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Volume 16
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Cancers, Volume 16, Issue 17 (September-1 2024) – 191 articles

Cover Story (view full-size image): Quadruplet induction regimens for patients with treatment-naïve, newly diagnosed multiple myeloma have shown impressive results in multiple trials. However, trials of 4-drug regimens typically use a 3-drug regimen as their comparator, limiting the ability to determine whether the benefit is from the specific combination or just the addition of more agents. We performed a meta-analysis of all trials that randomized patients into a 4-drug vs. 3-drug induction regimens. Our dataset included 11 trials (representing 6509 unique patients) with a goal of determining the PFS and OS benefit, if any, of a 4-drug combination. We also evaluated the toxicity profile of these regimens, recognizing that the addition of more agents to induction regimens may result in more adverse effects. View this paper
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12 pages, 1159 KiB  
Article
Clinical Interest in Exome-Based Analysis of Somatic Mutational Signatures for Non-Small Cell Lung Cancer
by Morgane Peroz, Hugo Mananet, Nicolas Roussot, Courèche Guillaume Kaderbhai, Valentin Derangère, Caroline Truntzer and François Ghiringhelli
Cancers 2024, 16(17), 3115; https://doi.org/10.3390/cancers16173115 - 9 Sep 2024
Viewed by 667
Abstract
Background: Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality. This study investigates the clinical interest of whole exome sequencing (WES) for analyzing somatic mutational signatures in patients with advanced or metastatic NSCLC treated with the current standard of care. [...] Read more.
Background: Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality. This study investigates the clinical interest of whole exome sequencing (WES) for analyzing somatic mutational signatures in patients with advanced or metastatic NSCLC treated with the current standard of care. Methods: Exome sequencing data and clinical characteristics from 132 patients with advanced or metastatic NSCLC were analyzed. Somatic mutational signatures including single base substitutions (SBSs), double base substitutions (DBSs), and copy number signatures were evaluated. Structural variations including tumor mutational burden (TMB), the number of neoantigens, TCR clonality, homologous recombination deficiency (HRD), copy number alterations (CNAs), and microsatellite instability (MSI) score were determined. The association between these genomic features, NSCLC subtypes, and patient outcomes (progression-free and overall survival) was evaluated. Conclusions: Exome sequencing offers valuable insights into somatic mutational signatures in NSCLC. This study identified specific signatures associated with a poor response to immune checkpoint inhibitor (ICI) therapy and chemotherapy, potentially aiding treatment selection and identifying patients unlikely to benefit from these approaches. Full article
(This article belongs to the Special Issue New Advances in Lung Cancer: Diagnosis, Pathophysiology and Emerging Treatments. A Selection of Papers from the 4th Joint Meeting on Lung Cancer of the FHU OncoAge (Nice, France) and the MD Anderson Cancer Center (Houston, TX, USA))
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11 pages, 980 KiB  
Article
The Real-World Efficacy and Safety of Direct-Acting Antivirals for Chronic Hepatitis C in Patients Active Malignancies
by Maria Dąbrowska, Jerzy Jaroszewicz, Marek Sitko, Justyna Janocha-Litwin, Dorota Zarębska-Michaluk, Ewa Janczewska, Beata Lorenc, Magdalena Tudrujek-Zdunek, Anna Parfieniuk-Kowerda, Jakub Klapaczyński, Hanna Berak, Łukasz Socha, Beata Dobracka, Dorota Dybowska, Włodzimierz Mazur, Łukasz Ważny and Robert Flisiak
Cancers 2024, 16(17), 3114; https://doi.org/10.3390/cancers16173114 - 9 Sep 2024
Viewed by 504
Abstract
Background: Over the past years, the introduction of direct-acting antivirals (DAAs) revolutionized chronic hepatitis C treatment. We aimed to characterize and assess treatment efficacy in three specific groups of patients treated with DAAs: those with active solid malignant tumors (SMTs), hematological diseases (HDs) [...] Read more.
Background: Over the past years, the introduction of direct-acting antivirals (DAAs) revolutionized chronic hepatitis C treatment. We aimed to characterize and assess treatment efficacy in three specific groups of patients treated with DAAs: those with active solid malignant tumors (SMTs), hematological diseases (HDs) and hepatocellular carcinomas (HCCs). Methods: A total of 203 patients with active oncological disease (SMT n = 61, HD = 67, HCC n = 74) during DAA treatment in 2015–2020 selected from the EpiTer-2 database were analyzed retrospectively and compared to 12,983 patients without any active malignancy. Results: Extrahepatic symptoms were more frequent in HD patients (17.2% vs. SMT = 10.3%, HCC = 8.2%, without = 7.8%, p = 0.004). HCC patients characterized with the highest ALT activity (81 IU/L vs. SMT = 59.5 IU/L, HD = 52 IU/L, without = 58 IU/L, p = 0.001) more often had F4 fibrosis as well (86.11% vs. SMT = 23.3%, HD = 28.8%, controls = 24.4%, p = 0.001). A significant majority of subjects in HCC, HD and SMT populations completed the full treatment plan (HCC = 91%; n = 67, HD = 97%; n = 65, SMT = 100%; n = 62). Concerning the treatment efficacy, the overall sustained virologic response, excluding non-virologic failures, was reported in 93.6% HD, 90.16% SMT and 80.6% in HCC patients. Conclusions: As presented in our study, DAA therapy has proven to be highly effective and safe in patients with active SMTs and HDs. However, therapy discontinuations resulting from liver disease progression remain to be the major concern in HCC patients. Full article
(This article belongs to the Special Issue Advances in the Prevention and Treatment of Liver Cancer)
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25 pages, 1718 KiB  
Review
Cellular and Microbial In Vitro Modelling of Gastrointestinal Cancer
by Kristina Žukauskaitė, Melissa Li, Angela Horvath, Sonata Jarmalaitė and Vanessa Stadlbauer
Cancers 2024, 16(17), 3113; https://doi.org/10.3390/cancers16173113 - 9 Sep 2024
Viewed by 855
Abstract
Human diseases are multifaceted, starting with alterations at the cellular level, damaging organs and their functions, and disturbing interactions and immune responses. In vitro systems offer clarity and standardisation, which are crucial for effectively modelling disease. These models aim not to replicate every [...] Read more.
Human diseases are multifaceted, starting with alterations at the cellular level, damaging organs and their functions, and disturbing interactions and immune responses. In vitro systems offer clarity and standardisation, which are crucial for effectively modelling disease. These models aim not to replicate every disease aspect but to dissect specific ones with precision. Controlled environments allow researchers to isolate key variables, eliminate confounding factors and elucidate disease mechanisms more clearly. Technological progress has rapidly advanced model systems. Initially, 2D cell culture models explored fundamental cell interactions. The transition to 3D cell cultures and organoids enabled more life-like tissue architecture and enhanced intercellular interactions. Advanced bioreactor-based devices now recreate the physicochemical environments of specific organs, simulating features like perfusion and the gastrointestinal tract’s mucus layer, enhancing physiological relevance. These systems have been simplified and adapted for high-throughput research, marking significant progress. This review focuses on in vitro systems for modelling gastrointestinal tract cancer and the side effects of cancer treatment. While cell cultures and in vivo models are invaluable, our main emphasis is on bioreactor-based in vitro modelling systems that include the gut microbiome. Full article
(This article belongs to the Section Cancer Pathophysiology)
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17 pages, 295 KiB  
Perspective
Immunotherapy and Radiotherapy for Older Patients with Locally Advanced Non-Metastatic Non-Small-Cell Lung Cancer Who Are Not Candidates for or Decline Surgery and Chemotherapy: A Practical Proposal by the International Geriatric Radiotherapy Group
by Nam P. Nguyen, Brandi R. Page, Huan Giap, Zineb Dahbi, Vincent Vinh-Hung, Olena Gorobets, Mohammad Mohammadianpanah, Micaela Motta, Maurizio Portaluri, Meritxell Arenas, Marta Bonet, Pedro Carlos Lara, Lyndon Kim, Fabien Dutheil, Elena Natoli, Gokoulakrichenane Loganadane, David Lehrman, Satya Bose, Sarabjot Kaur, Sergio Calleja Blanco and Alexander Chiadd Show full author list remove Hide full author list
Cancers 2024, 16(17), 3112; https://doi.org/10.3390/cancers16173112 - 9 Sep 2024
Viewed by 734
Abstract
The standard of care for locally advanced non-small-cell lung cancer (NSCLC) is either surgery combined with chemotherapy pre- or postoperatively or concurrent chemotherapy and radiotherapy. However, older and frail patients may not be candidates for surgery and chemotherapy due to the high mortality [...] Read more.
The standard of care for locally advanced non-small-cell lung cancer (NSCLC) is either surgery combined with chemotherapy pre- or postoperatively or concurrent chemotherapy and radiotherapy. However, older and frail patients may not be candidates for surgery and chemotherapy due to the high mortality risk and are frequently referred to radiotherapy alone, which is better tolerated but carries a high risk of disease recurrence. Recently, immunotherapy with immune checkpoint inhibitors (ICIs) may induce a high response rate among cancer patients with positive programmed death ligand 1 (PD-L1) expression. Immunotherapy is also well tolerated among older patients. Laboratory and clinical studies have reported synergy between radiotherapy and ICI. The combination of ICI and radiotherapy may improve local control and survival for NSCLC patients who are not candidates for surgery and chemotherapy or decline these two modalities. The International Geriatric Radiotherapy Group proposes a protocol combining radiotherapy and immunotherapy based on the presence or absence of PD-L1 to optimize the survival of those patients. Full article
(This article belongs to the Section Cancer Immunology and Immunotherapy)
25 pages, 1897 KiB  
Review
The Role of Predictive and Prognostic MRI-Based Biomarkers in the Era of Total Neoadjuvant Treatment in Rectal Cancer
by Sebastian Curcean, Andra Curcean, Daniela Martin, Zsolt Fekete, Alexandru Irimie, Alina-Simona Muntean and Cosmin Caraiani
Cancers 2024, 16(17), 3111; https://doi.org/10.3390/cancers16173111 - 9 Sep 2024
Viewed by 725
Abstract
The role of magnetic resonance imaging (MRI) in rectal cancer management has significantly increased over the last decade, in line with more personalized treatment approaches. Total neoadjuvant treatment (TNT) plays a pivotal role in the shift from traditional surgical approach to non-surgical approaches [...] Read more.
The role of magnetic resonance imaging (MRI) in rectal cancer management has significantly increased over the last decade, in line with more personalized treatment approaches. Total neoadjuvant treatment (TNT) plays a pivotal role in the shift from traditional surgical approach to non-surgical approaches such as ‘watch-and-wait’. MRI plays a central role in this evolving landscape, providing essential morphological and functional data that support clinical decision-making. Key MRI-based biomarkers, including circumferential resection margin (CRM), extramural venous invasion (EMVI), tumour deposits, diffusion-weighted imaging (DWI), and MRI tumour regression grade (mrTRG), have proven valuable for staging, response assessment, and patient prognosis. Functional imaging techniques, such as dynamic contrast-enhanced MRI (DCE-MRI), alongside emerging biomarkers derived from radiomics and artificial intelligence (AI) have the potential to transform rectal cancer management offering data that enhance T and N staging, histopathological characterization, prediction of treatment response, recurrence detection, and identification of genomic features. This review outlines validated morphological and functional MRI-derived biomarkers with both prognostic and predictive significance, while also exploring the potential of radiomics and artificial intelligence in rectal cancer management. Furthermore, we discuss the role of rectal MRI in the ‘watch-and-wait’ approach, highlighting important practical aspects in selecting patients for non-surgical management. Full article
(This article belongs to the Special Issue Application of Advanced Biomedical Imaging in Cancer Treatment)
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15 pages, 1754 KiB  
Article
Rhabdomyosarcoma of the Biliary Tract in Children: Analysis of Single Center Experience
by Ewa Święszkowska, Dorota Broniszczak, Piotr Kaliciński, Marek Szymczak, Marek Stefanowicz, Wiesława Grajkowska and Bożenna Dembowska-Bagińska
Cancers 2024, 16(17), 3110; https://doi.org/10.3390/cancers16173110 - 9 Sep 2024
Viewed by 466
Abstract
Rhabdomyosarcoma (RMS) of the biliary tract is a rare tumor in children, constituting 0.5–0.8% of all pediatric RMS. Still, it is the most common malignancy in this location in children. Due to its rarity and location, it may cause diagnostic and treatment difficulties. [...] Read more.
Rhabdomyosarcoma (RMS) of the biliary tract is a rare tumor in children, constituting 0.5–0.8% of all pediatric RMS. Still, it is the most common malignancy in this location in children. Due to its rarity and location, it may cause diagnostic and treatment difficulties. Above all, there are no therapeutic guidelines specific for this tumor location. The aim of the study was to present an analysis of our experience with the treatment of children with biliary tract rhabdomyosarcoma (RMS) and discuss clinical recommendations for this specific location published in the literature. A retrospective analysis of medical records of eight children with biliary tree RMS treated in one center between 1996–2022 was performed. Records of eight children, five boys and three girls aged 2 yrs 6 mo to 16 yrs 9 mo (median—6 yrs) were analyzed. All patients presented with jaundice as the first symptom. In two patients, initial diagnosis of a tumor was established. For the remaining six, the primary diagnoses were as follows: choledochal cyst—one, malformation of the biliary ducts—one, choledocholithiasis—one, cholangitis—three. In four patients, the extrahepatic bile ducts were involved; in four patients, both the intrahepatic and extrahepatic bile ducts were involved. Embryonal RMS was diagnosed in seven patients (three botryoides type). Alveolar RMS was found in one patient. Biopsy (three surgical, four during endoscopic retrograde cholangiopancreatography (ERCP)) was performed in seven patients. One child underwent primary partial tumor resection (R2). Seven patients received neoadjuvant chemotherapy, followed by delayed resection in five, including liver transplantation in one (five were R0). Two patients did not undergo surgery. Radiotherapy was administered in four patients (two in first-line treatment, two at relapse/progression). Six patients (75%) are alive with no evidence of disease, with follow-up ranging from 1.2 yrs to 27 yrs (median 11 yrs. and 4 mo.). Two patients died from disease, 2 y 9 mo and 3 y 7 mo from diagnosis. Children presenting with obstructive jaundice should be evaluated for biliary tract RMS. The treatment strategy should include biopsy and preoperative chemotherapy, followed by tumor resection and radiotherapy for residual disease and in case of relapse. Full article
(This article belongs to the Section Pediatric Oncology)
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11 pages, 1597 KiB  
Review
Minimal Requirements for Cancer Initiation: A Comparative Consideration of Three Prototypes of Human Leukemia
by Toshiyuki Hori
Cancers 2024, 16(17), 3109; https://doi.org/10.3390/cancers16173109 - 9 Sep 2024
Viewed by 847
Abstract
Even if its completed form is complex, cancer originates from one or two events that happened to a single cell. A simplified model can play a role in understanding how cancer initiates at the beginning. The pathophysiology of leukemia has been studied in [...] Read more.
Even if its completed form is complex, cancer originates from one or two events that happened to a single cell. A simplified model can play a role in understanding how cancer initiates at the beginning. The pathophysiology of leukemia has been studied in the most detailed manner among all human cancers. In this review, based on milestone papers and the latest research developments in hematology, acute promyelocytic leukemia (APL), chronic myeloid leukemia (CML), and acute myeloid leukemia (AML) with RUNX1-RUNX1T1 are selected to consider minimal requirements for cancer initiation. A one-hit model can be applied to the initiation of APL and CML whereas a two-hit model is more suitable to the initiation of AML with RUNX1-RUNX1T1 and other AMLs. Even in cancer cells with multiple genetic abnormalities, there must be a few mutant genes critical for the mutant clone to survive and proliferate. Such genes should be identified and characterized in each case in order to develop individualized target therapy. Full article
(This article belongs to the Special Issue Feature Review Paper Special Issue in Section Molecular Cancer Biology)
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19 pages, 4792 KiB  
Article
Curcumin-Dichloroacetate Hybrid Molecule as an Antitumor Oral Drug against Multidrug-Resistant Advanced Bladder Cancers
by Kunj Bihari Gupta, Truett L. Taylor, Siva S. Panda, Muthusamy Thangaraju and Bal. L. Lokeshwar
Cancers 2024, 16(17), 3108; https://doi.org/10.3390/cancers16173108 - 8 Sep 2024
Viewed by 727
Abstract
Tumor cells produce excessive reactive oxygen species (ROS) but cannot detoxify ROS if they are due to an external agent. An agent that produces toxic levels of ROS, specifically in tumor cells, could be an effective anticancer drug. CMC-2 is a molecular hybrid [...] Read more.
Tumor cells produce excessive reactive oxygen species (ROS) but cannot detoxify ROS if they are due to an external agent. An agent that produces toxic levels of ROS, specifically in tumor cells, could be an effective anticancer drug. CMC-2 is a molecular hybrid of the bioactive polyphenol curcumin conjugated to dichloroacetate (DCA) via a glycine bridge. The CMC-2 was tested for its cytotoxic antitumor activities and killed both naïve and multidrug-resistant (MDR) bladder cancer (BCa) cells with equal potency (<1.0 µM); CMC-2 was about 10–15 folds more potent than curcumin or DCA. Growth of human BCa xenograft in mice was reduced by >50% by oral gavage of 50 mg/kg of CMC-2 without recognizable systemic toxicity. Doses that used curcumin or DCA showed minimum antitumor effects. In vitro, the toxicity of CMC-2 in both naïve and MDR cells depended on increased intracellular ROS in tumor cells but not in normal cells at comparable doses. Increased ROS caused the permeabilization of mitochondria and induced apoptosis. Further, adding N-Acetyl cysteine (NAC), a hydroxyl radical scavenger, abolished excessive ROS production and CMC-2’s cytotoxicity. The lack of systemic toxicity, equal potency against chemotherapy -naïve and resistant tumors, and oral bioavailability establish the potential of CMC-2 as a potent drug against bladder cancers. Full article
(This article belongs to the Special Issue Feature Paper in Section “Cancer Therapy” in 2024)
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13 pages, 1686 KiB  
Systematic Review
Impact of Indocyanine Green Dose on Sentinel Lymph Node Mapping in Cervical Cancer: A Systematic Review
by Joel Laufer, Santiago Scasso and Andrea Papadia
Cancers 2024, 16(17), 3107; https://doi.org/10.3390/cancers16173107 - 8 Sep 2024
Viewed by 507
Abstract
Over the past decade, SLN mapping has become increasingly important in cervical cancer surgery. ICG is the most commonly used tracer due to its high bilateral detection rates, ease of use, and safety. However, there is no consensus on the optimal ICG dose, [...] Read more.
Over the past decade, SLN mapping has become increasingly important in cervical cancer surgery. ICG is the most commonly used tracer due to its high bilateral detection rates, ease of use, and safety. However, there is no consensus on the optimal ICG dose, leading to variability in outcomes. This systematic review aims to evaluate the impact of different ICG doses on SLN detection in early-stage cervical cancer, identifying the most effective and safe dose for clinical practice. A comprehensive search was conducted in MEDLINE/PubMed up to May 2024. Studies included assessed SLN mapping using ICG in stage IA2-IIA/IIB cervical cancer. Exclusions were applied to studies not reporting ICG dose or using multiple tracers without dose-specific results. Twelve studies were included, with ICG concentrations ranging from 0.25 mg/mL to 25 mg/mL and injection volumes from 1 to 10 mL. Overall SLN detection rates ranged from 88% to 100%, while bilateral detection rates varied between 74.1% and 98.5%. The most consistent results were obtained with an ICG concentration of 1.25 mg/mL and a 4 mL injection volume. In conclusion, an ICG concentration of 1.25 mg/mL with a 4 mL injection volume is recommended for effective SLN mapping in cervical cancer, achieving high detection rates with minimal variability. Standardizing this dose in clinical practice is suggested to improve reproducibility and outcomes. Full article
(This article belongs to the Special Issue Cervical Cancer: Screening and Treatment in 2024)
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13 pages, 1365 KiB  
Commentary
Amitotic Cell Division, Malignancy, and Resistance to Anticancer Agents: A Tribute to Drs. Walen and Rajaraman
by Razmik Mirzayans and David Murray
Cancers 2024, 16(17), 3106; https://doi.org/10.3390/cancers16173106 - 8 Sep 2024
Viewed by 1110
Abstract
Cell division is crucial for the survival of living organisms. Human cells undergo three types of cell division: mitosis, meiosis, and amitosis. The former two types occur in somatic cells and germ cells, respectively. Amitosis involves nuclear budding and occurs in cells that [...] Read more.
Cell division is crucial for the survival of living organisms. Human cells undergo three types of cell division: mitosis, meiosis, and amitosis. The former two types occur in somatic cells and germ cells, respectively. Amitosis involves nuclear budding and occurs in cells that exhibit abnormal nuclear morphology (e.g., polyploidy) with increased cell size. In the early 2000s, Kirsten Walen and Rengaswami Rajaraman and his associates independently reported that polyploid human cells are capable of producing progeny via amitotic cell division, and that a subset of emerging daughter cells proliferate rapidly, exhibit stem cell-like properties, and can contribute to tumorigenesis. Polyploid cells that arise in solid tumors/tumor-derived cell lines are referred to as polyploid giant cancer cells (PGCCs) and are known to contribute to therapy resistance and disease recurrence following anticancer treatment. This commentary provides an update on some of these intriguing discoveries as a tribute to Drs. Walen and Rajaraman. Full article
(This article belongs to the Special Issue The Role of Chromosomal Instability in Cancer)
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13 pages, 256 KiB  
Article
Brain Metastases as Inaugural Sign of Non-Small Cell Lung Carcinoma: Case Series and Review of Literature
by Alexandra Pușcașu, Fabien Moinard-Butot, Simon Nannini, Cathie Fischbach, Roland Schott and Laura Bender
Cancers 2024, 16(17), 3105; https://doi.org/10.3390/cancers16173105 - 8 Sep 2024
Viewed by 631
Abstract
In the era of immune checkpoint inhibitors (ICI), managing non-oncogene driven non-small cell lung cancer (NSCLC) with brain metastases (BM) is challenging, especially when brain involvement is the initial sign. Patients with newly diagnosed brain metastatic NSCLC without epidermal growth factor receptor (EFGR) [...] Read more.
In the era of immune checkpoint inhibitors (ICI), managing non-oncogene driven non-small cell lung cancer (NSCLC) with brain metastases (BM) is challenging, especially when brain involvement is the initial sign. Patients with newly diagnosed brain metastatic NSCLC without epidermal growth factor receptor (EFGR) nor anaplastic lymphoma kinase (ALK) alterations were retrospectively included. Twenty-five patients were analyzed; 15 (60%) had symptomatic BM as the first sign (group 1), while 10 (40%) had BM discovered during complementary examinations (group 2). Fourteen patients (56%) had concomitant extracerebral metastases, primarily in group 2. Eight (32%) had oligometastatic disease, with seven in group 1. Over half received chemotherapy and pembrolizumab as first-line treatment. BM surgical resection occurred in twelve (80%) patients in group 1 and one in group 2. Median cerebral progression-free survival was 10 months: 12 in group 1 and 5 in group 2. Median overall survival was 25 months: not reached in group 1 and 6 months in group 2. This case series highlights survival outcomes for patients with inaugural BM, a demographic underrepresented in pivotal trials. Oligometastatic disease and symptomatic BM as initial signs seem associated with better prognosis due to increased use of multimodal local approaches. Combining local approaches with first-line ICI+/− chemotherapy appears to improve survival in brain metastatic NSCLC. A literature review was conducted to explore key questions regarding upfront ICI alone or in combination with systemic drugs or local approaches in brain metastatic NSCLC. Full article
(This article belongs to the Section Cancer Metastasis)
20 pages, 2673 KiB  
Article
Immune Cell Molecular Pharmacodynamics of Lanreotide in Relation to Treatment Response in Patients with Gastroenteropancreatic Neuroendocrine Tumors
by Sabah Alaklabi, Orla Maguire, Harsha Pattnaik, Yali Zhang, Jacky Chow, Jianmin Wang, Hans Minderman and Renuka Iyer
Cancers 2024, 16(17), 3104; https://doi.org/10.3390/cancers16173104 - 7 Sep 2024
Viewed by 606
Abstract
The CLARINET trial led to the approval of lanreotide for the treatment of patients with gastroenteropancreatic neuroendocrine tumors (NETs). It is hypothesized that lanreotide regulates proliferation, hormone synthesis, and other cellular functions via binding to somatostatin receptors (SSTR1–5) present in NETs. However, our [...] Read more.
The CLARINET trial led to the approval of lanreotide for the treatment of patients with gastroenteropancreatic neuroendocrine tumors (NETs). It is hypothesized that lanreotide regulates proliferation, hormone synthesis, and other cellular functions via binding to somatostatin receptors (SSTR1–5) present in NETs. However, our knowledge of how lanreotide affects the immune system is limited. In vitro studies have investigated functional immune response parameters with lanreotide treatment in healthy donor T cell subsets, encompassing the breadth of SSTR expression, apoptosis induction, cytokine production, and activity of transcription factor signaling pathways. In our study, we characterized in vitro immune mechanisms in healthy donor T cells in response to lanreotide. We also studied the in vivo effects by looking at differential gene expression pre- and post-lanreotide therapy in patients with NET. Immune-focused gene and protein expression profiling was performed on peripheral blood samples from 17 NET patients and correlated with clinical response. In vivo, lanreotide therapy showed reduced effects on wnt, T cell receptor (TCR), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling in CD8+ T cells in responders compared to non-responders. Compared to non-responders, responders showed reduced effects on cytokine and chemokine signaling but greater effects on ubiquitination and proteasome degradation genes. Our results suggest significant lanreotide pharmacodynamic effects on immune function in vivo, which correlate with responses in NET patients. This is not evident from experimental in vitro settings. Full article
(This article belongs to the Special Issue Updates in Neuroendocrine Neoplasms)
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23 pages, 5206 KiB  
Article
Fibroblast Growth Factor 2 (FGF2) Activates Vascular Endothelial Growth Factor (VEGF) Signaling in Gastrointestinal Stromal Tumors (GIST): An Autocrine Mechanism Contributing to Imatinib Mesylate (IM) Resistance
by Sergei Boichuk, Pavel Dunaev, Aigul Galembikova and Elena Valeeva
Cancers 2024, 16(17), 3103; https://doi.org/10.3390/cancers16173103 - 7 Sep 2024
Viewed by 698
Abstract
We showed previously that the autocrine activation of the FGFR-mediated pathway in GIST lacking secondary KIT mutations was a result of the inhibition of KIT signaling. We show here that the FGF2/FGFR pathway regulates VEGF-A/VEGFR signaling in IM-resistant GIST cells. Indeed, recombinant FGF2 [...] Read more.
We showed previously that the autocrine activation of the FGFR-mediated pathway in GIST lacking secondary KIT mutations was a result of the inhibition of KIT signaling. We show here that the FGF2/FGFR pathway regulates VEGF-A/VEGFR signaling in IM-resistant GIST cells. Indeed, recombinant FGF2 increased the production of VEGF-A by IM-naive and resistant GIST cells. VEGF-A production was also increased in KIT-inhibited GIST, whereas the neutralization of FGF2 by anti-FGF2 mAb attenuated VEGFR signaling. Of note, BGJ 398, pan FGFR inhibitor, effectively and time-dependently inhibited VEGFR signaling in IM-resistant GIST T-1R cells, thereby revealing the regulatory role of the FGFR pathway in VEGFR signaling for this particular GIST cell line. This also resulted in significant synergy between BGJ 398 and VEGFR inhibitors (i.e., sunitinib and regorafenib) by enhancing their pro-apoptotic and anti-proliferative activities. The high potency of the combined use of VEGFR and FGFR inhibitors in IM-resistant GISTs was revealed by the impressive synergy scores observed for regorafenib or sunitinib and BGJ 398. Moreover, FGFR1/2 and VEGFR1/2 were co-localized in IM-resistant GIST T-1R cells, and the direct interaction between the aforementioned RTKs was confirmed by co-immunoprecipitation. In contrast, IM-resistant GIST 430 cells expressed lower basal levels of FGF2 and VEGF-A. Despite the increased expression VEGFR1 and FGFR1/2 in GIST 430 cells, these RTKs were not co-localized and co-immunoprecipitated. Moreover, no synergy between FGFR and VEGFR inhibitors was observed for the IM-resistant GIST 430 cell line. Collectively, the dual targeting of FGFR and VEGFR pathways in IM-resistant GISTs is not limited to the synergistic anti-angiogenic treatment effects. The dual inhibition of FGFR and VEGFR pathways in IM-resistant GISTs potentiates the proapoptotic and anti-proliferative activities of the corresponding RTKi. Mechanistically, the FGF2-induced activation of the FGFR pathway turns on VEGFR signaling via the overproduction of VEGF-A, induces the interaction between FGFR1/2 and VEGFR1, and thereby renders cancer cells highly sensitive to the dual inhibition of the aforementioned RTKs. Thus, our data uncovers the novel mechanism of the cross-talk between the aforementioned RTKs in IM-resistant GISTs lacking secondary KIT mutations and suggests that the dual blockade of FGFR and VEGFR signaling might be an effective treatment strategy for patients with GIST-acquired IM resistance via KIT-independent mechanisms. Full article
(This article belongs to the Special Issue Updates on the Molecular Profile of Gastrointestinal Stromal Tumors (Volume II))
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11 pages, 1254 KiB  
Article
HLA-A01 and HLA-B27 Supertypes, but Not HLA Homozygocity, Correlate with Clinical Outcome among Patients with Non-Small Cell Lung Cancer Treated with Pembrolizumab in Combination with Chemotherapy
by Afaf Abed, Anna Reid, Ngie Law, Michael Millward and Elin S. Gray
Cancers 2024, 16(17), 3102; https://doi.org/10.3390/cancers16173102 - 7 Sep 2024
Viewed by 580
Abstract
Introduction: Maximal heterozygosity on the human leukocyte antigen (HLA) loci has been found to be associated with improved survival and development of immune-related adverse events (irAEs) among NSCLC patients treated with immunotherapy. Here, we investigated the effect of germline HLA-I/-II on clinical outcomes [...] Read more.
Introduction: Maximal heterozygosity on the human leukocyte antigen (HLA) loci has been found to be associated with improved survival and development of immune-related adverse events (irAEs) among NSCLC patients treated with immunotherapy. Here, we investigated the effect of germline HLA-I/-II on clinical outcomes among NSCLC patients treated with first-line pembrolizumab in combination with chemotherapy. Method: We prospectively recruited patients with NSCLC who were commencing first-line pembrolizumab in combination with chemotherapy. DNA from white blood cells was used for high-resolution HLA-I/II typing. Results: Of the 65 patients recruited, 53 complied with the inclusion criteria. We did not find an association between HLA-I/-II homozygosity and clinical outcome among the studied population. However, the presence of HLA-A01 was associated with unfavourable PFS (HR = 2.32, 95%CI 1.13–4.77, p = 0.022) and worsening OS (HR = 2.86, 95%CI 1.06–7.70, p = 0.038). The presence of HLA-B27 was associated with improved PFS (HR = 0.35, 95%CI 0.18–0.71, p = 0.004) and trends toward improving OS. None of the HLA-I supertypes were associated with the development or worsening of irAEs. Conclusions: The absence of association between genomic HLA-I/-II homozygosity and clinical outcome among patients with advanced NSCLC treated with pembrolizumab in combination with chemotherapy might reflect a diminished role for HLA molecules among patients with low or no PD-L1. HLA-A01 and HLA-B27 might have a role in predicting clinical outcomes among this cohort of patients. Further studies are needed to explore biomarkers for this group of patients. Full article
(This article belongs to the Special Issue Advances in Metastatic Non-small Cell Lung Cancer–Implications on Diagnosis and Treatment as We Head towards 2024)
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12 pages, 9453 KiB  
Article
The Local Rhombus-Shaped Flap—An Easy and Reliable Technique for Oncoplastic Breast Cancer Surgery and Defect Closure in Breast and Axilla
by Hisham Fansa and Sora Linder
Cancers 2024, 16(17), 3101; https://doi.org/10.3390/cancers16173101 - 6 Sep 2024
Viewed by 501
Abstract
Primarily, breast-conserving therapy is an oncological intervention, but eventually it is judged by its cosmetic result. Remaining cavities from tumor resection can promote seromas, delay healing and cause lasting discomfort. Additionally, volume loss, dislocation of nipple/areola and fat necrosis lead to (cosmetically) unfavorable [...] Read more.
Primarily, breast-conserving therapy is an oncological intervention, but eventually it is judged by its cosmetic result. Remaining cavities from tumor resection can promote seromas, delay healing and cause lasting discomfort. Additionally, volume loss, dislocation of nipple/areola and fat necrosis lead to (cosmetically) unfavorable results, aggravated by radiotherapy. Oncoplastic surgery can reduce these sequelae. A local flap that has rarely been used in breast cancer surgery is the Limberg rhombic flap. The tumor defect is planned as a rhombus. The sides of the rhombus are of equal length and ideally have an angle of 60° and 120°. The flap that closes the defect is planned as an extension of equal length of the short diagonal. The second incision of the flap is placed according to the defect angle of 60°, running parallel to the defect at the same length. This creates a second rhombus. The flap is transposed into the defect, and the donor area is primarily closed. It is axially perfused and safe with a 1:1 length-to-width ratio. Compared to local perforator flaps, defect closure is easily managed without microsurgical skills. In the breast, the flap can be used in volume replacement and volume displacement techniques as an all-layer flap to cover defects, or it can be deepithelialized and buried. In the axilla, it can cover full-thickness defects when skin is involved. The advantages of the rhombic flap are its safety and simplicity to add volume and close defects, thus reducing the complexity of oncoplastic surgery. Full article
(This article belongs to the Special Issue Trends in Mastectomy and Breast Reconstruction for Cancer)
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26 pages, 2978 KiB  
Review
Scoping Review: Methods and Applications of Spatial Transcriptomics in Tumor Research
by Kacper Maciejewski and Patrycja Czerwinska
Cancers 2024, 16(17), 3100; https://doi.org/10.3390/cancers16173100 - 6 Sep 2024
Viewed by 906
Abstract
Spatial transcriptomics (ST) examines gene expression within its spatial context on tissue, linking morphology and function. Advances in ST resolution and throughput have led to an increase in scientific interest, notably in cancer research. This scoping study reviews the challenges and practical applications [...] Read more.
Spatial transcriptomics (ST) examines gene expression within its spatial context on tissue, linking morphology and function. Advances in ST resolution and throughput have led to an increase in scientific interest, notably in cancer research. This scoping study reviews the challenges and practical applications of ST, summarizing current methods, trends, and data analysis techniques for ST in neoplasm research. We analyzed 41 articles published by the end of 2023 alongside public data repositories. The findings indicate cancer biology is an important focus of ST research, with a rising number of studies each year. Visium (10x Genomics, Pleasanton, CA, USA) is the leading ST platform, and SCTransform from Seurat R library is the preferred method for data normalization and integration. Many studies incorporate additional data types like single-cell sequencing and immunohistochemistry. Common ST applications include discovering the composition and function of tumor tissues in the context of their heterogeneity, characterizing the tumor microenvironment, or identifying interactions between cells, including spatial patterns of expression and co-occurrence. However, nearly half of the studies lacked comprehensive data processing protocols, hindering their reproducibility. By recommending greater transparency in sharing analysis methods and adapting single-cell analysis techniques with caution, this review aims to improve the reproducibility and reliability of future studies in cancer research. Full article
(This article belongs to the Special Issue Spatial, Bulk, and Cell-Type-Related Transcriptomics in Cancer Research)
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4 pages, 177 KiB  
Editorial
Fecundity and Nutrient Deficiency Following Obesity Treatment: Implications for Young-Onset Cancer Risk in Offspring
by Savio George Barreto, Chris Moy, Stephen J. Pandol and Lilian Kow
Cancers 2024, 16(17), 3099; https://doi.org/10.3390/cancers16173099 - 6 Sep 2024
Viewed by 450
Abstract
Young-onset adult cancers have been an emerging problem over the last three decades in Australia [...] Full article
(This article belongs to the Section Cancer Epidemiology and Prevention)
18 pages, 1058 KiB  
Review
Developmental Therapeutics in Metastatic Prostate Cancer: New Targets and New Strategies
by Jingsong Zhang and Juskaran S. Chadha
Cancers 2024, 16(17), 3098; https://doi.org/10.3390/cancers16173098 - 6 Sep 2024
Viewed by 783
Abstract
There is an unmet need to develop new treatments for metastatic prostate cancer. With the development of targeted radioligand therapies, bispecific T cell engagers, antibody–drug conjugates and chimeric antigen receptor T cell (CAR T) therapies, tumor-associated cell surface antigens have emerged as new [...] Read more.
There is an unmet need to develop new treatments for metastatic prostate cancer. With the development of targeted radioligand therapies, bispecific T cell engagers, antibody–drug conjugates and chimeric antigen receptor T cell (CAR T) therapies, tumor-associated cell surface antigens have emerged as new therapeutic targets in metastatic prostate cancer. Ongoing and completed clinical trials targeting prostate-specific membrane antigen (PSMA), six transmembrane epithelial antigens of the prostate 1 (STEAP1), kallikrein-related peptidase 2 (KLK2), prostate stem cell antigen (PSCA), and delta-like protein 3 (DLL3) in metastatic prostate cancer were reviewed. Strategies for sequential or combinational therapy were discussed. Full article
(This article belongs to the Special Issue New Insights into Urologic Oncology)
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12 pages, 1254 KiB  
Article
Deep Learning Model for Predicting Lung Adenocarcinoma Recurrence from Whole Slide Images
by Ziyu Su, Usman Afzaal, Shuo Niu, Margarita Munoz de Toro, Fei Xing, Jimmy Ruiz, Metin N. Gurcan, Wencheng Li and M. Khalid Khan Niazi
Cancers 2024, 16(17), 3097; https://doi.org/10.3390/cancers16173097 - 6 Sep 2024
Viewed by 553
Abstract
Lung cancer is the leading cause of cancer-related death in the United States. Lung adenocarcinoma (LUAD) is one of the most common subtypes of lung cancer that can be treated with resection. While resection can be curative, there is a significant risk of [...] Read more.
Lung cancer is the leading cause of cancer-related death in the United States. Lung adenocarcinoma (LUAD) is one of the most common subtypes of lung cancer that can be treated with resection. While resection can be curative, there is a significant risk of recurrence, which necessitates close monitoring and additional treatment planning. Traditionally, microscopic evaluation of tumor grading in resected specimens is a standard pathologic practice that informs subsequent therapy and patient management. However, this approach is labor-intensive and subject to inter-observer variability. To address the challenge of accurately predicting recurrence, we propose a deep learning-based model to predict the 5-year recurrence of LUAD in patients following surgical resection. In our model, we introduce an innovative dual-attention architecture that significantly enhances computational efficiency. Our model demonstrates excellent performance in recurrent risk stratification, achieving a hazard ratio of 2.29 (95% CI: 1.69–3.09, p < 0.005), which outperforms several existing deep learning methods. This study contributes to ongoing efforts to use deep learning models for automatically learning histologic patterns from whole slide images (WSIs) and predicting LUAD recurrence risk, thereby improving the accuracy and efficiency of treatment decision making. Full article
(This article belongs to the Section Cancer Informatics and Big Data)
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11 pages, 968 KiB  
Review
Decision Variables for the Use of Radioactive Iodine in Patients with Thyroid Cancer at Intermediate Risk of Recurrence
by Samantha K. Newman, Armando Patrizio and Laura Boucai
Cancers 2024, 16(17), 3096; https://doi.org/10.3390/cancers16173096 - 6 Sep 2024
Viewed by 524
Abstract
The use of radioactive iodine (RAI) after total thyroidectomy for patients at the American Thyroid Association (ATA) who are at intermediate risk of recurrence is controversial. This is due to the lack of prospective randomized trials proving a benefit to recurrence or survival [...] Read more.
The use of radioactive iodine (RAI) after total thyroidectomy for patients at the American Thyroid Association (ATA) who are at intermediate risk of recurrence is controversial. This is due to the lack of prospective randomized trials proving a benefit to recurrence or survival of RAI therapy in this group. In the absence of such evidence, clinicians struggle to recommend for or against this therapeutic approach which frequently results in overtreatment. This review describes key elements in the decision-making process that help clinicians more comprehensively evaluate the need for RAI therapy in patients with thyroid cancer at intermediate risk of recurrence. A clear definition of the purpose of RAI therapy should be conveyed to patients. In this sense, adjuvant RAI therapy intends to decrease recurrence, and ablation therapy is used to facilitate surveillance. Better stratification of the intermediate risk category into a low–intermediate subgroup and an intermediate–high-risk subgroup results in less heterogeneity and a more precise prediction of recurrence risk. The evaluation of post-operative thyroglobulin levels may prevent the overtreatment of low–intermediate-risk patients when their thyroglobulin level is <2.5 ng/mL. the integration of tumor genomics (when available) alongside pathologic features can enhance the ability of the clinician to predict iodine concentration in thyroid cancer cells. Finally, a detailed consideration of the adverse effects of RAI, patients’ comorbidities, and patient preferences will result in a patient-centered personalized approach. Systematic examination of these variables will ultimately provide a framework for making more educated decisions on the use of RAI in patients at intermediate risk of recurrence that will prevent overtreatment and minimize harm. Full article
(This article belongs to the Special Issue Feature Paper in Section 'Cancer Epidemiology and Prevention' in 2024)
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11 pages, 1337 KiB  
Article
Real-Life Outcomes of Adjuvant Targeted Therapy and Anti-PD1 Agents in Stage III/IV Resected Melanoma
by Gabriele Roccuzzo, Paolo Fava, Chiara Astrua, Matteo Giovanni Brizio, Giovanni Cavaliere, Eleonora Bongiovanni, Umberto Santaniello, Giulia Carpentieri, Luca Cangiolosi, Camilla Brondino, Valentina Pala, Simone Ribero and Pietro Quaglino
Cancers 2024, 16(17), 3095; https://doi.org/10.3390/cancers16173095 - 6 Sep 2024
Viewed by 557
Abstract
This study was carried out at the Dermatologic Clinic of the University of Turin, Italy, to assess the effectiveness and safety of adjuvant therapy in patients who received either targeted therapy (TT: dabrafenib + trametinib) or immunotherapy (IT: nivolumab or pembrolizumab) for up [...] Read more.
This study was carried out at the Dermatologic Clinic of the University of Turin, Italy, to assess the effectiveness and safety of adjuvant therapy in patients who received either targeted therapy (TT: dabrafenib + trametinib) or immunotherapy (IT: nivolumab or pembrolizumab) for up to 12 months. A total of 163 patients participated, including 147 with stage III and 19 with stage IV with no evidence of disease. The primary outcomes were relapse-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS). At 48 months, both TT and IT approaches yielded comparable outcomes in terms of RFS (55.6–55.4%, p = 0.532), DMFS (58.2–59.8%, p = 0.761), and OS (62.4–69.5%, p = 0.889). Whilst temporary therapy suspension was more common among TT-treated patients compared to IT-treated individuals, therapy discontinuation due to adverse events occurred at comparable rates in both groups. Predictors of relapse included mitoses, lymphovascular invasion, ulceration, and positive sentinel lymph nodes. Overall, the proportion of BRAF-mutated patients receiving IT stood at 7.4%, lower than what was observed in clinical trials. Full article
(This article belongs to the Special Issue Advances in Skin Cancer: Diagnosis, Treatment and Prognosis)
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16 pages, 538 KiB  
Review
Transdermal Fentanyl in Patients with Cachexia—A Scoping Review
by Andrea Carlini, Emanuela Scarpi, Carla Bettini, Andrea Ardizzoni, Costanza Maria Donati, Laura Fabbri, Francesca Ghetti, Francesca Martini, Marianna Ricci, Elisabetta Sansoni, Maria Valentina Tenti, Alessio Giuseppe Morganti, Eduardo Bruera, Marco Cesare Maltoni and Romina Rossi
Cancers 2024, 16(17), 3094; https://doi.org/10.3390/cancers16173094 - 5 Sep 2024
Viewed by 720
Abstract
Cachectic patients frequently require transdermal fentanyl (TDF) for pain management, but data on its efficacy and safety are scarce and inconsistent. This scoping review aims to analyze the evidence concerning TDF administration in patients with cachexia irrespective of the underlying pathology. The primary [...] Read more.
Cachectic patients frequently require transdermal fentanyl (TDF) for pain management, but data on its efficacy and safety are scarce and inconsistent. This scoping review aims to analyze the evidence concerning TDF administration in patients with cachexia irrespective of the underlying pathology. The primary objective is to assess the analgesic efficacy and tolerability of TDF in cachectic patients. The secondary objective is to identify cachexia characteristics that may influence fentanyl pharmacokinetics (PK). A comprehensive search of PubMed, Embase, and Web of Science databases was conducted up to March 2024. The review included observational and clinical studies on cachectic patients with moderate to severe pain treated with TDF patches at any dosage or frequency. Phase 1 trials, animal studies, case reports, preclinical studies and conference abstracts were excluded. Nine studies were included: four studies reported that cachexia negatively impacted TDF efficacy, increasing required doses and lowering plasma concentrations; three studies found minimal or no impact of cachexia on TDF efficacy and PK; two studies suggested that cachexia might improve TDF outcomes. Study quality ranged from moderate to high, according to the National Institutes of Health (NIH) Quality Assessment Tool. The current evidence is insufficient to provide any definitive recommendations for TDF prescribing in cachectic patients. Full article
(This article belongs to the Section Cancer Survivorship and Quality of Life)
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16 pages, 3309 KiB  
Article
A Comprehensive Analysis of Skin Cancer Concerns and Protective Practices in Manitoba, Canada, Highlights Lack of Skin Cancer Awareness and Predominance of High-Risk Sun Exposure Behaviors
by François Lagacé, Santina Conte, Lorena A. Mija, Amina Moustaqim-Barrette, Farhan Mahmood, Jonathan LeBeau, Alyson McKenna, Mahan Maazi, Johnny Hanna, Alexandra Sarah Victoria Kelly, Elham Rahme, Travis J. Hrubeniuk, Sandra Peláez and Ivan V. Litvinov
Cancers 2024, 16(17), 3093; https://doi.org/10.3390/cancers16173093 - 5 Sep 2024
Viewed by 668
Abstract
The rapidly increasing skin cancer rates in Canada are alarming, with current data estimating that 1/3 of Canadians will be affected in their lifetime. Thus, deeper understanding of high-risk sun exposure behaviors is needed to help counter this trend. Only limited action has [...] Read more.
The rapidly increasing skin cancer rates in Canada are alarming, with current data estimating that 1/3 of Canadians will be affected in their lifetime. Thus, deeper understanding of high-risk sun exposure behaviors is needed to help counter this trend. Only limited action has been taken by federal/provincial governments to reduce skin cancer incidence. A cross-sectional survey study was conducted in Manitoba, with frequency counts, means, and percentages used to encapsulate responses. Age- and gender-adjusted odds ratios were calculated using logistic regression analyses. Our study identified worrying inadequacies in sun protective behaviors and attitudes, with the threat of such high-risk behaviors amplified by a lack of skin cancer awareness. Alarming elements were noted in participants’ sun exposure history (>65% reported a history of sunburns, >50% previously used a tanning bed, and >75% recently tanned for pleasure), beliefs and attitudes (>50% believe that they look better/healthier with a tan, and >40% believe that having a base tan is protective against further sun damage), and sun protection efforts (sun protective clothing was used <60% of the time, sunscreen was used by <50%, and there was a lack of knowledge about sunscreen characteristics in ~30% of respondents), in addition to significant differences being established between demographic subgroups (based on gender, age, skin phototype, income, and education attained). This study provides worrisome insight onto the grim landscape of sun protective behaviors and attitudes in Manitoba, which will inevitably translate into higher skin cancer rates and should serve as a call to action to promote targeted public health messaging in this jurisdiction and beyond. Full article
(This article belongs to the Special Issue Skin Cancer: Risk Factors and Prevention)
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17 pages, 1874 KiB  
Article
Apoptosis of Pancreatic Cancer Cells after Co-Treatment with Eugenol and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand
by Hyun Hee Kim, Suk-Young Lee and Dae-Hee Lee
Cancers 2024, 16(17), 3092; https://doi.org/10.3390/cancers16173092 - 5 Sep 2024
Viewed by 498
Abstract
Pancreatic cancer is a refractory cancer with limited treatment options. Various cancer types are resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Eugenol, the main component of clove oil, exhibits anticancer, anti-inflammatory, and antioxidant effects. However, no studies have reported that eugenol increases [...] Read more.
Pancreatic cancer is a refractory cancer with limited treatment options. Various cancer types are resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Eugenol, the main component of clove oil, exhibits anticancer, anti-inflammatory, and antioxidant effects. However, no studies have reported that eugenol increases TRAIL sensitivity by upregulating death receptor (DR) expression. Here, we aimed to investigate eugenol as a potent TRAIL sensitizer. Increased apoptosis and inhibition of cell proliferation was observed in pancreatic cancer cells treated with eugenol and TRAIL compared with those treated with eugenol alone. Eugenol upregulated the expression of DR5, inhibited the FLICE-inhibitory protein (FLIP), an anti-apoptotic protein, and increased p53, a tumor suppressor protein. In addition, eugenol induced the generation of reactive oxygen species (ROS) and caused endoplasmic reticulum (ER) stress. C/EBP-homologous protein (CHOP) knockdown using siRNA decreased the expression of DR5 and reduced the combined effects of eugenol and TRAIL. These results demonstrate that eugenol enhances TRAIL-induced apoptosis by upregulating DR5 through the ROS-mediated ER stress–CHOP pathway, which enhances ER stress by inducing p53 and downregulating FLIP expression. This suggests that eugenol has the potential to treat pancreatic cancer by increasing cell sensitivity to TRAIL. Full article
(This article belongs to the Section Cancer Pathophysiology)
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12 pages, 2767 KiB  
Article
Initial Experience of Single-Port Robotic Lobectomy for Large-Sized Non-Small Cell Lung Cancer: A Single-Center Retrospective Study
by Jun Hee Lee, Byung Mo Gu, Hwan Seok Yong, Soon Young Hwang and Hyun Koo Kim
Cancers 2024, 16(17), 3091; https://doi.org/10.3390/cancers16173091 - 5 Sep 2024
Viewed by 464
Abstract
Single-port robotic-assisted thoracic surgery (SP-RATS) lobectomy using the da Vinci Xi system has been performed by several pioneers. However, due to the severe collisions and the steep learning curve, this approach is not yet widely used. This study aimed to evaluate the feasibility [...] Read more.
Single-port robotic-assisted thoracic surgery (SP-RATS) lobectomy using the da Vinci Xi system has been performed by several pioneers. However, due to the severe collisions and the steep learning curve, this approach is not yet widely used. This study aimed to evaluate the feasibility of SP-RATS lobectomy for large-sized non-small cell lung cancer (NSCLC). As we believe that for large-sized tumors it is reasonable to make a slightly larger incision, we performed SP-RATS lobectomy for large-sized NSCLC (greater than 5 cm) through a single incision (6–8 cm). Eleven patients underwent SP-RATS lobectomy using the da Vinci Xi system at our institution from April 2022 to May 2024. The median tumor size on computed tomography and on pathology was 6.6 cm [interquartile range (IQR), 6.1–7.5 cm] and 6 cm [IQR, 5.1–7.1], respectively. The median total operative time was 198 min [IQR, 159–260 min], and the median postoperative length of stay was 4 days [IQR, 4–10 days], with no major postoperative complications (≥grade III on the Clavien–Dindo classification). Our approach may combine the benefits of single-port surgery with those of robotic surgery and is safe, feasible, and may promote better outcomes in patients with large-sized NSCLC. Full article
(This article belongs to the Special Issue State of the Art: Cardiothoracic Tumors)
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20 pages, 4232 KiB  
Article
Molecular Insights into the Anticancer Activity of Withaferin-A: The Inhibition of Survivin Signaling
by Renu Wadhwa, Jia Wang, Seyad Shefrin, Huayue Zhang, Durai Sundar and Sunil C. Kaul
Cancers 2024, 16(17), 3090; https://doi.org/10.3390/cancers16173090 - 5 Sep 2024
Viewed by 761
Abstract
Survivin, a member of the IAP family, functions as a homodimer and inhibits caspases, the key enzymes involved in apoptosis. Several Survivin inhibitors, including YM-155, Debio1143, EM1421, LQZ-7I, and TL32711, have emerged as potential anticancer drugs awaiting validation in clinical trials. Due to [...] Read more.
Survivin, a member of the IAP family, functions as a homodimer and inhibits caspases, the key enzymes involved in apoptosis. Several Survivin inhibitors, including YM-155, Debio1143, EM1421, LQZ-7I, and TL32711, have emerged as potential anticancer drugs awaiting validation in clinical trials. Due to the high cost and adverse side effects of synthetic drugs, natural compounds with similar activity have also been in demand. In this study, we conducted molecular docking assays to evaluate the ability of Wi-A and Wi-N to block Survivin dimerization. We found that Wi-A, but not Wi-N, can bind to and prevent the homodimerization of Survivin, similar to YM-155. Therefore, we prepared a Wi-A-rich extract from Ashwagandha leaves (Wi-AREAL). Experimental analyses of human cervical carcinoma cells (HeLa and ME-180) treated with Wi-AREAL (0.05–0.1%) included assessments of viability, apoptosis, cell cycle, migration, invasion, and the expression levels (mRNA and protein) of molecular markers associated with these phenotypes. We found that Wi-AREAL led to growth arrest mediated by the upregulation of p21WAF1 and the downregulation of several proteins (CDK1, Cyclin B, pRb) involved in cell cycle progression. Furthermore, Wi-AREAL treatment activated apoptosis signaling, as evidenced by reduced PARP-1 and Bcl-2 levels, increased procaspase-3, and elevated Cytochrome C. Additionally, treating cells with a nontoxic low concentration (0.01%) of Wi-AREAL inhibited migration and invasion, as well as EMT (epithelial–mesenchymal transition) signaling. By combining computational and experimental approaches, we demonstrate the potential of Wi-A and Wi-AREAL as natural inhibitors of Survivin, which may be helpful in cancer treatment. Full article
(This article belongs to the Section Molecular Cancer Biology)
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18 pages, 763 KiB  
Review
Future AI Will Most Likely Predict Antibody-Drug Conjugate Response in Oncology: A Review and Expert Opinion
by Navid Sobhani, Alberto D’Angelo, Matteo Pittacolo, Giuseppina Mondani and Daniele Generali
Cancers 2024, 16(17), 3089; https://doi.org/10.3390/cancers16173089 - 5 Sep 2024
Viewed by 941
Abstract
The medical research field has been tremendously galvanized to improve the prediction of therapy efficacy by the revolution in artificial intelligence (AI). An earnest desire to find better ways to predict the effectiveness of therapy with the use of AI has propelled the [...] Read more.
The medical research field has been tremendously galvanized to improve the prediction of therapy efficacy by the revolution in artificial intelligence (AI). An earnest desire to find better ways to predict the effectiveness of therapy with the use of AI has propelled the evolution of new models in which it can become more applicable in clinical settings such as breast cancer detection. However, in some instances, the U.S. Food and Drug Administration was obliged to back some previously approved inaccurate models for AI-based prognostic models because they eventually produce inaccurate prognoses for specific patients who might be at risk of heart failure. In light of instances in which the medical research community has often evolved some unrealistic expectations regarding the advances in AI and its potential use for medical purposes, implementing standard procedures for AI-based cancer models is critical. Specifically, models would have to meet some general parameters for standardization, transparency of their logistic modules, and avoidance of algorithm biases. In this review, we summarize the current knowledge about AI-based prognostic methods and describe how they may be used in the future for predicting antibody-drug conjugate efficacy in cancer patients. We also summarize the findings of recent late-phase clinical trials using these conjugates for cancer therapy. Full article
(This article belongs to the Special Issue Artificial Intelligence in Cancer Research: Knowledge Representation and Data Perspectives)
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15 pages, 4099 KiB  
Article
Exposed Phosphatidylserine as a Biomarker for Clear Identification of Breast Cancer Brain Metastases in Mouse Models
by Lulu Wang, Alan H. Zhao, Chad A. Arledge, Fei Xing, Michael D. Chan, Rolf A. Brekken, Amyn A. Habib and Dawen Zhao
Cancers 2024, 16(17), 3088; https://doi.org/10.3390/cancers16173088 - 5 Sep 2024
Viewed by 587
Abstract
Brain metastasis is the most common intracranial malignancy in adults. The prognosis is extremely poor, partly because most patients have more than one brain lesion, and the currently available therapies are nonspecific or inaccessible to those occult metastases due to an impermeable blood–tumor [...] Read more.
Brain metastasis is the most common intracranial malignancy in adults. The prognosis is extremely poor, partly because most patients have more than one brain lesion, and the currently available therapies are nonspecific or inaccessible to those occult metastases due to an impermeable blood–tumor barrier (BTB). Phosphatidylserine (PS) is externalized on the surface of viable endothelial cells (ECs) in tumor blood vessels. In this study, we have applied a PS-targeting antibody to assess brain metastases in mouse models. Fluorescence microscopic imaging revealed that extensive PS exposure was found exclusively on vascular ECs of brain metastases. The highly sensitive and specific binding of the PS antibody enables individual metastases, even micrometastases containing an intact BTB, to be clearly delineated. Furthermore, the conjugation of the PS antibody with a fluorescence dye, IRDye 800CW, or a radioisotope, 125I, allowed the clear visualization of individual brain metastases by optical imaging and autoradiography, respectively. In conclusion, we demonstrated a novel strategy for targeting brain metastases based on our finding that abundant PS exposure occurs on blood vessels of brain metastases but not on normal brain, which may be useful for the development of imaging and targeted therapeutics for brain metastases. Full article
(This article belongs to the Special Issue Brain Metastases: From Mechanisms to Treatment)
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10 pages, 1172 KiB  
Review
Clinical and Histologic Variants of CD8+ Cutaneous T-Cell Lymphomas
by Madisen A. Swallow, Goran Micevic, Amanda Zhou, Kacie R. Carlson, Francine M. Foss and Michael Girardi
Cancers 2024, 16(17), 3087; https://doi.org/10.3390/cancers16173087 - 5 Sep 2024
Viewed by 514
Abstract
Although the vast majority of CTCL subtypes are of the CD4+ T-helper cell differentiation phenotype, there is a spectrum of CD8+ variants that manifest wide-ranging clinical, histologic, and phenotypic features that inform the classification of the disease. CD8, like CD4, and cytotoxic molecules [...] Read more.
Although the vast majority of CTCL subtypes are of the CD4+ T-helper cell differentiation phenotype, there is a spectrum of CD8+ variants that manifest wide-ranging clinical, histologic, and phenotypic features that inform the classification of the disease. CD8, like CD4, and cytotoxic molecules (including TIA and granzyme) are readily detectable via IHC staining of tissue and, when expressed on the phenotypically abnormal T-cell population, can help distinguish specific CTCL subtypes. Nonetheless, given that the histopathologic differential for CD8+ lymphoproliferative disorders and lymphomas may range from very indolent lymphomatoid papulosis (LyP) to aggressive entities like CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (AECTCL), CD8 and/or cytotoxic molecule expression alone is insufficient for diagnosis and is not in itself an indicator of prognosis. We present a review of CTCL subtypes that can demonstrate CD8 positivity: CD8+ mycosis fungoides (MF), LyP type D, subcutaneous panniculitis-like T-cell lymphoma (SPTCL), primary cutaneous gamma/delta T-cell lymphoma (PCGDTL), CD8+ AECTCL, and acral CD8+ T-cell lymphoproliferative disorder (acral CD8+ TCLPD). These diseases may have different clinical manifestations and distinctive treatment algorithms. Due to the rare nature of these diseases, it is imperative to integrate clinical, histologic, and immunohistochemical findings to determine an accurate diagnosis and an appropriate treatment plan. Full article
(This article belongs to the Special Issue Cutaneous Lymphoma)
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15 pages, 638 KiB  
Review
The Surgical Renaissance: Advancements in Video-Assisted Thoracoscopic Surgery and Robotic-Assisted Thoracic Surgery and Their Impact on Patient Outcomes
by Jennifer M. Pan, Ammara A. Watkins, Cameron T. Stock, Susan D. Moffatt-Bruce and Elliot L. Servais
Cancers 2024, 16(17), 3086; https://doi.org/10.3390/cancers16173086 - 5 Sep 2024
Viewed by 476
Abstract
Minimally invasive thoracic surgery has advanced the treatment of lung cancer since its introduction in the 1990s. Video-assisted thoracoscopic surgery (VATS) and robotic-assisted thoracic surgery (RATS) offer the advantage of smaller incisions without compromising patient outcomes. These techniques have been shown to be [...] Read more.
Minimally invasive thoracic surgery has advanced the treatment of lung cancer since its introduction in the 1990s. Video-assisted thoracoscopic surgery (VATS) and robotic-assisted thoracic surgery (RATS) offer the advantage of smaller incisions without compromising patient outcomes. These techniques have been shown to be safe and effective in standard pulmonary resections (lobectomy and sub-lobar resection) and in complex pulmonary resections (sleeve resection and pneumonectomy). Furthermore, several studies show these techniques enhance patient outcomes from early recovery to improved quality of life (QoL) and excellent oncologic results. The rise of RATS has yielded further operative benefits compared to thoracoscopic surgery. The wristed instruments, neutralization of tremor, dexterity, and magnification allow for more precise and delicate dissection of tissues and vessels. This review summarizes of the advancements in minimally invasive thoracic surgery and the positive impact on patient outcomes. Full article
(This article belongs to the Special Issue Advancements in Lung Cancer Surgical Treatment and Prognosis)
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