile. Some drug class-related characteristics such as drug resistance, low complete remission (CR) rates, and indefinite treatment duration still remain with zanu, and the results from recently completed and ongoing fixed-duration clinical trials, combining zanu with an anti-BCL2 agent, are eagerly awaited with the possible promise of a reduced treatment duration and lower financial burden. Full article

(This article belongs to the Special Issue Advanced Research in Oncology in 2023)

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11 pages, 1476 KiB

Open AccessArticle

An Integrated CT and MRI Imaging Model to Differentiate between Adrenal Adenomas and Pheochromocytomas

by Marta Araujo-Castro, Iñigo García Sanz, César Mínguez Ojeda, María Calatayud, Felicia A. Hanzu, Mireia Mora, Almudena Vicente Delgado, Concepción Blanco Carrera, Paz de Miguel Novoa, María del Carmen López García, Laura Manjón-Miguélez, Pablo Rodríguez de Vera Gómez, María del Castillo Tous, Rebeca Barahona San Millán, Mónica Recansens, Mariana Tomé Fernández-Ladreda, Nuria Valdés, Paola Gracia Gimeno, Cristina Robles Lazaro, Theodora Michalopoulou, Victoria Gómez Dos Santos, Cristina Alvarez-Escola, Rogelio García Centeno, Cristina Lamas and Aura Herrera-Martínez Show full author list Hide full author list

Cancers 2023, 15(14), 3736; https://doi.org/10.3390/cancers15143736 - 23 Jul 2023

Cited by 2 | Viewed by 1561

Abstract

Purpose: to perform an external validation of our predictive model to rule out pheochromocytoma (PHEO) based on unenhanced CT in a cohort of patients with PHEOs and adenomas who underwent adrenalectomy. Methods: The predictive model was previously developed in a retrospective cohort of [...] Read more.

Purpose: to perform an external validation of our predictive model to rule out pheochromocytoma (PHEO) based on unenhanced CT in a cohort of patients with PHEOs and adenomas who underwent adrenalectomy. Methods: The predictive model was previously developed in a retrospective cohort of 1131 patients presenting with adrenal lesions. In the present study, we performed an external validation of the model in another cohort of 214 patients with available histopathological results. Results: For the external validation, 115 patients with PHEOs and 99 with adenomas were included. Our previously described predictive model combining the variables of high lipid content and tumor size in unenhanced CT (AUC-ROC: 0.961) had a lower diagnostic accuracy in our current study population for the prediction of PHEO (AUC: 0.750). However, when we excluded atypical adenomas (with Hounsfield units (HU) > 10, n = 39), the diagnostic accuracy increased to 87.4%. In addition, in the whole cohort (including atypical adenomas), when MRI information was included in the model, the diagnostic accuracy increased to up to 85% when the variables tumor size, high lipid content in an unenhanced CT scan, and hyperintensity in the T2 sequence in MRI were included. The probability of PHEO was <0.3% for adrenal lesions <20 mm with >10 HU and without hyperintensity in T2. Conclusion: Our study confirms that our predictive model combining tumor size and lipid content has high reliability for the prediction of PHEO when atypical adrenal lesions are excluded. However, for atypical adrenal lesions with >10 HU in an unenhanced CT scan, MRI information is necessary for a proper exclusion of the PHEO diagnosis. Full article

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

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14 pages, 299 KiB

Open AccessReview

The Role of Lymphadenectomy in Early-Stage NSCLC

by Beatrice Manfredini, Carmelina Cristina Zirafa, Pier Luigi Filosso, Alessandro Stefani, Gaetano Romano, Federico Davini and Franca Melfi

Cancers 2023, 15(14), 3735; https://doi.org/10.3390/cancers15143735 - 23 Jul 2023

Cited by 4 | Viewed by 1459

Abstract

Lung cancer remains the leading cause of cancer-related death worldwide. The involvement of lymph nodes by the tumor has a strong impact on survival of patients. For this reason, lymphadenectomy plays a crucial role in the staging and prognosis of NSCLC, to define [...] Read more.

Lung cancer remains the leading cause of cancer-related death worldwide. The involvement of lymph nodes by the tumor has a strong impact on survival of patients. For this reason, lymphadenectomy plays a crucial role in the staging and prognosis of NSCLC, to define the most appropriate therapeutic strategies concerning the stage of the disease. To date, the benefit, in terms of survival, of the different extents of lymphadenectomy remains controversial in the scientific community. It is recognized that metastatic involvement of mediastinal lymph nodes in lung cancer is one of the most significant prognostic factors, in terms of survival, and it is therefore mandatory to identify patients with lymph node metastases who may benefit from adjuvant therapies, to prevent distant disease and local recurrences. The purpose of this review is to evaluate the role of lymphadenectomy in early-stage NSCLC in terms of efficacy and accuracy, comparing systematic, sampling, and lobe-specific lymph node dissection and analyzing the existing critical issue, through a search of the most relevant articles published in the last decades. Full article

(This article belongs to the Special Issue Innovation in the Treatment of Thoracic Cancers)

14 pages, 598 KiB

Open AccessReview

The Role of Salvage Radical Prostatectomy in Patients with Radiation-Resistant Prostate Cancer

by Jake Drobner, Alain Kaldany, Mihir S. Shah and Saum Ghodoussipour

Cancers 2023, 15(14), 3734; https://doi.org/10.3390/cancers15143734 - 23 Jul 2023

Cited by 3 | Viewed by 2305

Abstract

There are multiple treatment strategies for patients with localized prostate adenocarcinoma. In intermediate- and high-risk patients, external beam radiation therapy demonstrates effective long-term cancer control rates comparable to radical prostatectomy. In patients who opt for initial radiotherapy but have a local recurrence of [...] Read more.

There are multiple treatment strategies for patients with localized prostate adenocarcinoma. In intermediate- and high-risk patients, external beam radiation therapy demonstrates effective long-term cancer control rates comparable to radical prostatectomy. In patients who opt for initial radiotherapy but have a local recurrence of their cancer, there is no unanimity on the optimal salvage approach. The lack of randomized trials comparing surgery to other local salvage therapy or observation makes it difficult to ascertain the ideal management. A narrative review of existing prospective and retrospective data related to salvage radical prostatectomy after radiation therapy was undertaken. Based on retrospective and prospective data, post-radiation salvage radical prostatectomy confers oncologic benefits, with overall survival ranging from 84 to 95% at 5 years and from 52 to 77% at 10 years. Functional morbidity after salvage prostatectomy remains high, with rates of post-surgical incontinence and erectile dysfunction ranging from 21 to 93% and 28 to 100%, respectively. Factors associated with poor outcomes after post-radiation salvage prostatectomy include preoperative PSA, the Gleason score, post-prostatectomy staging, and nodal involvement. Salvage radical prostatectomy represents an effective treatment option for patients with biochemical recurrence after radiotherapy, although careful patient selection is important to optimize oncologic and functional outcomes. Full article

(This article belongs to the Special Issue Salvage Therapy for Recurrent Prostate Cancer—Optimizing Oncological and Functional Outcomes)

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14 pages, 937 KiB

Open AccessReview

Cellular Therapy for Lung Cancer: Focusing on Chimeric Antigen Receptor T (CAR T) Cells and Tumor-Infiltrating Lymphocyte (TIL) Therapy

by Vatsala Katiyar, Jason Chesney and Goetz Kloecker

Cancers 2023, 15(14), 3733; https://doi.org/10.3390/cancers15143733 - 23 Jul 2023

Cited by 11 | Viewed by 3077

Abstract

Lung cancer is a leading cause of morbidity and mortality in the United States and worldwide. The introduction of immune checkpoint inhibitors has led to a marked improvement in the outcomes of lung cancer patients. Despite these advances, there is a huge unmet [...] Read more.

Lung cancer is a leading cause of morbidity and mortality in the United States and worldwide. The introduction of immune checkpoint inhibitors has led to a marked improvement in the outcomes of lung cancer patients. Despite these advances, there is a huge unmet need for therapeutic options in patients who are not candidates for targeted or immunotherapy or those who progress after first-line treatment. With its high mutational burden, lung cancer appears to be an attractive target for novel personalized treatment approaches. In this review, we provide an overview of two adoptive cell therapy approaches–chimeric antigen receptors (CAR) T-cell therapy and Tumor-infiltrating lymphocytes (TILs) in lung cancer with an emphasis on current challenges and future perspectives. While both these therapies are still in the early phases of development in lung cancer and need more refinement, they harbor the potential to be effective treatment options for this group of patients with otherwise poor prognoses. Full article

(This article belongs to the Collection Diagnosis and Treatment of Primary and Secondary Lung Cancers)

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15 pages, 662 KiB

Open AccessReview

Breaking the ‘Undruggable’ Barrier: Anti-PD-1/PD-L1 Immunotherapy for Non-Small Cell Lung Cancer Patients with KRAS Mutations—A Comprehensive Review and Description of Single Site Experience

by Izabela Chmielewska, Paweł Krawczyk, Anna Grenda, Magdalena Wójcik-Superczyńska, Natalia Krzyżanowska, Michał Gil and Janusz Milanowski

Cancers 2023, 15(14), 3732; https://doi.org/10.3390/cancers15143732 - 23 Jul 2023

Cited by 4 | Viewed by 2935

Abstract

Kirsten rat sarcoma viral oncogene homologue (KRAS) gene mutations are among the most commonly found oncogenic alterations in non-small cell lung cancer (NSCLC) patients. Unfortunately, KRAS mutations have been considered “undruggable” for many years, making treatment options very limited. Immunotherapy targeting [...] Read more.

Kirsten rat sarcoma viral oncogene homologue (KRAS) gene mutations are among the most commonly found oncogenic alterations in non-small cell lung cancer (NSCLC) patients. Unfortunately, KRAS mutations have been considered “undruggable” for many years, making treatment options very limited. Immunotherapy targeting programmed death-ligand 1 (PD-L1), programmed death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) has emerged as a promising therapeutic option for NSCLC patients. However, some studies have suggested a lower response rate to immunotherapy in KRAS-mutated NSCLC patients with the coexistence of mutations in the STK11 (Serine/Threonine Kinase 11) gene. However, recent clinical trials have shown promising results with the combination of immunotherapy and chemotherapy or immunotherapy and KRAS inhibitors (sotorasib, adagrasib) in such patients. In other studies, the high efficacy of immunotherapy has been demonstrated in NSCLC patients with mutations in the KRAS gene that do not coexist with other mutations or coexist with the TP53 gene mutations. In this paper, we review the available literature on the efficacy of immunotherapy in KRAS-mutated NSCLC patients. In addition, we presented single-site experience on the efficacy of immunotherapy in NSCLC patients with KRAS mutations. The effectiveness of chemoimmunotherapy or immunotherapy as well as KRAS inhibitors extends the overall survival of advanced NSCLC patients with the G12C mutation in the KRAS gene to 2–3 years. This type of management has become the new standard in the treatment of NSCLC patients. Further studies are needed to clarify the potential benefits of immunotherapy in KRAS-mutated NSCLC patients and to identify potential biomarkers that may help predict response to therapy. Full article

(This article belongs to the Special Issue Advanced in Targeted Therapies in Cancer)

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23 pages, 1904 KiB

Open AccessReview

Unveiling the Therapeutic Potential of Squalene Synthase: Deciphering Its Biochemical Mechanism, Disease Implications, and Intriguing Ties to Ferroptosis

by David Figueredo Picón and Rachid Skouta

Cancers 2023, 15(14), 3731; https://doi.org/10.3390/cancers15143731 - 22 Jul 2023

Cited by 11 | Viewed by 2912

Abstract

Squalene synthase (SQS) has emerged as a promising therapeutic target for various diseases, including cancers, owing to its pivotal role in the mevalonate pathway and the antioxidant properties of squalene. Primarily, SQS orchestrates the head-to-head condensation reaction, catalyzing the fusion of two farnesyl [...] Read more.

Squalene synthase (SQS) has emerged as a promising therapeutic target for various diseases, including cancers, owing to its pivotal role in the mevalonate pathway and the antioxidant properties of squalene. Primarily, SQS orchestrates the head-to-head condensation reaction, catalyzing the fusion of two farnesyl pyrophosphate molecules, leading to the formation of squalene, which has been depicted as a highly effective oxygen-scavenging agent in in vitro studies. Recent studies have depicted this isoprenoid as a protective layer against ferroptosis due to its potential regulation of lipid peroxidation, as well as its protection against oxidative damage. Therefore, beyond its fundamental function, recent investigations have unveiled additional roles for SQS as a regulator of lipid peroxidation and programmed cell death pathways, such as ferroptosis—a type of cell death characterized by elevated levels of lipid peroxide, one of the forms of reactive oxygen species (ROS), and intracellular iron concentration. Notably, thorough explorations have shed light on the distinctive features that set SQS apart from other members within the isoprenoid synthase superfamily. Its unique biochemical structure, intricately intertwined with its reaction mechanism, has garnered significant attention. Moreover, considerable evidence substantiates the significance of SQS in various disease contexts, and its intriguing association with ferroptosis and lipid peroxidation. The objective of this report is to analyze the existing literature comprehensively, corroborating these findings, and provide an up-to-date perspective on the current understanding of SQS as a prospective therapeutic target, as well as its intricate relationship with ferroptosis. This review aims to consolidate the knowledge surrounding SQS, thereby contributing to the broader comprehension of its potential implications in disease management and therapeutic interventions. Full article

(This article belongs to the Topic Advances in Anti-Cancer Drugs)

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20 pages, 4081 KiB

Open AccessArticle

Microtubule Dynamics Deregulation Induces Apoptosis in Human Urothelial Bladder Cancer Cells via a p53-Independent Pathway

by Yiannis Drosos, Eumorphia G. Konstantakou, Aggeliki-Stefania Bassogianni, Konstantinos-Stylianos Nikolakopoulos, Dimitra G. Koumoundourou, Sophia P. Markaki, Ourania E. Tsitsilonis, Gerassimos E. Voutsinas, Dimitrios Valakos, Ema Anastasiadou, Dimitris Thanos, Athanassios D. Velentzas and Dimitrios J. Stravopodis

Cancers 2023, 15(14), 3730; https://doi.org/10.3390/cancers15143730 - 22 Jul 2023

Cited by 3 | Viewed by 2054

Abstract

Bladder cancer (BLCA) is the sixth most common type of cancer and has a dismal prognosis if diagnosed late. To identify treatment options for BLCA, we systematically evaluated data from the Broad Institute DepMap project. We found that urothelial BLCA cell lines are [...] Read more.

Bladder cancer (BLCA) is the sixth most common type of cancer and has a dismal prognosis if diagnosed late. To identify treatment options for BLCA, we systematically evaluated data from the Broad Institute DepMap project. We found that urothelial BLCA cell lines are among the most sensitive to microtubule assembly inhibition by paclitaxel treatment. Strikingly, we revealed that the top dependencies in BLCA cell lines include genes encoding proteins involved in microtubule assembly. This highlights the importance of microtubule network dynamics as a major vulnerability in human BLCA. In cancers such as ovarian and breast, where paclitaxel is the gold standard of care, resistance to paclitaxel treatment has been linked to p53-inactivating mutations. To study the response of BLCA to microtubule assembly inhibition and its mechanistic link with the mutational status of the p53 protein, we treated a collection of BLCA cell lines with a dose range of paclitaxel and performed a detailed characterization of the response. We discovered that BLCA cell lines are significantly sensitive to low concentrations of paclitaxel, independently of their p53 status. Paclitaxel induced a G2/M cell cycle arrest and growth inhibition, followed by robust activation of apoptosis. Most importantly, we revealed that paclitaxel triggered a robust DNA-damage response and apoptosis program without activating the p53 pathway. Integration of transcriptomics, epigenetic, and dependency data demonstrated that the response of BLCA to paclitaxel is independent of p53 mutational signatures but strongly depends on the expression of DNA repair genes. Our work highlights urothelial BLCA as an exceptional candidate for paclitaxel treatment. It paves the way for the rational use of a combination of paclitaxel and DNA repair inhibitors as an effective, novel therapeutic strategy. Full article

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25 pages, 4889 KiB

Open AccessReview

Global Impact of Monoclonal Antibodies (mAbs) in Children: A Focus on Anti-GD2

by Cristina Larrosa, Jaume Mora and Nai-Kong Cheung

Cancers 2023, 15(14), 3729; https://doi.org/10.3390/cancers15143729 - 22 Jul 2023

Cited by 6 | Viewed by 3147

Abstract

Monoclonal antibodies (mAbs), as the name implies, are clonal antibodies that bind to the same antigen. mAbs are broadly used as diagnostic or therapeutic tools for neoplasms, autoimmune diseases, allergic conditions, and infections. Although most mAbs are approved for treating adult cancers, few [...] Read more.

Monoclonal antibodies (mAbs), as the name implies, are clonal antibodies that bind to the same antigen. mAbs are broadly used as diagnostic or therapeutic tools for neoplasms, autoimmune diseases, allergic conditions, and infections. Although most mAbs are approved for treating adult cancers, few are applicable to childhood malignancies, limited mostly to hematological cancers. As for solid tumors, only anti-disialoganglioside (GD2) mAbs are approved specifically for neuroblastoma. Inequities of drug access have continued, affecting most therapeutic mAbs globally. To understand these challenges, a deeper dive into the complex transition from basic research to the clinic, or between marketing and regulatory agencies, is timely. This review focuses on current mAbs approved or under investigation in pediatric cancer, with special attention on solid tumors and anti-GD2 mAbs, and the hurdles that limit their broad global access. Beyond understanding the mechanisms of drug resistance, the continual discovery of next generation drugs safer for children and easier to administer, the discovery of predictive biomarkers to avoid futility should ease the acceptance by patient, health care professionals and regulatory agencies, in order to expand clinical utility. With a better integration into the multimodal treatment for each disease, protocols that align with the regional clinical practice should also improve acceptance and cost-effectiveness. Communication and collaboration between academic institutions, pharmaceutical companies, and regulatory agencies should help to ensure accessible, affordable, and sustainable health care for all. Full article

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Graphical abstract

20 pages, 4854 KiB

Open AccessArticle

Lactate Can Modulate the Antineoplastic Effects of Doxorubicin and Relieve the Drug’s Oxidative Damage on Cardiomyocytes

by Valentina Rossi, Marzia Govoni and Giuseppina Di Stefano

Cancers 2023, 15(14), 3728; https://doi.org/10.3390/cancers15143728 - 22 Jul 2023

Cited by 3 | Viewed by 1331

Abstract

Background: Doxorubicin (DOXO) is currently administered as the first-choice therapy for a variety of malignancies. Cancer cells exhibit enhanced glycolysis and lactate production. This metabolite affects gene expression and can play a role in chemoresistance. Aim of this study: We investigated whether the [...] Read more.

Background: Doxorubicin (DOXO) is currently administered as the first-choice therapy for a variety of malignancies. Cancer cells exhibit enhanced glycolysis and lactate production. This metabolite affects gene expression and can play a role in chemoresistance. Aim of this study: We investigated whether the enhanced lactate levels that characterize neoplastic tissues can modify the response of cancer cells to DOXO. Methods: After exposing cancer cells to increased lactate levels, we examined whether this metabolite could interfere with the principal mechanisms responsible for the DOXO antineoplastic effect. Results: Increased lactate levels did not affect DOXO-induced topoisomerase poisoning but offered protection against the oxidative damage caused by the drug. This protection was related to changes in gene expression caused by the combined action of DOXO and lactate. Oxidative damage significantly contributed to the heavy cardiotoxicity following DOXO treatment. In cultured cardiomyocytes, we confirmed that DOXO-induced DNA damage and oxidative stress can be significantly mitigated by exposing the cells to increased lactate levels. Conclusions: In addition to contributing to elucidating the effects of the combined action of DOXO and lactate, our results suggest a possible method to reduce the heavy drug cardiotoxicity, a major side effect leading to therapy discontinuation. Full article

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11 pages, 1643 KiB

Open AccessArticle

Treatment Patterns and Outcomes for Patients with Ampullary Carcinoma Who Do Not Undergo Surgery

by Benjin D. Facer, Jordan M. Cloyd, Ashish Manne, Kenneth L. Pitter, Dayssy A. Diaz, Jose G. Bazan and Eric D. Miller

Cancers 2023, 15(14), 3727; https://doi.org/10.3390/cancers15143727 - 22 Jul 2023

Viewed by 1406

Abstract

Surgical resection is the standard of care for ampullary adenocarcinoma (AC). Many patients are ineligible due to comorbidities/advanced disease. Evidence for the optimal non-operative management of localized AC is lacking. We hypothesize that patients treated with chemotherapy (CT) and definitive radiation (DRT) will [...] Read more.

Surgical resection is the standard of care for ampullary adenocarcinoma (AC). Many patients are ineligible due to comorbidities/advanced disease. Evidence for the optimal non-operative management of localized AC is lacking. We hypothesize that patients treated with chemotherapy (CT) and definitive radiation (DRT) will have superior survival (OS) compared to those treated with CT alone. We performed a retrospective review of the National Cancer Database from 2004 to 2017 to identify patients with non-metastatic AC and no surgical intervention. Patients were categorized as having received no treatment, palliative radiotherapy (PRT) alone, CT alone, CT + PRT, DRT alone, or CT + DRT. We utilized Kaplan–Meier analysis to determine OS and the log-rank test to compare survival curves. Among 2176 patients, treatment groups were: No treatment (71.2%), PRT alone (1.9%), CT alone (13.1%), CT + PRT (1.6%), DRT alone (2.4%), and CT + DRT (9.7%). One-year OS varied by treatment group, ranging from 35.1% (PRT alone) to 59.4% (CT + DRT). The one-year OS in a matched cohort was not significantly different between CT alone and CT + DRT (HR 0.87, 95% CI 0.69–1.10, p = 0.87). Most patients with non-metastatic AC not treated with surgery do not receive any treatment. There is no difference in one-year OS between those undergoing CT alone and CT + DRT. Full article

(This article belongs to the Section Cancer Therapy)

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16 pages, 747 KiB

Open AccessReview

Immunotherapy Approaches in Isocitrate-Dehydrogenase-Mutant Low-Grade Glioma

by Marco Gallus, Darwin Kwok, Senthilnath Lakshmanachetty, Akane Yamamichi and Hideho Okada

Cancers 2023, 15(14), 3726; https://doi.org/10.3390/cancers15143726 - 22 Jul 2023

Cited by 7 | Viewed by 2478 | Correction

Abstract

Low-grade gliomas (LGGs) are slow-growing tumors in the central nervous system (CNS). Patients characteristically show the onset of seizures or neurological deficits due to the predominant LGG location in high-functional brain areas. As a molecular hallmark, LGGs display mutations in the isocitrate dehydrogenase [...] Read more.

Low-grade gliomas (LGGs) are slow-growing tumors in the central nervous system (CNS). Patients characteristically show the onset of seizures or neurological deficits due to the predominant LGG location in high-functional brain areas. As a molecular hallmark, LGGs display mutations in the isocitrate dehydrogenase (IDH) enzymes, resulting in an altered cellular energy metabolism and the production of the oncometabolite D-2-hydroxyglutarate. Despite the remarkable progress in improving the extent of resection and adjuvant radiotherapy and chemotherapy, LGG remains incurable, and secondary malignant transformation is often observed. Therefore, novel therapeutic approaches are urgently needed. In recent years, immunotherapeutic strategies have led to tremendous success in various cancer types, but the effect of immunotherapy against glioma has been limited due to several challenges, such as tumor heterogeneity and the immunologically “cold” tumor microenvironment. Nevertheless, recent preclinical and clinical findings from immunotherapy trials are encouraging and offer a glimmer of hope for treating IDH-mutant LGG patients. Here, we aim to review the lessons learned from trials involving vaccines, T-cell therapies, and IDH-mutant inhibitors and discuss future approaches to enhance the efficacy of immunotherapies in IDH-mutant LGG. Full article

(This article belongs to the Special Issue Low Grade Gliomas)

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18 pages, 2476 KiB

Open AccessArticle

Cancer Associated Macrophage-like Cells Are Prognostic for Highly Aggressive Prostate Cancer in Both the Non-Metastatic and Metastatic Settings

by Daniel J. Gironda, Raymond C. Bergan, R. Katherine Alpaugh, Daniel C. Danila, Tuan L. Chuang, Brenda Y. Hurtado, Thai Ho and Daniel L. Adams

Cancers 2023, 15(14), 3725; https://doi.org/10.3390/cancers15143725 - 22 Jul 2023

Viewed by 1803

Abstract

Despite advancements in the early-stage detection and expansion of treatments for prostate cancer (PCa), patient mortality rates remain high in patients with aggressive disease and the overtreatment of indolent disease remains a major issue. Prostate-specific antigen (PSA), a standard PCa blood biomarker, is [...] Read more.

Despite advancements in the early-stage detection and expansion of treatments for prostate cancer (PCa), patient mortality rates remain high in patients with aggressive disease and the overtreatment of indolent disease remains a major issue. Prostate-specific antigen (PSA), a standard PCa blood biomarker, is limited in its ability to differentiate disease subtypes resulting in the overtreatment of non-aggressive indolent disease. Here we assess engorged cancer-associated macrophage-like cells (CAMLs), a ≥50 µm, cancer-specific, polynucleated circulating cell type found in the blood of patients with PCa as a potential companion biomarker to PSA for patient risk stratification. We found that rising PSA is positively correlated with increasing CAML size (r = 0.307, p = 0.004) and number of CAMLs in circulation (r = 0.399, p < 0.001). Over a 2-year period, the presence of a single engorged CAML was associated with 20.9 times increased likelihood of progression (p = 0.016) in non-metastatic PCa, and 2.4 times likelihood of progression (p = 0.031) with 5.4 times likelihood of death (p < 0.001) in metastatic PCa. These preliminary data suggest that CAML cell monitoring, in combination with PSA, may aid in differentiating non-aggressive from aggressive PCas by adding biological information that complements traditional clinical biomarkers, thereby helping guide treatment strategies. Full article

(This article belongs to the Special Issue Analyze Cancer Screening and Make Predictions and Prognoses Using Biomarkers)

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21 pages, 5827 KiB

Open AccessArticle

Metformin Treatment Reduces CRC Aggressiveness in a Glucose-Independent Manner: An In Vitro and Ex Vivo Study

by Marie Boutaud, Clément Auger, Mireille Verdier and Niki Christou

Cancers 2023, 15(14), 3724; https://doi.org/10.3390/cancers15143724 - 22 Jul 2023

Cited by 3 | Viewed by 1609

Abstract

(1) Background: Metformin, an anti-diabetic drug, seems to protect against aggressive acquisition in colorectal cancers (CRCs). However, its mechanisms are still really unknown, raising questions about the possibility of its positive impact on non-diabetic patients with CRC. (2) Methods: An in vitro study [...] Read more.

(1) Background: Metformin, an anti-diabetic drug, seems to protect against aggressive acquisition in colorectal cancers (CRCs). However, its mechanisms are still really unknown, raising questions about the possibility of its positive impact on non-diabetic patients with CRC. (2) Methods: An in vitro study based on human colon cancer cell lines and an ex vivo study with different colon cancer stages with proteomic and transcriptomic analyses were initiated. (3) Results: Metformin seems to protect from colon cancer invasive acquisition, irrespective of glucose concentration. (4) Conclusions: Metformin could be used as an adjuvant treatment to surgery for both diabetic and non-diabetic patients in order to prevent the acquisition of aggressiveness and, ultimately, recurrences. Full article

(This article belongs to the Special Issue Colorectal Cancer: Tumour Microenvironment, Cellular Heterogeneity and Therapeutics)

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24 pages, 1548 KiB

Open AccessReview

NAFLD-Related HCC: Focus on the Latest Relevant Preclinical Models

by Jing Fang, Séverine Celton-Morizur and Chantal Desdouets

Cancers 2023, 15(14), 3723; https://doi.org/10.3390/cancers15143723 - 22 Jul 2023

Cited by 6 | Viewed by 3348

Abstract

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and one of the deadliest cancers worldwide. Despite extensive research, the biological mechanisms underlying HCC’s development and progression remain only partially understood. Chronic overeating and/or sedentary-lifestyle-associated obesity, which promote Non-Alcoholic Fatty [...] Read more.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and one of the deadliest cancers worldwide. Despite extensive research, the biological mechanisms underlying HCC’s development and progression remain only partially understood. Chronic overeating and/or sedentary-lifestyle-associated obesity, which promote Non-Alcoholic Fatty Liver Disease (NAFLD), have recently emerged as worrying risk factors for HCC. NAFLD is characterized by excessive hepatocellular lipid accumulation (steatosis) and affects one quarter of the world’s population. Steatosis progresses in the more severe inflammatory form, Non-Alcoholic Steatohepatitis (NASH), potentially leading to HCC. The incidence of NASH is expected to increase by up to 56% over the next 10 years. Better diagnoses and the establishment of effective treatments for NAFLD and HCC will require improvements in our understanding of the fundamental mechanisms of the disease’s development. This review describes the pathogenesis of NAFLD and the mechanisms underlying the transition from NAFL/NASH to HCC. We also discuss a selection of appropriate preclinical models of NAFLD for research, from cellular models such as liver-on-a-chip models to in vivo models, focusing particularly on mouse models of dietary NAFLD-HCC. Full article

(This article belongs to the Collection Primary Liver Cancer)

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38 pages, 1655 KiB

Open AccessReview

Macrophage-Based Therapeutic Strategies in Hematologic Malignancies

by Saeed Khalili, Fatemeh Zeinali, Atousa Moghadam Fard, Seyed Reza Taha, Andarz Fazlollahpour Naghibi, Kimia Bagheri, Mahdieh Shariat Zadeh, Yeghaneh Eslami, Khashayar Fattah, Naghmeh Asadimanesh, Armin Azarimatin, Bahman Khalesi, Faezeh Almasi and Zahra Payandeh

Cancers 2023, 15(14), 3722; https://doi.org/10.3390/cancers15143722 - 22 Jul 2023

Cited by 1 | Viewed by 2338

Abstract

Macrophages are types of immune cells, with ambivalent functions in tumor growth, which depend on the specific environment in which they reside. Tumor-associated macrophages (TAMs) are a diverse population of immunosuppressive myeloid cells that play significant roles in several malignancies. TAM infiltration in [...] Read more.

Macrophages are types of immune cells, with ambivalent functions in tumor growth, which depend on the specific environment in which they reside. Tumor-associated macrophages (TAMs) are a diverse population of immunosuppressive myeloid cells that play significant roles in several malignancies. TAM infiltration in malignancies has been linked to a poor prognosis and limited response to treatments, including those using checkpoint inhibitors. Understanding the precise mechanisms through which macrophages contribute to tumor growth is an active area of research as targeting these cells may offer potential therapeutic approaches for cancer treatment. Numerous investigations have focused on anti-TAM-based methods that try to eliminate, rewire, or target the functional mediators released by these cells. Considering the importance of these strategies in the reversion of tumor resistance to conventional therapies and immune modulatory vaccination could be an appealing approach for the immunosuppressive targeting of myeloid cells in the tumor microenvironment (TME). The combination of reprogramming and TAM depletion is a special feature of this approach compared to other clinical strategies. Thus, the present review aims to comprehensively overview the pleiotropic activities of TAMs and their involvement in various stages of cancer development as a potent drug target, with a focus on hematologic tumors. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Treatment Resistance)

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17 pages, 3612 KiB

Open AccessArticle

The 2EF Antibody Targets a Unique N-Terminal Epitope of Trop-2 and Enhances the In Vivo Activity of the Cancer-Selective 2G10 Antibody

by Emanuela Guerra, Marco Trerotola, Valeria Relli, Rossano Lattanzio, Martina Ceci, Khouloud Boujnah, Ludovica Pantalone, Roberta Di Pietro, Manuela Iezzi, Nicola Tinari and Saverio Alberti

Cancers 2023, 15(14), 3721; https://doi.org/10.3390/cancers15143721 - 22 Jul 2023

Cited by 5 | Viewed by 2222

Abstract

Trop-2 proteolytic processing in cancer cells exposes epitopes that were specifically targeted by the 2G10 antibody. We sought additional recognition of Trop-2 within difficult-to-reach, densely packed tumor sites. Trop-2 deletion mutants were employed in immunization and screening procedures, and these led to the [...] Read more.

Trop-2 proteolytic processing in cancer cells exposes epitopes that were specifically targeted by the 2G10 antibody. We sought additional recognition of Trop-2 within difficult-to-reach, densely packed tumor sites. Trop-2 deletion mutants were employed in immunization and screening procedures, and these led to the recognition of a novel epitope in the N-terminal region of Trop-2, by the 2EF antibody. The 2EF mAb was shown to bind Trop-2 at cell–cell junctions in MCF-7 breast cancer cells, and in deeply seated sites in prostate cancer, that were inaccessible to benchmark anti-Trop-2 antibodies. The 2EF antibody was shown to inhibit the growth of HT29 colon tumor cells in vitro, with the highest activity at high cell density. In vivo, 2EF showed anticancer activity against SKOv3 ovarian, Colo205, HT29, HCT116 colon and DU-145 prostate tumors, with the highest impact on densely packed tumor sites, whereby 2EF outcompeted benchmark anti-Trop-2 antibodies. Given the different recognition modes of Trop-2 by 2EF and 2G10, we hypothesized the effective interaction of the two mAb in vivo. The 2EF mAb was indeed demonstrated to enhance the activity of 2G10 against tumor xenotransplants, opening novel avenues for Trop-2-targeted therapy. We humanized 2EF by state-of-the-art CDR grafting/re-modeling, yielding the Hu2EF for therapy of Trop-2-expressing tumors in patients. Full article

(This article belongs to the Special Issue Advances in Cancer Immunotherapy)

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