Authors: Brian Harvey Avanceña Villanueva Lemmuel L. Tayo Kuo-Pin Chuang
Background/Objectives: Brain tumors, particularly gliomas, have high mortality and are limited in treatment options, often complicated by severe conditions, which can be fatal. Given the increasing incidence and adverse effects of current drugs, an in silico drug repurposing approach using hub gene clusters to streamline and accelerate the search for new therapies. Methods: The GSE66354, GSE68848, GSE74195, and GSE43290 datasets were used to identify DEGs using GEO2R. A gene co-expression network was constructed using the STRING PPI database. Preserved clusters revealed hub genes, which were used for GO and KEGG pathway enrichment analyses. Drug repurposing screening was performed through drug–gene interactions in DGIdb. Suggestive drugs were then validated through GSEA-CMAP and BOILED-Egg. Results: The study identified three key gene clusters that serve a role in synaptic transmission and transmembrane transport, synaptic vesicle neurotransmission, and extracellular matrix formation. Five drugs passed the drug screening, which are Gabapentin, Pyrantel, Resveratrol, Trifluoperazine, and Valproic acid. Conclusions: Valproic acid and Gabapentin are highly suggestive as candidate repurposed drugs. This study enhances our understanding of brain tumor genetics and supports the development of new immunotherapeutic strategies.
]]>Authors: Rahul Dilawari Aparajita Sharma Jagdish Verma Richa Thakur Dipayan Das Nitesh Priyadarshi
In cancer biology, the microbiome has emerged as a revolutionary field, revealing host–microbe interactions that drive cancer initiation, development, metastasis, and therapeutic response. The microbiome plays a mechanistic role in carcinogenesis by directly regulating host cell proliferation, apoptosis, and genomic stability, and indirectly through immune regulation and chronic inflammation. Depending on the microbial genetic makeup and host environment, microbial genotoxins, metabolites, and signaling molecules can either induce tumor growth or exert beneficial anticancer effects. Infectious agents are estimated to trigger a significant proportion of cancers globally, although the mechanistic pathways of the broader microbiome remain less well quantified. Likewise, it has been shown that microbiomes modulate the toxicity and efficacy of cancer treatments—specifically immunotherapy and chemotherapy—by mediating anti-tumor reactions and altering drug metabolism. Microbiome-based diagnostics, predictive markers, and therapeutic strategies like dietary modifications, probiotics, synthetic microbes, and fecal microbiota transplantation have collectively benefited from these breakthroughs. Despite rapid progress, integrating microbiome research into oncology is hindered by patient variability, methodological hurdles, and the difficulty of identifying definitive causal links. Large-scale clinical trials are essential for verifying the functional impact of microbiome-targeted treatments. The current review evaluates the mechanistic influence of microbiomes on cancer diagnosis and therapeutics.
]]>Authors: Mehmet Bugrahan Duz Seda Salman Yilmaz Sahra Acir Mustafa Ozen
Oral cancer remains a major global health problem with high morbidity and mortality rates, and despite advances in therapeutic approaches, challenges persist in early diagnosis and effective disease management. MicroRNAs (miRNAs) are endogenous, small non-coding RNAs that regulate gene expression at the post-transcriptional level and play fundamental roles in maintaining cellular homeostasis, as well as in the initiation and progression of multiple malignancies, including oral cancer. Dysregulation of miRNAs contributes to oral carcinogenesis by modulating key cellular processes such as cell proliferation, apoptosis, invasion, metastasis, and angiogenesis. Altered miRNA expression profiles have been consistently identified in oral cancer tissues and body fluids, including saliva and blood, supporting their potential utility as reliable biomarkers for early detection, prognosis, and disease monitoring. Circulating miRNAs, in particular, represent a promising non-invasive diagnostic tool for assessing disease progression and therapeutic response. Moreover, miRNAs are actively involved in regulating sensitivity and resistance to chemotherapy and radiotherapy, with specific miRNAs either enhancing treatment efficacy or promoting therapeutic resistance. This review aims to highlight the critical role of miRNAs in oral cancer pathogenesis, diagnosis, prognosis, and treatment, exploring their potential as biomarkers and therapeutic targets to improve early detection, patient outcomes, and personalized treatment strategies.
]]>Authors: Sashana Dixon Nicola Ewen Hall Karelys Diaz-Davila Helen A. Crentsil Ana M. Castejon Richard N. L. Lamptey
Metastatic castration-resistant prostate cancer (mCRPC) is a prevalent malignancy marked by molecular heterogeneity, which contributes to resistance to standard therapies and poor clinical prognosis. Advances in genomic and transcriptomic profiling have identified key drivers such as alterations in AR, TP53, PTEN, and RB1, which also enable cancer cells to circumvent therapies. Despite such advances, the underlying mechanisms involved in mCRPC drug resistance are complex, creating an urgent need for novel therapies to improve clinical outcomes. To address this clinical problem, strategies focused on targeting underlying molecular and metabolic supportive pathways using nano-delivery systems of diverse drugs could be promising in both CRPC and mCRPC therapy. This review provides an overview of the current understanding of the genomic and microenvironmental landscape of mCRPC and explores emerging classification frameworks aimed at improving patient outcomes. We highlight the potential of integrative multi-omics approaches to inform precision oncology and guide the development of more effective, personalized treatments for prostate cancer therapy.
]]>Authors: Keisy Rodriguez-Villafañe Clara Santiago Juan E. Figueroa Edwin Figueroa Yamixa Delgado
Background/Objectives: In Puerto Rico (PR), lung cancer mortality remains high because diagnoses frequently occur at advanced stages. Although low-dose computed tomography (LDCT) lowers lung cancer–specific mortality, this screening is difficult to operationalize locally due to high false-positive rates, radiology capacity constraints, payer limitations, and geographic barriers affecting rural populations. Methods: We performed a narrative review on the literature from 2001–2026 of established and emerging detection strategies—LDCT; serum biomarkers (CEA, CYFRA-21-1, NSE, ProGRP, SCC-Ag, HE4, Hp, TAAb); breath analysis (FeNO and VOCs); and liquid biopsy (ctDNAs/CTCs/miRNAs). We assessed technical performance, feasibility, and health-system fit in PR and then synthesized these findings into an implementable biomarker-first triage workflow for are. Results: Multiplex serum panels analyzed with machine learning outperform single markers and TAAb provide high specificity with biological lead time, supporting their use as a triage gateway before LDCT. Breathomics is also feasible at the point of care. Liquid biopsy has modest sensitivity in very-early disease yet provides molecular adjudication for indeterminate nodules. A stepwise pathway—expanded risk assessment, integrated multi-panel testing in primary care, LDCT reserved for biomarker-positive individuals, and liquid biopsy when imaging is inconclusive—can enrich pre-test probability, reduce unnecessary scans, align with capitation, and protect limited radiology capacity. Conclusions: An integrated, non-invasive, biomarker-first triage model offers a pragmatic, equitable route to earlier lung cancer detection in PR and resource stewardship, while reducing disparities.
]]>Authors: Liat Oren Yael Fisher Oz Mordechai
Background: DNA methylation profiling has become an important diagnostic tool in pediatric neuro-oncology, particularly for tumors with overlapping morphology or unusual immunophenotypes. Methods: We report four pediatric brain tumor cases evaluated by histopathology and immunohistochemistry, supplemented by targeted next-generation sequencing (NGS) and DNA methylation profiling using the DKFZ Brain Tumor Classifier (v12.8); one case also underwent DKFZ Sarcoma Classifier analysis (v13.2). Results: Methylation profiling provided clinically meaningful diagnostic insights across all cases. In two patients, methylation results supported integrated interpretation in diagnostically challenging settings without changing management. In two cases, methylation profiling prompted major diagnostic revisions with significant therapeutic consequences: (i) a tumor initially diagnosed as atypical teratoid/rhabdoid tumor was reclassified as CNS Ewing sarcoma, confirmed by an EWSR1-FLI1 fusion and immunophenotype, leading to a change to Ewing-based therapy; and (ii) a tumor interpreted as high-grade astrocytoma/glioblastoma was reclassified as a CNS tumor with BCOR internal tandem duplication, enabling a curative-intent approach and revised prognostic counseling. Conclusions: These cases illustrate that DNA methylation profiling can complement histopathology, resolve diagnostically ambiguous tumors, and in selected patients substantially alter treatment decisions and expected outcomes. Early integration of methylome profiling may improve precision diagnostics and reduce the risk of inappropriate therapy in pediatric brain tumors.
]]>Authors: Caleb Wyckoff Christopher Osgood Ellen Jing Michael Stacey
Background/Objectives: Chondrosarcoma, glioblastoma, acute myeloid leukemia, chronic lymphocytic leukemia, and cholangiocarcinoma cancers all contain mutations in the gene isocitrate dehydrogenase 2 (IDH2). The mutant IDH2 enzyme metabolizes alpha-ketoglutarate (αKG) into the potent oncometabolite D-2-hydroxyglutarate (D2HG) in the mitochondria of these cancers, leading to altered cellular metabolism. Emerging evidence suggests that mitochondrial transfer between cancer and recipient cells represents an important form of intercellular communication that may influence cellular metabolism. The presence of intercellular TNTs between IDH2-mutant chondrosarcoma cells motivated an investigation into mitochondria-associated physiological changes occurring during an intercellular exchange with immune cells. A mitochondrial transfer is a two-way process, and we hypothesized that mitochondria-associated material derived from IDH2-mutant chondrosarcoma cells is exchanged with normal cells through TNTs. We further hypothesized that disruption of the actin cytoskeleton will inhibit this transfer. Accordingly, our objectives were to (1) quantify the extent and directionality of the mitochondrial exchange between IDH2-mutant cells and wild-type cells and to modulate this process via cytoskeletal inhibitors, and (2) measure the metabolic changes associated with the coculture and mitochondrial exchange. Methods: IDH2-mutant chondrosarcoma cells were cocultured with immune cells in vitro to quantify the extent and directionality of the mitochondrial exchange, and cytochalasin B was used as a cytoskeletal inhibitor to disrupt actin-dependent transfer. Metabolic changes associated with coculture and mitochondrial exchange were assessed using Seahorse extracellular flux analysis. Results: The experimental data presented here demonstrate a bidirectional exchange of mitochondria-associated material between IDH2-mutant chondrosarcoma cells and immune cells in vitro, accompanied by metabolic alterations in both cell types. Conclusions: These findings advance our understanding of intercellular communication in the tumor microenvironment and provide a foundation for future studies examining the functional and therapeutic relevance of a mitochondrial exchange in IDH2-mutant cancers.
]]>Authors: Koji Takahashi Takaaki Ikegami Arisa Kato Nana Yamada Terunao Iwanaga Takafumi Sakuma Junichi Senoo Hidehiro Kamezaki
Hepatocellular carcinoma (HCC) exhibits a striking male predominance, particularly in Hepatitis B Virus (HBV) endemic regions. While lifestyle factors and estrogen protection are traditional explanations, they fail to fully account for this disparity. This review elucidates the molecular mechanisms driving this gender gap, focusing on the interplay between the Androgen Receptor (AR), viral replication, and the suppression of NKG2D-mediated immune surveillance. We synthesized experimental and clinical findings linking AR signaling, the viral protein HBx, and the regulation of NKG2D ligands (MICA/MICB). Current evidence identifies a positive feedback loop where AR enhances HBV replication, while HBx amplifies AR activity. Crucially, this axis systematically dismantles innate immunity: AR signaling represses MICA/B transcription via miRNA networks and upregulates ADAM metalloproteases, leading to ligand shedding and the release of soluble MICA (sMICA), effectively blinding Natural Killer (NK) cells. We propose that historical failures of anti-androgen monotherapy likely stemmed from ignoring this immune modulation. Consequently, targeting the AR-NKG2D axis represents a promising strategy to sensitize tumors to immunotherapy, suggesting that future therapeutic approaches should combine AR modulation with immune checkpoint inhibitors or shedding-blockade.
]]>Authors: Jessica McIntyre Rahaba Marima Babatunde Alabi Gopika Ramkilawon Benny Mosoane
Background: Cervical cancer is the second most prevalent malignancy among South African women, with high-risk human papillomavirus (HPV) infection as a critical risk factor. HPV plays a central role in cervical carcinogenesis, particularly in high-grade squamous intraepithelial lesions (HSIL). Increased programmed death ligand 1 (PD-L1) expression has been implicated in cervical carcinoma tumorigenesis. Using immunohistochemistry, this study investigated the correlation between high-risk HPV-driven cervical intraepithelial neoplasia (CIN) and PD-L1 expression. Methods: An analytical cross-sectional study was conducted on archival tissue from the Department of Anatomical Pathology, University of Pretoria (2018–2021). Formalin-fixed paraffin-embedded tissues from loop electrosurgical excisions, cone biopsies, punch biopsies, and polypectomies were analysed. PD-L1 expression was assessed using the combined proportion score (CPS). Three pathologists independently evaluated histological grade, p16 immunohistochemistry, and PD-L1 expression. Results: Among 108 cases (mean age: 37.36 years), 89.8% were CIN 3, 9.3% CIN 2, and 0.9% CIN 2–3. p16 was positive in 97.2% of cases. PD-L1 expression (CPS ≥ 1) was observed in 9.3% of cases, with a mean CPS of 1.57%. No significant association was found between PD-L1 expression and CIN grade (p = 0.6433, Cramer’s V = 0.1191) or between PD-L1 and p16 positivity (p = 1, Cramer’s V = 0.05976). Conclusions: This study demonstrates no correlation between PD-L1 expression and high-risk HPV-driven high-grade CIN. These findings suggest that immune checkpoint inhibition targeting PD-L1 may have limited therapeutic relevance in HSIL among South African women.
]]>Authors: Nerea Laura Keller Gina Votta-Velis José Alejandro Aguirre Alain Borgeat
Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by late diagnosis, early metastasis, and poor response to therapy. Liquid biopsy approaches, including circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and exosomes, offer a minimally invasive method to monitor tumor burden, progression, and treatment response in real time. This review aims to synthesize recent findings on CTCs in PDAC, evaluate detection technologies, and explore their clinical and translational potential. Methods: We conducted a comprehensive literature search using PubMed and Google Scholar, focusing on original studies and reviews published within the past 15 years. Articles were selected based on relevance to CTC biology, detection methods, clinical correlations, and integration with other biomarkers. Attention was paid to studies published since 2018 and landmark earlier works. Results: CTCs are detectable in PDAC patients and are consistently associated with worse survival and higher recurrence rates. However, detection sensitivity varies widely by method. EpCAM-based platforms like CellSearch® detect CTCs in ~7–48% of cases, while newer size-based and microfluidic approaches report rates above 75%. CTCs exhibit epithelial–mesenchymal and stem-like phenotypes and can form clusters with high metastatic potential. Recent studies demonstrate molecular heterogeneity and show that CTC-derived organoids are feasible for functional studies. Nonetheless, technical variability and the lack of standardization remain major obstacles. Conclusions: CTCs represent a promising biomarker for prognosis and treatment monitoring in PDAC. Further refinement of enrichment techniques, molecular profiling strategies, and prospective clinical validation are needed to integrate CTC assays into routine PDAC management.
]]>Authors: Emily Do Surajit Hansda
The innate immune system’s core sensor, the NLRP3 inflammasome (Nucleotide-binding Oligomerization Domain, Leucine-rich Repeat, and Pyrin Domain-Containing Protein 3), is a pivotal multi-protein complex that detects cellular danger and microbial threats. While its activation is fundamental for host defense, chronic dysregulation of NLRP3 is a central driver of pathology in diverse diseases, ranging from neurodegeneration to cancer. This review comprehensively examines the complex and often paradoxical roles of the NLRP3 inflammasome in these two distinct domains. In neurodegenerative disorders, including Alzheimer’s and Parkinson’s, aberrant NLRP3 activation drives persistent neuroinflammation, leading to synaptic dysfunction and neuronal loss through the sustained release of mature IL-1β and IL-18. Conversely, NLRP3 exhibits a striking bimodal role in oncology; it can promote tumorigenesis by fueling chronic inflammation, metastasis, and immune evasion in certain tumor microenvironments, yet simultaneously enhances anti-tumor immunity and pyroptotic cell death in other specific contexts. This context-dependent function highlights a critical therapeutic challenge. We delineate the shared molecular pathways, contrast disease-specific outcomes, and the current landscape of therapeutic strategies aimed at modulating NLRP3. Understanding the nuanced role of the inflammasome offers novel insights into the convergence of chronic inflammation, neurodegeneration, and tumor biology, and holds promise for the development of targeted, context-dependent therapies with dual clinical applications.
]]>Authors: Anna N. Tsapieva Nadezhda V. Duplik Anastasiya O. Morozova Tatiana A. Filatenkova Varvara D. Karanina Alexander N. Chernov Mariia A. Suvorova Lili Zhang Aleksandr A. Matichin Iana V. Agatsarskaya Ekaterina A. Iz’yurova Mihail V. Miroshnikov Yaroslav A. Gushchin Elena Egidarova Kseniya P. Bogatireva Alexander N. Suvorov
Objectives. Pancreatic cancer remains one of the most lethal malignancies, and the lack of effective therapies highlights the need for novel treatment strategies. In this study, we evaluated the antitumor potential of the attenuated Streptococcus pyogenes strain GURSA1—engineered to knockout the M protein completely—in a murine model of orthotopically transplanted pancreatic ductal adenocarcinoma. Methods. Female C57Bl/6 mice received intratumoral injections of GURSA1 at doses of 5 × 105 or 1 × 106 CFU per animal. Animal survival, body weight, tumor engraftment, metastasis intensity, tumor mass and volume, and hematological, biochemical, histological, and microbiological parameters were assessed. Results. Intratumoral administration of GURSA1 produced dose-dependent antitumor effects on tumor growth and metastatic burden, but did not result in a statistically significant survival benefit. The strain reduced tumor engraftment, the overall metastasis score, and the incidence of hemorrhagic ascites, while also decreasing tumor mass and volume, with the strongest effects observed at a dose of 1 × 106 CFU. Treatment increased platelet counts and reduced urea and ALT levels toward values observed in intact mice, without affecting anemia, neutrophilia, or changes in AST, alkaline phosphatase, glucose, and total protein levels. Conclusions. These findings demonstrate that GURSA1 attenuates partial reduction in primary tumor burden in vivo and support further investigation of this strain as a potential oncolytic agent.
]]>Authors: Manish Charan Tanisha Mukherjee Krina Patel Ramesh K. Ganju
Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine disease marked by rapid growth, early metastatic spread, and poor outcomes. The addition of immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis to first-line chemotherapy has recently reshaped the treatment landscape for extensive-stage SCLC (ES-SCLC); however, the resulting survival gains remain modest compared with non-small lung cancer (NSCLC). This review explores the molecular features of the SCLC immune landscape that contribute to its predominantly “cold” tumor phenotype, including low MHC class I expression, T-cell exhaustion, and a profoundly immunosuppressive tumor microenvironment (TME). We summarize key clinical findings from landmark trials and examine mechanisms of both primary and acquired resistance against ICIs in SCLC. In addition, we have reviewed the growing role of precision medicine in SCLC, including molecular subtyping (SCLC-A, -N, -P, and -I) and the development of next-generation immunotherapies such as bispecific T-cell engagers (BiTEs), B7-H3, targeted therapy, and antibody–drug conjugates. By combining existing clinical evidence with new molecular insights, this review article presents strategies to overcome the existing therapeutic plateau and enhance personalized immunotherapy approaches in SCLC.
]]>Authors: Sofia Carralas Antunes Joana Nogueira Daniel Gomes Pinto Leda Viegas de Carvalho
Cervical cancer is strongly associated with persistent infection by high-risk human papillomavirus (HPV). Recent advances in immunotherapy have redefined the therapeutic landscape of this disease. We aim to review the biological rationale, clinical evidence, and biomarker standardization supporting the use of immune checkpoint inhibitors (ICIs) in cervical cancer. A comprehensive review of recent literature and pivotal phase II–III clinical trials was performed, focusing on the PD-1/PD-L1 and CTLA-4 pathways, mechanisms of immune evasion, and predictive biomarkers. Persistent HPV infection leads to immune dysregulation and PD-L1 upregulation through E6/E7-mediated activation of the PI3K/AKT/mTOR and JAK/STAT pathways. ICIs have demonstrated significant improvements in overall survival, progression-free survival, and objective response rates in advanced and recurrent disease. PD-L1 immunohistochemistry using standardized assays such as 22C3 pharmDx and SP263 remains the key biomarker for treatment selection, while emerging molecular markers (TMB, MSI, HLA-I expression) are under investigation. Immunotherapy represents a major step forward in cervical cancer management, integrating molecular diagnostics and immune modulation into clinical practice. Continued efforts to refine biomarkers, optimize combination strategies, and expand global access will be essential to achieve equitable outcomes and disease elimination goals.
]]>Authors: Rabia S. Angiras Dilson Lobo Athiyamaan M. Senthiappan Sourjya Banerjee Srinivas Challapalli Johan Sunny Abhishek Krishna Paul Simon
Introduction: Radiotherapy plays a critical role in the management of head and neck squamous-cell carcinoma (HNSCC); however, the influence of overall treatment time on patient outcomes remains an area of ongoing investigation. The use of radiation, either in conjunction with concurrent chemotherapy or on its own, is crucial when treating HNSCC. Despite the longstanding hypothesis that treatment gaps may adversely affect tumor response and overall survival, there is a paucity of literature on this particular area. This study aims to bridge the knowledge gap and assess the correlation of treatment gaps on recurrences in HNSCC patients. Materials and Methodology: This retrospective study is based on an analysis of data obtained from a single institution between 2017 and 2021. Patients were selected on the basis of the presence of treatment gaps. Data were extracted from medical records and analyzed to evaluate the association between overall treatment time and various patient and treatment-related factors. Various factors thought to contribute to treatment gaps, such as age, TNM Stage, radiation dose, and use of concurrent chemotherapy, were also examined. Results: A total of 212 patients with treatment gaps were evaluated. Of these, 80 individuals experienced recurrences. It was observed that compared to distant metastases, locoregional failure was more frequent (n = 2, 4.2% vs. n = 45, 95.74%). The patients underwent both adjuvant and definitive therapy and were treated with a dose range of 60–70 Gy and concurrent cisplatin chemotherapy. It was noticed that this cohort had a range of 4–43 days of treatment gaps. Notably, 19 out of 47 patients had treatment gaps ≤ 5 days, while 28 out of 47 had gaps exceeding 5 days. It was also observed that patients with treatment gaps of >5 days had poorer quality of life and overall survival. Conclusions: This study identified that the Overall Treatment Time (OTT) had a strong statistical correlation with the development of recurrences. Further, the age of the patient, presence of neutropenia and the duration of the treatment gap were also identified to significantly correlate with the chance of developing recurrences.
]]>Authors: Graham Pawelec Suzanne Ostrand-Rosenberg Tamas Fülöp Flore Van Leemput Chris P. Verschoor
Most clinical cancer therapy trials do not specifically consider the effect of patient age on treatment outcomes, and many even exclude older individuals. This is despite the fact that solid cancers are age-associated diseases and that there are many shared hallmarks between biological ageing and cancer. Thus, there is an increasing awareness of the serious gaps remaining in our knowledge of how older adults respond to cancer treatments, particularly immunotherapies. Emerging evidence suggests that it is not only the physiological and immunological changes associated with chronological ageing that impacts cancer treatment, but also those heterogeneous differences that impact treatment outcomes, such as frailty, comorbidities, and more generally, biological ageing. Importantly, it remains unclear which of these factors are negative or positive contributors, as has been illuminated by recent evidence pertaining to the incidence and severity of immune-related adverse events and survival. Much of our information on older patients in this context is essentially anecdotal, mostly deriving from the treatment of older adults in real-world practice or clinical trials that happened to include some older patients. Given the lack of comprehensive articles on the heterogeneity of ageing as a core determinant of cancer treatment outcomes, we briefly consider the state of the art of cancer research and treatment in the older patient, with an emphasis on immunotherapy and geriatric oncology.
]]>Authors: Ana Arance Roberto Díaz Eva Muñoz-Couselo Teresa Puértolas Almudena García Castaño Rafael López Castro Gretel Benítez López Rubén de Toro María Quindós Enrique Espinosa Pablo Ayala de Miguel Margarita Majem
In the context of advanced BRAF-mutant melanoma, the treatment landscape has undergone a paradigm shift due to the impact of immune checkpoint inhibitors and BRAF/MEK inhibitors. This article presents three clinically illustrative melanoma cases that served as focal points for in-depth discussions during 12 expert meetings held across Spain. These include a treatment-naïve metastatic melanoma patient, a patient experiencing a recurrence while on anti-PD-1 adjuvant therapy, and a third patient whose melanoma relapsed ≥6 months after the end of adjuvant therapy. The discussions revolved around optimal treatment sequencing, emphasizing the challenges and alternatives discussed in each scenario. The common view aligned towards a nuanced approach that involves navigating the complexities of treatment choices. The conclusions underscore the need for personalized therapeutic strategies and highlight the ongoing challenge of refining real-life evidence-based algorithms for the management of metastatic BRAF-mutant melanoma.
]]>Authors: Karim Khaled Hala Jardaly Byeongsang Oh
Background: The belief that “sugar feeds cancer” is widespread and has strongly influenced public perceptions, patient behavior, and dietary recommendations, despite uncertainty regarding its scientific validity. This belief largely stems from misinterpretation of the Warburg effect, which describes altered glucose metabolism in cancer cells rather than dietary sugar dependence. The objective of this review was to critically evaluate whether dietary sugar intake directly contributes to cancer development or progression by examining the totality of epidemiological, experimental, and mechanistic evidence. Methods: We conducted a narrative review of human epidemiological studies, experimental animal and cell-based models, and mechanistic investigations published between 1980 and July 2025. Evidence was synthesized across cancer types, sugar sources, and biological pathways, with careful consideration of study design, exposure relevance, and key confounders, including obesity, insulin resistance, and overall dietary patterns. Results: Across cancer types, epidemiological evidence showed predominantly null or inconsistent associations between sugar intake and cancer risk or outcomes, with positive findings largely confined to metabolically susceptible subgroups and often attenuated after adjustment for adiposity and energy intake. Experimental studies suggested potential tumor-promoting effects under non-physiological conditions, while mechanistic data indicated that sugar influences cancer risk indirectly through insulin signaling, inflammation, and metabolic dysfunction rather than direct tumor fueling. Conclusions: Current evidence does not support the hypothesis that dietary sugar directly “feeds” cancer in humans. Overemphasis on sugar avoidance risks nutritional and psychological harm, particularly among cancer patients. Evidence-based guidance should prioritize overall dietary quality, metabolic health, and patient well-being rather than isolated sugar restriction.
]]>Authors: Anastasia Xagara Filippos Koinis Konstantinos Tsapakidis Ioannis Samaras Evangelia Chantzara Konstantina Vasilieva Alexandros Lazarou Vassilis Georgoulias Athanasios Kotsakis
Immunotherapy has revolutionized the management of patients with cancer. Immune checkpoint inhibition (ICI) is a promising treatment option that targets the molecular mechanisms that cancer cells exploit to prevent immune-mediated elimination. ICI therapy can cause exceptional long-term tumor remissions, in some cases, even after treatment discontinuation. Despite its success, many patients acquire resistance or fail to respond due to immune escape mechanisms mediated by the tumor and its microenvironment. Pre-existing immunity status of individuals seems to play a fundamental role in immunotherapy response and eventually tumor progression, as it orchestrates tumor-immune interactions. Different immune cell subsets, both in the tumor microenvironment and the peripheral blood, are established mediators that contribute to immune escape in various tumor types. Based on these findings, the elucidation of the mechanisms implicated in the regulation of these immune cells has become a priority for investigators focused on improving the efficacy of ICI. This will be essential for identifying responders as well as for developing novel therapeutic modalities to improve clinical outcomes. Herein, we summarize preclinical and clinical evidence proposing a predictive role of pre-existing immunity for clinical responses to immunotherapies.
]]>Authors: Frederick H. Silver Tanmay Deshmukh Gayathri Kollipara
Background: There are approximately 5.4 M basal cell (BCC) and squamous cell (SCC) carcinomas diagnosed each year, and the number is increasing. Currently, the gold standard for skin cancer diagnosis is histopathology, which requires the surgical excision of the tumor followed by pathological evaluation of a tissue biopsy. The three-dimensional (3D) nature of human tissue suggests that two-dimensional (2D) cross sections may be insufficient in some cases to represent the complex structure due to sampling bias. There is a need for new techniques that can be used to classify skin lesion types and margins noninvasively. Methods: We use optical coherence tomography volume scan images and AI to noninvasively create 3D images of basal cell and squamous cell carcinomas. Results: Three-dimensional optical coherence tomography images can be broken down into a series of cross sections that can be classified as benign or cancerous using convolutional neural network models developed in this study. These models can identify cancerous regions as well as clear edges. Cancerous regions can also be verified based on visual review of the color-coded images and the loss of the green and blue subchannel pixel intensities. Conclusions: Three-dimensional optical coherence tomography cross sections of cancerous lesions can be collected noninvasively, and AI can be used to classify skin lesions and detect clear lesion edges. These images may provide a means to speed up treatment and promote better patient screening, especially in older patients who will likely develop several lesions as they age.
]]>Authors: Satyendra Batra Prashant Prabhakar Debabrata Mohapatra Noreen Grace George Neha Goel Bhavika Rishi Aroonima Misra Amitabh Singh
The tumor microenvironment (TME) plays an important role in the development, progression, and treatment response of pediatric cancers, yet remains less elucidated compared to adult malignancies. Pediatric tumors are unique with a low mutational burden, an immature immune landscape, and unique stromal interactions. The resultant “cold” immune microenvironments limits the effectiveness of conventional immunotherapies. This review summarizes the key cellular and non-cellular components of the pediatric TME—including T cells, NK cells, tumor-associated macrophages, cancer-associated fibroblasts, extracellular matrix remodeling, angiogenesis, and hypoxia—and describes how these elements shape tumor behavior and therapy resistance. The role of TME in common pediatric cancers like leukemia, lymphoma, neuroblastoma, brain tumors, renal tumors, and sarcomas is discussed. Emerging therapeutic strategies targeting immune checkpoints, macrophage polarization, angiogenic pathways, and stromal barriers are discussed.
]]>Authors: Suzanne Hippolite Magagoum Gael Tchokomeni Siwe Fleury Augustin Nsole Biteghe Allan Martin Huysamen Dirk Lang Roger Hunter Stefan Barth
Background: Melanoma and triple-negative breast cancer (TNBC) are the most aggressive skin and breast cancers, often diagnosed at late stages with limited treatment options. The melanoma-associated antigen melanotransferrin (MTf) is overexpressed in these solid tumors, where it drives tumorigenesis, progression, and chemoresistance. Its inhibition correlates with tumor regression, making MTf a promising therapeutic target. This study aimed to develop a novel, selectively targeted antibody–drug conjugate (ADC) against MTf-expressing melanoma and TNBC cancer cells using SNAP-tag fusion protein conjugation technology. Methods: We generated an L49(scFv)-SNAP-tag antibody fusion protein engineered through the genetic fusion of a humanized anti-MTf single-chain variable fragment (scFv) with a SNAP-tag fusion protein capable of site-specific self-labelling with O6-benzylguanine (BG) modified substrates in 1:1 stoichiometry. Binding and internalization of the conjugate labeled with BG-Alexa 488 (L49(scFv)-SNAP-Alexa488) were assessed by confocal microscopy and flow cytometry in MTf-overexpressing cell lines. Cytotoxicity was evaluated using the cell viability XTT assay after conjugating the SNAP-fusion protein to the potent monomethyl auristatin-F (BG-AURIF). Results: The L49(scFv)-SNAP-Alexa488 conjugate demonstrated specific binding and internalization into MTf-positive melanoma and TNBC cells. The corresponding ADC, L49(scFv)-SNAP-Linker-AURIF, exerted potent, antigen and dose-dependent cytotoxicity, with IC50 values in the nanomolar range (4.77–34.43 nM). Conclusions: We successfully generated a novel SNAP-tag-based ADC that selectively eliminates MTf-overexpressing tumor cells. This proof-of-concept highlights MTF’s value as a therapeutic target and demonstrates that a smaller-format, non-cleavable linker SNAP-tag-based ADC can achieve potent nanomolar cytotoxicity, supporting further development of MTF-targeted immunotherapies for melanoma and TNBC.
]]>Authors: Anne-Marie Mosbæk Ellegaard Tim Svenstrup Poulsen Estrid Høgdall
Background: Ovarian cancer is one of the most lethal gynecological malignancies, often diagnosed at an advanced stage. The prognosis is generally poor, with high recurrence rates and limited long-term survival. Understanding the genetic and molecular mechanisms underlying ovarian cancer is crucial for improving early diagnosis, developing targeted therapies, and enhancing patient outcomes. Methods: In this study, the clinical molecular reports of 50 ovarian cancer patients referred to the experimental cancer unit at Herlev Hospital were analyzed. The aim was to assess the number of patients being potential candidates for targeted biological therapy. Additionally, using the reports, we aimed to identify patients with potential germline mutations in cancer-predisposing genes. The possible consequences were annotated using gene lists from four hospitals in Denmark. Each hospital had its own distinct, published gene list, reflecting the genes that it considered potential carriers of germline mutations predisposing to cancer. Results: A total of twenty out of fifty patients (40%) had targetable biomarkers for biological treatment. CCNE1 amplification was identified as the most frequent variant (43%). Seven out of fifty patients (14%) had potential germline mutations in cancer-predisposing genes. Conclusions: In conclusion, the finding of a potential germline mutation in the SMARCA4 gene highlights how differences in hospital-specific gene lists may impact patient referral for genetic counseling.
]]>Authors: Giovannino Silvestri Aditi Chatterjee
Hematological malignancies such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML), lymphomas, and multiple myeloma remain difficult to model ex vivo because conventional two-dimensional (2D) cultures and murine systems fail to reproduce the spatial, metabolic, vascular, and immune complexity of human bone marrow and lymphoid niches. Recent advances in three-dimensional (3D) platforms—including spheroids, engineered organoid-like marrow models, and microfluidic niche-on-a-chip systems—now allow for a more physiological replication of stromal, endothelial, and immune interactions that drive resistance and relapse. In this review, we introduce explicit definitions distinguishing spheroids, organoid-like constructs, true hematopoietic organoids, and microfluidic devices to establish a unified framework for hematologic 3D modeling. We synthesize applications across AML, CML, lymphoma, and myeloma, highlighting mechanistic insights, strengths, and limitations unique to each disease. Finally, we outline a translational roadmap that integrates bioprinting, perfusable vasculature, immune reconstitution, and AI-driven analytics toward next-generation patient-specific platforms. These innovations position 3D marrow-mimetic systems as essential tools for precision oncology in blood cancers.
]]>Authors: Devi Lal Himani Pandey
Background: Colorectal cancer (CRC) is a major contributor to cancer-related mortality globally. Despite significant advances in therapeutic strategies, CRC continues to exhibit high recurrence rates. This underscores the urgent need for reliable, non-invasive biomarkers to improve diagnostic precision, early detection, and clinical outcomes. Methods: Gene expression datasets from the GEO database were analyzed to identify differentially expressed genes between CRC and normal tissue samples. Hub genes were identified through an integrative approach combining module membership, gene significance, differential expression, and network centrality. Prognostic significance was assessed via overall survival analysis, and diagnostic utility through ROC curve and AUC. Further integrative analysis included immune cell infiltration, promoter methylation, genetic alterations, and regulatory network construction. Results: An integrated approach identified 989 candidate hub genes. Of these, 128 genes demonstrated significant prognostic potential: 67 were associated with poor overall survival and 61 with favorable outcomes. These genes exhibited patterns of co-expression and positive correlations with immune cell infiltration, particularly B cells, dendritic cells, macrophages, mast cells, and monocytes. Twenty-three hub genes, including MACC1, YEATS4, HMMR, TIGD2, CENPE, GNL3, GMPS, NCAPG, RRM1, DLGAP5, YARS2, CCT8, MET, ZWILCH, KPNA2, KIF15, TRUB1, AURKA, NUDT21, PBK, TOMM20, KIAA1549, and MCM4, showed high diagnostic accuracy in distinguishing CRC from normal tissues. Furthermore, 18 hub genes exhibited statistically significant differential promoter methylation and may serve as promising candidates for epigenetic biomarkers in CRC. Conclusions: Our findings provide a strong foundation for developing more accurate multi-gene prognostic and diagnostic panels and personalized therapies for CRC, with the goal of improving clinical outcomes and reducing the global burden of this disease.
]]>Authors: Sunanda Kulshrestha Sabuj Samaddar Anshika Singh Kunal Yadav Deepanshu Aul Tulika Singh Sonika Kumari Sharma Samarendra Kumar Singh
Gallbladder cancer (GBC), an aggressive malignancy of the biliary tract, is characterized by pronounced geographical variation and a poor prognosis, with a five-year survival rate below 20%. Despite its low global incidence, it ranks as the fifth most prevalent gastrointestinal cancer. The aim of this review is to provide a comprehensive understanding of the molecular mechanisms underpinning GBC progression, with a particular focus on the pivotal role of transcription factors (TFs) in its pathogenesis. This review delineates how aberrant regulation of TFs contributes to tumor initiation, progression, and therapeutic resistance, and to discuss the translational potential of targeting these factors for clinical benefit. Tumor suppressor TFs such as p53 and p16 frequently undergo genetic alterations, including mutations, deletions, or epigenetic silencing, leading to impaired cell cycle control, DNA repair, and apoptosis. Conversely, oncogenic TFs including TCF4, MYBL2, NF-kB, AP-1, Snail, c-MYC, SP1, FOXK1, KLF-5, STAT3 and BIRC7 are often upregulated in GBC, promoting unchecked proliferation, epithelial–mesenchymal transition (EMT), metastasis, and therapeutic resistance. This review aims to bridge current molecular insights with emerging therapeutic approaches, with particular emphasis on innovative interventions such as proteolysis-targeting chimeras (PROTACs), RNA-based therapeutics, CRISPR-driven genome editing, and epigenetic modulators, which collectively represent promising strategies for achieving more effective and personalized treatment outcomes in patients with GBC.
]]>Authors: Constantin N. Baxevanis Angelos D. Gritzapis
A central obstacle in contemporary oncology is tumor relapse and metastatic recurrence [...]
]]>Authors: Ademar Dantas da Cunha Junior Larissa Ariel Oliveira Carrilho Paulo Ricardo Santos Nunes Filho Luca Cantini Laura Vidal Maria Carolina Santos Mendes José Barreto Campello Carvalheira Kamal S. Saini
The inflammatory milieu surrounding tumors plays a pivotal yet paradoxical role in promoting carcinogenesis. Rather than simply acting as a host defense mechanism, chronic low-grade inflammation actively nurtures tumor development and supports hallmarks such as sustained proliferative signaling, apoptosis resistance, angiogenesis, and metastasis. Obesity, characterized by a chronic inflammatory state, exacerbates this tumor-promoting environment through metabolic imbalances like insulin resistance, hyperglycemia, and dyslipidemia. These conditions stimulate oncogenic signaling pathways and reshape the tumor microenvironment. Obesity-associated cytokines, altered adipokines, and insulin-related growth signals synergistically enhance processes such as epithelial-to-mesenchymal transition (EMT) and matrix remodeling. This review explores the mechanistic interplay between obesity-induced inflammation and insulin resistance in cancer progression, discusses the molecular pathways involved, and highlights emerging therapeutic approaches targeting these intersecting tumor promotion axes.
]]>Authors: Juan Luis Alcázar Cristian Morales Carolina Venturo Florencia de la Maza Laura Lucio Manuel Lozano José Carlos Vilches Rodrigo Orozco Manuela Ludovisi
Background: Ovarian cancer remains a major contributor to cancer-related morbidity and mortality worldwide. Primary cytoreductive surgery is the cornerstone of treatment, and accurate preoperative assessment of tumor resectability is critical to guiding optimal therapeutic strategies in patients with advanced tubo-ovarian cancer. Methods: A narrative review about the role of ultrasound for assessing tumor spread and prediction of tumor resectability was performed. Results: The ISAAC study represents the largest prospective multicenter trial to date comparing the diagnostic performance of ultrasound (US), computed tomography (CT), and whole-body diffusion-weighted magnetic resonance imaging (WB-DWI/MRI) in predicting non-resectability, using surgical and histopathological findings as the reference standard. Key strengths of the study include the use of standardized imaging and intraoperative reporting protocols across ESGO-accredited high-volume oncologic centers. All three imaging modalities were performed within four weeks prior to surgery by independent, blinded expert operators. US demonstrated diagnostic accuracy comparable to that of CT and WB-DWI/MRI. The study also defined modality-specific thresholds for the Peritoneal Cancer Index (PCI) and Predictive Index Value (PIV), offering quantitative tools to support surgical decision-making. A noteworthy secondary finding was patient preference: in a cohort of 144 participants who underwent all three imaging modalities, nearly half preferred US, while WB-DWI/MRI was the least favored due to discomfort and examination duration. Conclusions: The ISAAC study represents a significant advancement in imaging-based prediction of surgical non-resectability in tubo-ovarian cancer. Its findings suggest that, in expert hands, ultrasound can match or even surpass cross-sectional imaging for preoperative staging, supporting its integration into routine clinical practice, particularly in resource-constrained settings.
]]>Authors: Francisco J. Pelegrín-Mateo Javier Gallego Plazas
Colorectal liver metastases (CRLM) management remains a complex conundrum in the context of potential curable disease. The combination of systemic therapy and surgery, with overall survival outcomes up to 58% at five years, has become the gold standard. Locoregional therapies have gained evidence in complementing surgery or even substituting it in selected cases. Adequate patient selection is paramount, but prognostic models have certain limitations that prevent their full implementation in clinical practice. A plethora of prognostic factors exists, with variable evidence supporting their definitive role. Thus, CRLM management decisions frequently vary depending on multidisciplinary team experience and hospital access to systemic and locoregional treatments. Definition of resectability has evolved in recent years due to technical developments in surgical and non-surgical approaches. Complexity is added when trying to fully understand the integration between local and systemic treatment. Whereas evidence in the context of resectable disease has been attempted in several phase III trials, definitive conclusions regarding the best approach to potentially resectable disease cannot be drawn. In addition, liver transplantation has gained evidence and is proposed in selected patients, raising a challenge regarding its integration and wider implementation. In this review, current standards in the management of CRLM regarding patient selection, resectability, surgical and non-surgical locoregional strategies, as well as the best systemic approach are covered.
]]>Authors: Laura Antolino Germana de Nucci Stefania Scarpino Giuseppe Bianco Gianluca Lopez Paolo Aurello Niccolò Petrucciani Roberto Santoro Giuseppe Nigri Salvatore Agnes Gianpiero Manes Francesco A. D’Angelo
Pancreatic cancer is expected to become the second leading cause of death by 2030 in Western countries. There is a need to pinpoint high-risk populations since extensive screening would be economically impractical. Methods: This study, conducted on liquid biopsies of patients affected by pancreatic ductal adenocarcinoma (PDAC), sequenced, by NGS, the main genes involved in pancreatic carcinogenesis. Results: The study was discontinued due to a low recruitment rate. NGS analysis, conducted on included patients, revealed the TP53 variant rs1042522 in 30 out of 35 patients, with a cytosine (C) replaced by a guanine (G), hence inserting an Arginine in the final protein instead of a Proline. The presence of the rs1042522 variant confers an odds ratio of 6.11 for PaC and an OR of 20 for homozygosity G/G when comparing our cohort of PaC patients to a healthy population from the 1000GenomeProject. Conclusion: These findings could identify a very-high-risk population deserving of being screened for PDAC, even though a wider validation of rs1042522 as a risk factor is needed. Impact: These preliminary data may open the way for identification of a population more prone to developing pancreatic cancer.
]]>Authors: Michael Enwere Edward Irobi Victoria Chime Ada Ezeogu Adamu Onu Mohamed Toufic El Hussein Gbadebo Ogungbade Emmanuel Davies Omowunmi Omoniwa Charles Omale Mercy Neufeld Ojochide Akagwu Terkaa Atim Laurens Holmes
Background: Despite advances in gene-targeted and immunotherapies, many aggressive cancers—including glioblastoma and triple-negative breast cancer—remain refractory to treatment. Mounting evidence implicates metabolic reprogramming, especially dysregulation of glucose and glutamine metabolism, as a core hallmark of tumor progression. Natural compounds with metabolic-modulatory effects have emerged as promising adjuncts in oncology. Research Question and Objectives: This review investigates the following question: How can metabolic-targeted therapies—particularly those modulating the Warburg effect and glutamine metabolism—improve cancer treatment outcomes, and what role do natural compounds play in this strategy? The objectives were to (1) evaluate the therapeutic potential of metabolic interventions targeting glucose and glutamine metabolism, (2) assess natural compounds with metabolic regulatory activity, (3) examine integration of metabolic-targeted therapies with conventional treatments, and (4) identify metabolic vulnerabilities in resistant malignancies. Methods: A qualitative systematic review (QualSR) was conducted following PRISMA guidelines. A total of 87 peer-reviewed studies published between 2000 and 2024 were included. Inclusion criteria required clearly defined mechanistic or clinical endpoints and, for clinical trials, sample sizes ≥ 30. Data extraction focused on tumor response, survival, metabolic modulation, and safety profiles. Results: Curcumin significantly reduced serum TNF-α and IL-6 (both p = 0.001) and improved antioxidant capacity (p = 0.001). EGCG downregulated ERα (p = 0.002) and upregulated tumor suppressors p53 and p21 (p = 0.001, p = 0.02). High-dose intravenous vitamin C combined with chemoradiotherapy yielded a 44.4% pathologic complete response rate in rectal cancer. Berberine suppressed Akt/mTOR signaling and glutamine transporter SLC1A5 across tumor types (q < 10−10). However, poor bioavailability (e.g., EGCG t½ = 3.4 ± 0.3 h) and systemic toxicity limit their standalone clinical application. Conclusions: Metabolic-targeted therapies—particularly natural compounds acting on glucose and glutamine pathways—offer a viable adjunct to standard cancer therapies. Clinical translation will require biomarker-driven patient stratification, improved delivery systems, and combination trials to optimize the therapeutic impact in treatment-resistant cancers.
]]>Authors: Ugo Testa Germana Castelli Elvira Pelosi
The development of molecular profiling approaches for AML patients such as whole genome sequencing, whole exome sequencing and transcriptomic sequencing have greatly contributed to better understanding of leukemia development, progression and treatment responsiveness/resistance. These studies have generated a new knowledge about driver events operating in AML that can be translated into clinics, thus favoring the mutations; using this approach, more than 50% of older AML patients display molecular alterations, such as IDH1, IDH2, FLT3 (FLT3-TKD and FLT3-ITD), NPM1 and KMT2A rearrangements that can be targeted by specific drugs. Preclinical and clinical studies have supported the use of drugs targeting these molecular alterations as first-line therapy in association with induction chemotherapy in chemotherapy-fit patients or with a hypomethylating agent in association with a Bcl-2 inhibitor (Venetoclax) in chemotherapy-unfit patients. These studies have shown promising results that need to be confirmed through randomized clinical studies specifically involving the enrollment of older AML patients.
]]>Authors: Tia Tafla Abinaya Balasubramanian Janaki K. Iyer
Cancer is a public health concern due to the incidence, prevalence, morbidity, and mortality associated with it. While chemotherapy, radiotherapy, surgery, and immunotherapy are common treatments, there is still ongoing research to find targeted and innovative therapies that are more efficacious. The effect of probiotics on cancer progression and treatment has been actively investigated using different in vitro and in vivo models. Similarly, the role of prebiotics alone or in combination with probiotics, referred to as synbiotics, has also been evaluated in the context of cancers. Recently, the therapeutical potential of postbiotics is also being determined. Many studies have demonstrated that these agents can have onco-suppressive effects and can also prevent cancer in some instances. In this review, we summarize the different studies that have utilized these therapeutics in the prevention and treatment of a variety of cancers. We also discuss the different molecular mechanisms that enable these agents to be effective against cancers. Finally, we address safety and the need for more robust clinical trials that will aid in designing strategies involving these biotics in the prevention and treatment of cancer.
]]>Authors: Junyan Wang Benjamin B. Gyau Jun Xu Angela M. Major John Hicks Tsz-Kwong Man
Background: Osteosarcoma (OS) is a fast-growing malignant bone tumor that occurs most often in children and teenagers. Development of pulmonary metastasis is the primary cause of treatment failure and mortality. Our previous studies demonstrated that cytoplasmic p27 interacts with PAK1, enhancing PAK1 phosphorylation and promoting OS pulmonary metastasis. However, the cellular functions of p27 and PAK1 are primarily regulated by phosphorylation, and the roles of specific phosphorylation residues in modulating OS metastatic potential remain unclear. Methods: To study tumor invasiveness and lung metastasis, we employed a CRISPR-based knock-in method to introduce specific mutations—p27-T157A, p27-T157D, PAK1-T423E, and PAK1-K299R—into the 143B OS cell line, followed by in vitro invasion and orthotopic xenograft mouse experiments. These residues were selected for their therapeutic potential, as T157 regulates p27 nuclear–cytoplasmic shuttling, while T423 and K299 modulate PAK1 kinase activity. Results: No significant differences in pulmonary metastasis were observed across p27 mutants compared to parental controls. However, the p27-T157D mutant exhibited increased cytoplasmic mislocalization, elevated PAK1-S144 phosphorylation, and enhanced in vitro invasiveness compared to the p27-T157A mutant and parental 143B cells. The PAK1-K299R mutant, designed to be kinase-dead, showed negligible S144 phosphorylation, consistent with loss of kinase activity. Unexpectedly, this mutant displayed increased T423 phosphorylation and in vitro invasiveness, and significantly enhanced pulmonary metastasis in vivo compared to the PAK1-T423E mutant and parental controls. Conclusions: These findings highlight the complexity of targeting specific p27 and PAK1 phosphorylation sites as an anti-metastatic strategy for OS. While p27-T157 phosphorylation influences cytoplasmic localization and invasiveness, it does not significantly alter metastatic outcomes. Conversely, PAK1-T423 phosphorylation is critical in driving OS metastatic potential, and the kinase-dead K299R mutant’s unexpected pro-metastatic effect suggests that kinase-independent mechanisms or compensatory pathways may contribute to metastasis. Our findings suggest the necessity for a more comprehensive understanding of the phosphorylation dynamics of p27 and PAK1 in metastatic OS. They also indicate that conventional kinase inhibition may be insufficient and underscore the potential benefits of alternative or combinatorial therapeutic strategies, such as targeting kinase-independent functions or other upstream kinases involved in these regulatory pathways.
]]>Authors: Alfonso Agüera-Sánchez Emilio Peña-Ros Irene Martínez-Martínez Francisco García-Molina
Adenoma-like adenocarcinoma (ALAC) of the colon is a recently recognized histological subtype of colorectal adenocarcinoma, characterized by a villous architecture, low-grade cytologic atypia, and deceptive bland morphology despite its invasive potential, which can mimic non-invasive adenomas, leading to underdiagnosis in limited biopsy samples. Herein, we report the case of an 81-year-old male presenting with right-upper-quadrant pain that was found to have a hepatic abscess and a 4 cm villous lesion in the ascending colon. Histopathological examination of the right hemicolectomy specimen revealed a villous adenocarcinoma with invasion of the muscularis propria, consistent with adenoma-like adenocarcinoma. Isolated loss of PMS2 indicated a mismatch repair deficiency. However, adjuvant therapy was not indicated. The patient remained recurrence-free for three years, until he died from unrelated causes in the context of progressive frailty and comorbidities, with no evidence of cancer progression. This case highlights the diagnostic challenges posed by ALAC and underscores the importance of recognizing its distinct morphological features. Awareness of this entity is essential to avoid misclassification and ensure adequate treatment, especially given its typically favorable prognosis with low metastatic potential.
]]>Authors: Adam Yusuf Paramahansa Pramanik
Prostate cancer exhibits highly variable behavior, from slow-growing localized tumors to aggressive metastatic disease, yet early prognostic indicators remain limited. In this study, we examined B7-H3 (CD276) expression, a molecule linked to immune suppression and cancer progression in diagnostic biopsy specimens from 248 patients with localized or metastatic prostate cancer. We found that elevated B7-H3 levels were significantly more common in metastatic cases and independently associated with reduced overall and disease-specific survival. Moreover, high B7-H3 expression correlated with increased PSA values and higher Gleason grades. These findings endorse B7-H3 as a robust prognostic marker and potential therapeutic target in advanced prostate cancer management.
]]>Authors: Sahar Mack Thibaud Koessler Philippe Bichard Jean-Louis Frossard
Pancreatic cancer (PC) is one of the most aggressive and lethal malignancies, mainly due to its late detection [...]
]]>Authors: Alessandro Posa Enza Genco Pierluigi Barbieri Mario Ariano Marcello Lippi Alessandro Maresca Roberto Iezzi
Prompt and accurate identification of liver metastases from neuroendocrine tumors, arising from the gastrointestinal system and from the pancreas, through the means of both anatomical and functional diagnostic imaging techniques is mandatory. A patient’s prognosis and treatment planning are dependent on these diagnostic procedures. The aim of this narrative review is to depict the common appearance of liver metastases, as well as to depict atypical imaging patterns. Moreover, this review will cover the differential diagnosis between liver metastases from neuroendocrine tumors and other primary and secondary malignant liver lesions, as well as benign liver lesions.
]]>Authors: Chen Yeh Hung-Chih Lai Nathan Grabbe Xavier Willett Shu-Ti Lin
Background: Many patients harbor minimal residual disease (MRD)—small clusters of residual tumor cells that survive therapy and evade conventional detection but drive recurrence. Although advances in molecular and computational methods have improved circulating tumor DNA (ctDNA)-based MRD detection, these approaches face challenges: ctDNA shedding fluctuates widely across tumor types, disease stages, and histological features. Additionally, low levels of driver mutations originating from healthy tissues can create background noise, complicating the accurate identification of bona fide tumor-specific signals. These limitations underscore the need for refined technologies to further enhance MRD detection beyond DNA sequences in solid malignancies. Methods: Profiling circulating cell-free mRNA (cfmRNA), which is hyperactive in tumor and non-tumor microenvironments, could address these limitations to inform postoperative surveillance and treatment strategies. This study reported the development of OncoMRD BREAST, a customized, gene signature-informed cfmRNA assay for residual disease monitoring in breast cancer. OncoMRD BREAST introduces several advanced technologies that distinguish it from the existing ctDNA-MRD tests. It builds on the patient-derived gene signature for capturing tumor activities while introducing significant upgrades to its liquid biopsy transcriptomic profiling, digital scoring systems, and tracking capabilities. Results: The OncoMRD BREAST test processes inputs from multiple cutting-edge biomarkers—tumor and non-tumor microenvironment—to provide enhanced awareness of tumor activities in real time. By fusing data from these diverse intra- and inter-cellular networks, OncoMRD BREAST significantly improves the sensitivity and reliability of MRD detection and prognosis analysis, even under challenging and complex conditions. In a proof-of-concept real-world pilot trial, OncoMRD BREAST’s rapid quantification of potential tumor activity helped reduce the risk of incorrect treatment strategies, while advanced predictive analytics contributed to the overall benefits and improved outcomes of patients. Conclusions: By tailoring the assay to individual tumor profiles, we aimed to enhance early identification of residual disease and optimize therapeutic decision-making. OncoMRD BREAST is the world’s first and only gene signature-powered test for monitoring residual disease in solid tumors.
]]>Authors: Maryem Rhanoui Khaoula Alaoui Belghiti Mounia Mikram
Background: Clinical imaging is an important part of health care providing physicians with great assistance in patients treatment. In fact, segmentation and grading of tumors can help doctors assess the severity of the cancer at an early stage and increase the chances of cure. Despite that Deep Learning for cancer diagnosis has achieved clinically acceptable accuracy, there still remains challenging tasks, especially in the context of insufficient labeled data and the subsequent need for expensive computational ressources. Objective: This paper presents a lightweight classification and segmentation deep learning model to assist in the identification of cancerous tumors with high accuracy despite the scarcity of medical data. Methods: We propose a multi-task architecture for classification and segmentation of cancerous tumors in the Brain, Skin, Prostate and lungs. The model is based on the UNet architecture with different pre-trained deep learning models (VGG 16 and MobileNetv2) as a backbone. The multi-task model is validated on relatively small datasets (slightly exceed 1200 images) that are diverse in terms of modalities (IRM, X-Ray, Dermoscopic and Digital Histopathology), number of classes, shapes, and sizes of cancer pathologies using the accuracy and dice coefficient as statistical metrics. Results: Experiments show that the multi-task approach improve the learning efficiency and the prediction accuracy for the segmentation and classification tasks, compared to training the individual models separately. The multi-task architecture reached a classification accuracy of 86%, 90%, 88%, and 87% respectively for Skin Lesion, Brain Tumor, Prostate Cancer and Pneumothorax. For the segmentation tasks we were able to achieve high precisions respectively 95%, 98% for the Skin Lesion and Brain Tumor segmentation and a 99% precise segmentation for both Prostate cancer and Pneumothorax. Proving that the multi-task solution is more efficient than single-task networks.
]]>Authors: Muqaddas Qureshi Muhammad Tanveer Alam Ahsanullah Unar
Gynecological malignancies (ovarian, endometrial, and cervical cancers), including disseminated intravascular coagulation (DIC), often provoke systemic coagulopathy. In recent years, tumor-derived, tissue factor–positive microparticles (TF+ MPs) have emerged as potent drivers of cancer-associated thrombosis and possibly DIC. These small (0.1–1 µm) membrane vesicles bud from cancer cell surfaces and carry procoagulant factors (phosphatidylserine and TF) on their surface. We review how TF+ MPs are generated by tumor cells and amplify the extrinsic coagulation cascade, potentially triggering DIC in patients with advanced gynecologic cancers. Clinical studies have linked el evated TF+ MP levels and activity to venous thromboembolism (VTE) in cancer, and small case series suggest dramatically high MP–TF activity in cancer-related DIC. We summarize evidence that TF+ MPs from ovarian tumors carry exceptionally high TF procoagulant activity (median ~80 pg/mL), and nearly all patients with cancer-associated VTE or DIC have MP–TF levels above normal. This review discusses diagnostic implications (e.g., measuring MP–TF activity as a biomarker) and treatment strategies (through the reduction in tumors, anticoagulation, and experimental TF inhibitors) in this setting. We also identify gaps in knowledge (standardized MP assays, prospective studies) and propose future directions (targeting MP formation or TF signaling). Two summary tables highlight recent studies of TF+ MPs in gynecologic cancer and their clinical outcomes. Illustrative figures depict the TF+ MP-triggered coagulation cascade and a conceptual framework for clinical management. Understanding TF+ MPs in gynecological cancer could improve the prediction and management of DIC and related thromboses.
]]>Authors: Sergio Da Silva
Conventional wisdom holds that nuclear oncogenes and tumor suppressors initiate malignant transformation. However, mounting research suggests that mitochondrial dysfunction—rooted in the unique evolutionary history and genetic autonomy of mitochondria—may serve as a more fundamental driver of oncogenesis. This paper proposes a “mitochondria-first” hypothesis of cancer, emphasizing the pivotal role of mitochondrial DNA (mtDNA) mutations, metabolic reprogramming, and immune evasion. By examining the evolutionary conflict between host and mitochondria, evaluating high mtDNA mutation rates, and highlighting the disruptive potential of mitochondrial transfer to immune cells, we outline robust mechanisms through which mitochondria could ignite cancer development. We also discuss emerging diagnostic and therapeutic approaches that target mitochondrial integrity, offering a potential paradigm shift in oncology.
]]>Authors: Karim Khaled Hala Jardaly Orouba Almilaji
Background: Prostate cancer is a leading malignancy among men globally, with its incidence expected to rise due to aging populations and shifting lifestyles. While established risk factors include age, ethnicity, and genetics, the role of modifiable dietary factors, particularly sugar intake, remains less clear. Emerging evidence suggests that high sugar consumption may promote carcinogenesis through insulin resistance, chronic inflammation, and hormonal dysregulation. This systematic review aimed to evaluate the current evidence on the association between dietary sugar intake and prostate cancer risk. Methods: A systematic search was conducted across six databases for observational studies published between January 2005 and April 2025. Eligible studies assessed the associations between quantitative sugar intake and prostate cancer outcomes. Screening, data extraction, and a risk of bias assessment (using ROBINS-E) were performed independently by multiple reviewers. Results: Six studies met the inclusion criteria, comprising four prospective cohorts, one case–control study, and one cross-sectional study, with a combined sample of 11,583 men from the USA, Canada, Sweden, and France. Three studies reported a significant positive association between a high intake of dietary sugars and prostate cancer risk, two found no association, and one showed mixed findings depending on the type of sugar. Heterogeneity in the exposure assessments and confounder control limited the comparability. Conclusions: This review suggests a possible association between high dietary sugar intake and increased prostate cancer risk, especially from added sugars and sugar-sweetened beverages. However, inconsistent findings and methodological limitations highlight the need for robust, prospective studies with standardized assessments to understand this relationship better.
]]>Authors: Gabriel Boudagh Ahmad Alnasart Kenan Abou Chaer Paul Naylor Milton Mutchnick
Background: Hepatocellular carcinoma (HCC) remains a significant global health burden, particularly among vulnerable populations. This retrospective study investigates trends in HCC incidence and age at diagnosis within an urban medical center population, focusing on the impact of hepatitis C virus (HCV) treatment and racial disparities. Methods: The study includes 484 patients diagnosed with HCC between 2000 and 2023. Results: A significant decline in HCC incidence was observed with a peak in incidences between 2015 and 2017 (p < 0.02). The increase and subsequent decline were driven by a decline in HCV-related cases, particularly among the African American (AA) population. This trend was not seen for patients with other risk factors for HCC. An increase in age at diagnosis in HCV patients but not other risk patients was observed in AA (62 vs. 69 years p = 0.001) but not non-AA patients (66 vs. 67 p = 0.16). This increase in age for AA HCV patients could be due to an aging population, changing risk factor profiles, and/or limitations in surveillance and early detection of HCC. Conclusions: This study highlights the critical role of HCV treatment in reducing HCC incidence, particularly within the AA population. These findings emphasize the need for sustained efforts in surveillance, early detection, and targeted prevention strategies to address the evolving epidemiology of HCC and improve outcomes across all populations.
]]>Authors: Philippe Westerlinck
Introduction: This article provides a comprehensive analysis of predictive models for individual cancer risk, examining their development, application, and evaluation. The study covers various cancer types, highlighting the diversity and sophistication of models over time. Methods: Utilizing data from PubMed, Web of Science, and Scopus, the research includes models developed for 22 cancer types, with significant emphasis on breast and colorectal cancers due to their prevalence and early detection benefits. Results: The analysis reveals an uneven distribution of models, often concentrated in the United States and the United Kingdom, with a notable gap in models for rarer cancers. Key methodologies such as logistic regression and Cox proportional hazards models dominate the field, reflecting a preference for established statistical techniques. The study underscores the importance of incorporating multiple risk factors, including genetic, environmental, lifestyle, and clinical data, to enhance predictive accuracy. Despite advancements, the article identifies a critical need for external validation and standardization in reporting practices to improve model reliability and generalizability. Conclusions The findings emphasize the potential of these models in personalized cancer prevention and early detection, while also calling for continued research and methodological harmonization to address existing gaps and challenges.
]]>Authors: Nadja Grübel Anika Wickert Felix Sahm Bernd Schmitz Anja Osterloh Rebecca Kassubek Ralph König Christian Rainer Wirtz Jens Engelke Andrej Pala Mona Laible
Gliomas are incurable, heterogeneous brain tumors, with rare forms often constituting diagnostic and treatment challenges. Molecular diagnostics, mainly implemented through the World Health Organization (WHO) 2021 guidelines, have refined the classification, but highlight difficulties in diagnosing rare gliomas remain. This case series analyzes four patients with rare gliomas treated at the University Hospital, Ulm, between 2002 and 2024. Patients were selected based on unique histopathological features and long-term clinical follow-up. Clinical records, imaging, and histological data were reviewed. Molecular diagnostics followed WHO 2021 guidelines. Quality of life was assessed using standardized tools including the EQ-5D-5L, EQ VAS, the Distress Thermometer, and the Montreal Cognitive Assessment (MoCA). In the first case, a 51-year-old male’s diagnosis evolved from pleomorphic xanthoastrocytoma to a high-grade glioma with pleomorphic and pseudopapillary features, later identified as a neuroepithelial tumor with a PATZ1 fusion over 12 years. Despite multiple recurrences, extensive surgical interventions led to excellent outcomes. The second case involved a young female with long-term survival of astroblastoma, demonstrating significant improvements in both longevity and quality of life through personalized care. The third case involved a patient with oligodendroglioma, later transforming into glioblastoma, emphasizing the importance of continuous diagnostic reevaluation and adaptive treatment strategies, contributing to prolonged survival and quality of life improvements. Remarkably, the patient has achieved over 20 years of survival, including 10 years of being both therapy- and progression-free. The fourth case presents a young woman with neurofibromatosis type 1, initially misdiagnosed with glioblastoma based on histopathological findings. Subsequent molecular diagnostics revealed a subependymal giant cell astrocytoma-like astrocytoma, highlighting the critical role of early advanced diagnostic techniques. These cases underscore the importance of precise molecular diagnostics, individualized treatments, and ongoing diagnostic reevaluation to optimize outcomes. They also address the psychological impact of evolving diagnoses, stressing the need for comprehensive patient support. Even in complex cases, extensive surgical interventions can yield favorable results, reinforcing the value of adaptive, multidisciplinary strategies based on evolving tumor characteristics.
]]>Authors: Sandhya Shukla Arvind Shukla Adarsha Upadhyay Navin Ray Fowzul Fahad Arulkumar Nagappan Sayan Dutta Raj Mongre
Breast cancer is one of the most common and difficult-to-treat cancers affecting women globally. Long-term treatment success is still limited by problems like drug resistance, toxicity, and recurrence, even with advancements in conventional therapies. The application of substances derived from plants for medical purposes, or phytotherapy, has become a viable adjunctive approach to the treatment of breast cancer. An integrative approach to phytotherapy is examined in this review, focusing on how it can alter important molecular pathways implicated in the development, progression, and metastasis of breast cancer. By focusing on important signaling cascades like TGF-β, Wnt, Hedgehog, Notch, IL-6, Integrins, VEGF, HER2, EGFR, PI3K/Akt, and MAPK, and estrogen receptor pathways, a variety of phytochemicals, such as flavonoids, alkaloids, terpenoids, and polyphenols, demonstrate strong anticancer effects. This review also discusses how they affect immune modulation, angiogenesis, cell cycle regulation, and apoptosis. Moreover, it also emphasizes the challenges with these natural compounds’ bioavailability, standardization, and clinical translation while highlighting preclinical and clinical research that supports their therapeutic potential. This review attempts to give a thorough grasp of how plant-based compounds can support efficient and focused breast cancer treatments by fusing molecular insights with phytotherapeutic approaches.
]]>Authors: Giammaria Fiorentini Donatella Sarti Andrea Mambrini Gianmaria Mattioli Massimo Bonucci Laura Ginocchi Giuseppe Cristina Girolamo Ranieri Salvatore Bonanno Carlo Milandri Roberto Nani Patrizia Dentico Grazia Lazzari Antonella Ciabattoni Caterina Fiorentini
The applicability of RHT in the treatment and supportive care of tumors has been discussed for years in many publications. There are hundreds of articles that have reported on the good acceptance and feasibility of HT, as well as its value in terms of controlling malignant diseases, enhancing response and, in some randomized controlled trials (RCTs), clear improvements in OS. Despite this, HT has never fully been accepted as a standard treatment among radiation and medical oncologists. The increased activity that HT offers in the context of chemotherapy (CHT), radiotherapy (RT), chemoradiotherapy (CRT), and immunotherapy, thus facilitating programmed cell death (PCD), has been documented in many studies. This aspect has been demonstrated in many tumors, including soft tissue sarcoma, cancers of the cervix, esophagus, stomach, colon/rectum, pancreas, breast, head and neck, and prostate, and bone metastases. HT improves cancer cell death through many modalities, targeting both the tumor microenvironment (TME) and the cancer cells directly. Targeted HT increases the temperature of the primary tumor and surrounding tissues to 39–43 °C, causing the tumor cells to become more immune-responsive. HT can also activate the immune response of the TME through inducing heat shock proteins (HSPs), which also promote an immunological response and PCD. HT can oxygenate hypoxic tumors, facilitating RT-induced DNA damage in cancer cells. At present, it seems that the combination of HT and RT, CHT, and immunotherapy might lead to immune enhancement effects in the TME, making cancer cells more responsive to immunotherapies. This narrative review presents the novel aspects of HT reported in recent years.
]]>Authors: Jozsef Dudas Rudolf Glueckert Maria do Carmo Greier Benedikt Gabriel Hofauer
Tumor cells and the tumor microenvironment (TME) produce factors, including neurotrophins, that induce axonogenesis and neurogenesis, and increase local nerve density. Proliferative growing cancer cell clusters and disseminated invasive tumor cells undergoing partial epithelial-to-mesenchymal transition (pEMT) can invade peripheral nerves. In the early stages of tumor–nerve interactions, Schwann cells (SCs) dedifferentiate, become activated and migrate to cancer cell nests; later, they induce pEMT in tumor cells and activate tumor cell migration along nerves. The SC–tumor–nerve interaction attracts myeloid-derived suppressor cells (MDSCs) and inflammatory monocytes, and the latter differentiate into macrophages. SCs and MDSCs are responsible for the activation of transforming growth factor-beta (TGF-beta) signaling. Intra-tumoral innervation is followed by perineural invasion (PNI), which has an unfavorable prognosis. What are the interventional options against PNI: local reduction in tumor nerves or inhibition of TGF-beta-related events, inhibition of downstream signaling of TGF-beta or immune activation, or intervention against immunosuppression? This systematic review is based on the Prisma 2009 search method and provides an overview of tumor–nerve interaction.
]]>Authors: Sandhya Shukla Arvind Shukla Navin Ray Adarsha Upadhyay Fowzul Fahad Sayan Dutta Arulkumar Nagappan Raj Mongre
Globally, women’s cancer-related morbidity and death are still caused mainly by gynecologic cancer. Antioxidant and anti-inflammatory drugs have shown promise in treating gynecologic cancer because of the complex interactions among oxidative stress, inflammation, and the development of tumors. This review focuses on how these drugs, which include polyphenols, terpenoids, and thiols-related phytochemical-derived compounds target different pathways associated with developing and progressing gynecologic cancer. We investigate what factors affect the tumor microenvironment, specifically how they affect immunological response and vasculogenesis. Through the review of recent studies, we have gained an extensive understanding of the molecular pathways that anti-inflammatory and antioxidant drugs use to achieve their therapeutic benefits. Gynecologic cancer is still a potent cause of cancer-related deaths and fatalities for women globally. Antioxidant and anti-inflammatory drugs have shown promise in treating gynecologic cancer because of the complex interactions among oxidative stress, inflammation, and the development of tumors. This review focuses on how these drugs target different pathways associated with developing and progressing gynecologic cancer. We investigate what factors affect the tumor microenvironment, specifically how they affect immunological response and vasculogenesis. Through the review of recent studies, we have gained an extensive understanding of the molecular pathways that anti-inflammatory and antioxidant drugs use to achieve their therapeutic benefits.
]]>Authors: Frederick H. Silver Tanmay Deshmukh Gayathri Kollipara Aanal Patel
Approximately 5.4 million nonmelanoma skin cancers are treated each year in the US. Of this number 80 to 90% are basal cell carcinomas. In this study, we compare optical coherence tomography (OCT) images and vibrational optical coherence tomography (VOCT) measurements made on small and large nodular basal cell carcinomas (BCCs) using histopathology, OCT images, and VOCT physical measurements. OCT images were broken into green, blue, and red subchannel images and compared to histopathology conducted on the excised tissue. While our results suggest that both small and large BCCs have similar morphologies that include circular nodules with palisading cells surrounding the lesions, no part of the excised lesions appeared like normal skin. In the small lesion, the nodule is surrounded by tissue that may be considered to have “clear” margins even though the rete ridges are missing, and the ECM does not resemble normal skin. The edges of the lesion are free of palisading cells with only some inflammatory cells being present. In contrast, the mechanovibrational spectrum of the large lesion appeared to have an increased amount of large fibrotic peaks with decreased vibrations for normal cells and cancer-associated fibroblasts compared to the smaller nodule. These results indicate that it is possible to identify the location of the BCC nodules noninvasively using VOCT. The ability to noninvasively identify nodular BCCs using this technique makes it a useful adjunct to visual inspection and dermoscopy to identify cancerous lesions seen in the clinic. Since VOCT can be operated remotely, it can serve as a noninvasive screening tool to be used by general practitioners in areas where dermatologists are in short supply.
]]>Authors: Juan Luis Alcázar Francisco Vargas Guillem Boscá Blanca Salazar Juan Carlos Aguilar Cynthia Catalan Arleana Balazs Daniela Burky Magdalena Pertkiewicz José Carlos Vilches Rodrigo Orozco
Background: Our goal was to assess the diagnostic performance of the IOTA 3-step strategy for discriminating benign from malignant adnexal masses. Methods: Systematic review and meta-analysis design. A systematic search across three databases (Medline [PubMed], SCOPUS, and Web of Science) was conducted to identify primary studies reporting on the use of the IOTA three-step strategy from January 2012 to July 2024. Prospective cohort studies utilizing the three-step strategy, with histologic diagnosis or conservative management confirming spontaneous resolution or persistence in cases of benign-appearing masses for at least one year of follow-up, were used as the reference standard. Studies unrelated to the topic, those not addressing the IOTA three-step strategy, studies focusing on other prediction models, letters to the editor, commentaries, narrative reviews, consensus documents, and studies lacking data for constructing a 2 × 2 table were excluded. Quantitative synthesis was done, calculating the pooled sensitivity, specificity, and positive and negative likelihood ratios. Qualitative synthesis was done using QUADAS-2. Results: A total of 448 citations were initially identified, with 7 studies meeting inclusion criteria, comprising 5722 patients. The mean prevalence of ovarian malignancy was 28%. The quality of the studies was considered good. IOTA 3-step strategy showed a pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of the three-step strategy for adnexal mass classification were 94% (95% CI = 91–95%), 94% (95% CI = 91–97%), 17.0 (95% CI = 10–28.8), and 0.07 (95% CI = 0.05–0.1), respectively. Heterogeneity for sensitivity was moderate, and for specificity it was high. Conclusions: We conclude that the three-step strategy has good diagnostic performance, reducing the need for expert examiner evaluation.
]]>Authors: Polyxeni Spiliopoulou Pantelis Rousakis Chrysanthi Panteli Evangelos Eleutherakis-Papaiakovou Magdalini Migkou Nikolaos Kanellias Ioannis Ntanasis-Stathopoulos Panagiotis Malandrakis Foteini Theodorakakou Despina Fotiou Evangelos Terpos Vassilios Myrianthopoulos Maria Gavriatopoulou Ourania E. Tsitsilonis Efstathios Kastritis Meletios Athanasios Dimopoulos Gerasimos Terzis
Background/Objectives: Multiple myeloma is a malignancy of plasma cells detected in the bone marrow, inducing symptoms like anemia, hypercalcemia, renal problems, and bone fractures in multiple myeloma patients, affecting their quality of life. The bone marrow microenvironment plays a crucial role in the prognosis and progression of the disease. The purpose of this study was to examine the relationship between the percentages of the major cell populations of the bone marrow, including immune cells, and physical function/quality of life in multiple myeloma patients after first-line treatment. Methods: Twenty-one multiple myeloma patients (N = 14 men, N = 7 women) participated in the study after completing first-line treatment. Bone marrow and blood samples were taken one hundred days after transplantation, while physical function (6 min walking test, handgrip test, maximal aerobic power, and isometric strength), health-related quality of life (QLQ-C30), and body composition (DXA) were assessed 2–5 days later. Flow cytometry was used to assess the percentages of plasma cells, mast cells, B cells (total, precursors, naïve, and memory), T cells (total, CD27− and CD27+), NK/NKT cells (total, CD27− and CD27+), eosinophils, monocytes, neutrophils, myeloid progenitors, erythroblasts, and erythroid progenitors, expressed as percentages of total nucleated cells of the bone marrow. Results: The percentage of CD27+ NK/NKT cells was correlated with five parameters of the quality of life questionnaire: physical function (r = 0.78, p = 0.005), role functioning (r = 0.69, p = 0.020), fatigue (r = −0.86, p = 0.000), pain (r = 0.68, p = 0.021), and dyspnea (r = −0.80, p = 0.003). Conclusions: In conclusion, stronger immune surveillance in the bone marrow from CD27+ NK/NKT cells is correlated with better quality of life in multiple myeloma patients.
]]>Authors: Joanne Moffatt Jo Morrison Srividya Sundararajan Rebecca Newhouse Laura Atherton Jonathan Frost Philip Rolland Kirsty Milford Katharine Edey Jane Borley Amy Sanders Axel Walther Claire Newton
Background: Adult granulosa cell tumours (AGCT) of the ovary account for 2–5% of ovarian tumours, with 30% occurring in women of childbearing age. Despite a good prognosis, up to 25% recur. There is a paucity of high-quality evidence to guide management. Objective: To describe management of AGCT across multiple gynaecological cancer centres. Methods: Retrospective analysis of electronic patient records from six gynaecological cancer centres in Southwest England between 2000 and 2021 (n = 119). Results: We included 107 patients with a median follow-up of 60 months (0–261 months). Most (97/107; 90.7%) were diagnosed with stage I disease (31.8% stage Ic). Primary management was staging surgery in 33/107 (30.8%), hysterectomy and bilateral salpingo-oophorectomy (BSO) (28/107; 26.2%), or conservation of an ovary (17/107; 15.9%). Three had a subsequent pregnancy. A quarter (27/107; 25.2%) were diagnosed with recurrent disease. Fifteen patients (15/107; 14%) had multiple recurrences. Recurrence was more likely if cyst rupture was reported at surgery (38.7%) compared with no rupture (14.3%; p < 0.001). The recurrence rate was higher with ovarian conservation (6/17; 35.3%) compared with BSO (21/90; 23.3%; p < 0.01), and all recurrences involved the residual ovary. Of the 11 deaths, 6 (54.5%) were attributed to progressive disease. Conclusions: Although survival with early-stage disease is good, ovarian cystectomy or unilateral ovarian conservation was associated with increased risk of recurrence. There is no conclusive evidence to support a contralateral oophorectomy in pre-menopausal women, but completion surgery should at least be considered, either immediately or after childbearing/assisted reproductive treatment.
]]>Authors: Eithar Mohamed Sara Goodman Leah Cooksey Daniel M. Fletcher Olivia Dean Viktoriya B. Boncheva Ken I. Mills Kim H. Orchard Barbara-ann Guinn
Background: Adult B-cell acute lymphoblastic leukaemia (aB-ALL) is characterised by abnormal differentiation and proliferation of lymphoid progenitors. Despite a significant improvement in relapse-free and overall survival for children with B-ALL, aB-ALL has a particularly poor prognosis with a 5-year survival rate of 20%. First remission is achieved for most patients, but relapse is common with a high associated mortality. New treatments such as immunotherapy offer an opportunity to extend remission and prevent relapse. Methods: aB-ALL antigens were identified using different sources—immunoscreening, protoarrays, two microarrays and one cancer-testis antigen database, and a review of the genomic analyses of aB-ALL. A total of 385 aB-ALL-associated gene products were examined for their association with patient survival. Results: We identified 87 transcripts with differential expression between aB-ALL and healthy volunteers (peripheral blood, bone marrow and purified CD19+ cells), and 42 that were associated with survival. Enrichr analysis showed that the Transforming Growth Factor-β (TGFβ), Wnt and Hippo pathways were highly represented (p < 0.02). We found that SOX4 and ROCK1 were upregulated in all types of B-ALL (ROCK1 having a p < 0.001 except in t(8;14) patients), as well as SMAD3 and TEAD4 upregulation being associated with survival (p = 0.0008, 0.05 and 0.001, respectively). Expression of each aB-ALL antigen was verified by qPCR, but only TEAD4 showed significant transcript upregulation in aB-ALL compared to healthy volunteer CD19+ cells (p = 0.01). Conclusions: We have identified a number of antigens and their pathways that play key roles in aB-ALL and may act as useful targets for future immunotherapy strategies.
]]>Authors: Franklin Eduardo Corea-Dilbert Muhammad Zubair Afzal
Breast cancer is a complex disease that is one of the leading causes of cancer-related mortality in women worldwide. Of the subtypes of breast cancer, the most aggressive subtype is triple negative breast cancer (TNBC) due to its lack of targets that could be leveraged for treatment in other subtypes. Current treatment options for both local and metastatic TNBC include radiation therapy, chemotherapy, surgery, targeted therapy, and immunotherapy, which has been gaining popularity in recent years. The role of targeted therapy in TNBC is somewhat limited due to the paucity of therapeutic personalized targets, and, due to the heterogeneity of the disease, the effectiveness of these different modalities varies from patient to patient. These unique elements are the foundation of personalized medicine where genomics and transcriptomics play a critical role in increasing granularity in patients’ disease and treatment. The purpose of these molecular tools is to identify biomarkers that could be used to further characterize each patient’s unique disease features and to predict how certain treatment modalities will affect patient survival and prognosis. The interplay between these biomarkers and molecular pathways involved in treatment response with disease progression and aggressiveness is a complex phenomenon. In this review, we describe the current state of the literature in regard to biomarkers that show promise in the clinical setting to predict response to treatments such as chemotherapy, radiation, and surgery in locally advanced and metastatic TNBC.
]]>Authors: Paola Avena Lucia Zavaglia Ivan Casaburi Vincenzo Pezzi
Organoid culture is an emerging and promising 3D culture system by which three-dimensional cell aggregates have been produced from different organs and tissues. This new innovative culture technology preserves parental gene expression, as well as the biological features of parental cells in vitro and ensures maintenance of three-dimensional cell culture for prolonged periods, opening new encouraged scientific scenarios and making them a functioning and valid system for testing new drugs for tissue engineering studies and precision oncology medicine. Various research focused on organoids has been performed in perfusion bioreactors, an advanced device able to mimic the tumor environment, providing a physiological growth state and a long-term culture viability. Perfusion bioreactors have been used for the maintenance and growth of organoids as well as for tumor patient samples improving proliferation while supporting the development of extracellular matrix (ECM). The ability to mimic the tumor environment and to maintain patient-derived biopsies for a long time makes perfusion bioreactors an essential model for preclinical testing.
]]>Authors: Kala Hickey Stephanie Gill Zoë Breen Kaitlyn Harding Hannah Yaremko Alex Mathieson Patti Power David Pace Joannie Neveu
Peritoneal carcinomatosis is a common presentation found in advanced-stage gastrointestinal (GI) and gynecological cancers. Combined cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is associated with significant survival benefits for select patients. CRS/HIPEC is not currently provided in Newfoundland and Labrador (NL). The Canadian HIPEC Collaborative Group recommends that centres complete a minimum of one case monthly to maintain competency and achieve good outcomes. Thus, we aimed to demonstrate that the annual patient volume in NL justifies the feasibility of implementing a combined surgical and gynecological oncology CRS/HIPEC program. Methods: A retrospective chart review of the NL Cancer Care Registry identified patients with stage IV colorectal, appendiceal, or gastric cancer and stage III to IV epithelial ovarian cancer over a 1-year period (1 January 2020–31 December 2020) to identify the number of patients meeting the criteria for CRS/HIPEC and/or those referred out of province to receive the treatment. The results are presented as proportions and percentages. Results: Thirty-one patients were eligible to receive CRS/HIPEC during the study period (11 GI, 20 gynecological). Of the GI patients, 63% were referred out of province for the procedure. Gynecological patients underwent CRS and systemic therapy +/− outpatient intraperitoneal chemotherapy in NL. Conclusions: Allowing patients to receive this standard of care treatment near home reduces financial, social, and emotional stressors. Our results confirm a sufficient patient volume to support a combined CRS/HIPEC program in NL. The implementation of this program will require multidisciplinary collaboration, specialized training, equipment, and protocol development.
]]>Authors: Kathryn E. Royse Tina M. Smith Cissy M. Tan Eric Y. Lin Robert G. Neumann Jessica E. Harris Elizabeth W. Paxton Winnie M. Tong
Background: Few studies have compared the risk of reoperation by timing in breast reconstruction surgery after mastectomy. We evaluated the first and total number of reoperations by reconstruction timing in women with breast cancer undergoing primary mastectomy. Methods: A cohort study of 23,301 primary mastectomies in women with breast cancer undergoing either immediate breast reconstruction (IBR) or delayed reconstruction was carried out within Kaiser Permanente between 2010 and 2022. The first reoperation rate was calculated using cause-specific Cox Proportional Hazards Models, while Multiplicative Cox Proportional Hazards Models were used to account for mortality and timing in reoperation. Patients were continuously monitored for death, outcome of interest, loss to follow-up through healthcare membership termination, or study end date (31 December 2022). Results: In total, 78.4% (n = 18,276) of the cohort underwent IBR. The average follow-up time was 5.9 years (±3.8). The following covariates were imbalanced (standardized mean difference [SMD] ≥ 0.20) between IBR and delayed groups: BMI, smoking status, year of mastectomy, bilateral procedures, and reconstruction type. The crude incidence of first reoperation was 33.04% vs. 31.72% in IBR vs. delayed patients and the risk of reoperation was 18% higher in IBR patients (HR = 1.18, 95% CI = 1.12–1.25). There was no difference in the risk of reoperation by timing (p > 0.05) when assessing multiple reoperations. The reoperation risk was the highest for IBR patients who did not complete reconstruction or single-stage reconstruction. In addition, the first reoperation rate of IBR patients was higher in those who underwent expander–implant-based reconstruction. Conclusions: The first reoperation rate was higher in IBR patients compared to those who delayed reconstruction, although we failed to detect a difference for multiple returns to surgery, except in certain subgroups. Assessing reoperation risk by timing among different reconstruction modalities can aid patients in making informed decisions about the type of breast reconstruction to undergo.
]]>Authors: Elbek Fozilov Anthony Weng Snigdha Kanadibhotla Nina D. Kosciuszek Zhaosheng Jin Sherif R. Abdel-Misih
This paper reviews the surgical management of peritoneal carcinomatosis as new surgical methods have been developed within the past few decades. Traditional methods included cytoreductive surgery with hyperthermic intraperitoneal chemotherapy; however, a new method has been developed, Pressurized Intraperitoneal Aerosol Chemotherapy. This method is minimally invasive while allowing for promising outcomes in those who have exhausted therapy options or require palliative therapy. The goal of this paper is to compare and contrast the traditional and standard method with the newer method for intraoperative delivery of chemotherapy.
]]>Authors: Vadanasundari Vedarethinam
Bladder cancer, a highly heterogeneous disease, necessitates precise diagnostic and therapeutic strategies to enhance patient outcomes. Metabolomics, through comprehensive small-molecule analysis, provides valuable insights into cancer-associated metabolic alterations at the cellular, tissue, and systemic levels. Concurrently, molecular imaging modalities like PET, MRI, and CT enable the non-invasive, real-time visualization of tumor biology, facilitating the spatial and functional assessment of biomarkers. Key findings highlight the identification of metabolomic profiles correlated with cancer progression, recurrence, and treatment responses across serum, urine, and tissue samples. Advanced analytical platforms, such as LC-MS and NMR, uncover distinct metabolic signatures and pathway alterations in glycolysis, amino acid metabolism, and lipid biosynthesis. Molecular imaging further enhances staging accuracy and treatment monitoring by visualizing metabolic activity and receptor expression. The integration of these technologies addresses the limitations of invasive diagnostic methods and paves the way for precision oncology. Future advancements should focus on multi-omics integration, AI-driven analysis, and large-scale clinical validation to ensure broad accessibility and transformative impacts on bladder cancer management.
]]>Authors: Diogo Nóbrega Catelas Lucinda Correia Alexandra Santos Catarina Pereira Diogo Rodrigues Afonso Faria Guilherme Madeira Pedro Cardoso Vânia Oliveira
Background: Multimodal treatment of bone sarcomas has improved survival and allowed limb salvage surgery in the majority of these patients. Periprosthetic joint infection (PJI) constitutes a challenging complication. Controversy remains regarding the risk factors for PJI. Here, we aim to identify them. We also discuss pathogens and treatments. Methods: The authors reviewed the institutional database to retrieve endoprostheses implanted after bone sarcoma resection from 2014 to 2021. In total, 66 eligible patients were identified. Results: A total of 14 (21.21%) periprosthetic infections were diagnosed. Of these, 10 occurred in men (71.43%, p = 0.143). Mean BMI, age at the time of surgery, and ASA score were significantly higher among patients who developed PJI (p = 0.003, 0.044, and 0.033, respectively). Site was an important factor as well (p = 0.029). The number of comorbidities and the Charlson Comorbidity Index were also higher among these patients (p = 0.264, 0.060, respectively). Histology did not play a role in PJI (p = 0.385). Conclusions: Our data allow surgeons to better understand and control risk factors for PJI. We identified BMI, age, ASA score, site, and the Charlson Comorbidity Index as the main risk factors. Polymicrobial infections and methicillin-resistant Staphylococcus aureus are associated with recurrent infections. A multicentric study with a larger cohort is needed.
]]>Authors: Constantin N. Baxevanis Ourania E. Tsitsilonis Maria Goulielmaki Nikolaos Tsakirakis Angelos D. Gritzapis
Cancer vaccines offer an exciting option for active immunotherapy, providing a potentially safe and effective treatment that also prevents or minimizes toxic side effects in vaccinated patients. Clinical results from previous phase III clinical trials have suggested that the efficacy of cancer vaccines largely depends on their potential to trigger robust immunological responses. A preexisting immune response to cancer-specific peptides is crucial for achieving a meaningful clinical outcome during vaccinations. However, various factors may hinder the effectiveness of therapeutic vaccines. By overcoming these challenges, cancer vaccines have the potential to become a cornerstone in immunotherapy. This review aims to share our insights on the major challenges that are encountered when optimizing the potential of cancer vaccines, particularly focusing on important aspects regulating their clinical efficacy, such as vaccine composition, the adjuvant to be used and the HLA-restricting element for the tumor peptides targeted by a particular vaccine. Additionally, we discuss several obstacles which hindered the successful clinical development of therapeutic cancer vaccines, such as the standard of care, the clinical design, and the choice of the antigen(s) to be included in vaccine formulation. The identification of patients that are most likely to respond to vaccinations by developing immunological responses and the desirable clinical efficacy are also crucial, and, therefore, predictive biomarkers are strictly required. Finally, we present our views on future prospects that may lead to an enhancement of the anticancer effects of vaccines, ensuring their pivotal role in cancer immunotherapy.
]]>Authors: Dario Leotta Andrea Duminuco Marina Silvia Parisi Laura Caruso Uros Markovic Ermelinda Longo Francesco Di Raimondo Giuseppe Alberto Palumbo Annalisa Chiarenza
Chronic lymphocytic leukemia (CLL) represents the most frequent leukemia in the Western world, with an incidence of 4 [...]
]]>Authors: Carmelo Laface Eleonora Lauricella Girolamo Ranieri Francesca Ambrogio Felicia Maria Maselli Elena Parlagreco Giulia Bernardi Elena Fea Gianmauro Numico
During the last decade, a new therapeutic revolution has involved the management of hepatocellular carcinoma (HCC). This is made possible thanks to the documented efficacy of immunotherapy for this disease. In addition, new evidence has demonstrated the role of the gut–liver axis and gut microbiota in host homeostasis, tumor development, and response to therapies. In particular, intestinal dysbiosis can alter the tumor microenvironment, leading to the activation of intracellular signaling pathways that promote carcinogenesis. The composition of gut microbiota proved to influence the immune checkpoint inhibitors (ICIs) efficacy and drug toxicities. Therefore, this review aims to deepen knowledge about the immunomodulatory role of gut microbiota and its possible employment as diagnostic and predictive biomarkers in diagnosis and response to HCC immunotherapy, respectively. The research was conducted through the analysis of Pubmed and Web of Science (WoS) databases for literature studies on the relationship between gut microbiota and HCC from 2015 to 2025.
]]>Authors: Guillaume Mestrallet
Background/Objectives: The accurate prediction of overall survival (OS) in cancer patients is crucial for personalized treatment strategies. Methods: In this study, we developed machine learning models to predict OS by integrating clinical and mutational features from a cohort of 25,508 cancer patients. Key features included tumor mutational burden (TMB), microsatellite instability (MSI), fraction of genome altered (FGA), copy number alterations (CNA), age, sex, race, cancer type, and metastasis status. Results: We applied multiple Random Forest, Gradient Boosting, and Ensemble models, achieving an accuracy of 74% for overall survival status, and a C-Index of 0.76 using the Random Survival Forest model. Importantly, FGA, age, MSI score, TMB, cancer type, and metastasis status were identified as major predictors of OS across all models. We also integrated treatment data from 16,603 patients, demonstrating that therapies like platinum, carboplatin, and taxanes are associated with differences in survival predictions, with some therapeutic regimens showing minimal impact. Conclusions: Our findings highlight the potential of using machine learning to predict OS by incorporating both clinical and mutational features. These models offer a promising approach for improving patient outcomes and could be further validated in prospective studies for clinical use.
]]>Authors: Yi-Ling Chen Nicholas Pascuzzi Alejandro Ruiz Kuan-Hui Ethan Chen
Mirtrons represent a new subclass of microRNAs (miRNAs) that are processed through non-canonical biogenesis pathways. Unlike canonical miRNAs, which require Drosha-mediated cleavage, mirtrons are generated via the splicing of short intronic sequences, bypassing Drosha entirely. While mirtrons are found across a variety of organisms, their conservation between species is relatively low. This evolutionary divergence has resulted in mirtrons acquiring species-specific regulatory functions. In humans, mirtrons remain an understudied group of regulatory RNAs. However, emerging evidence highlights their critical roles in cancer biology. These small RNAs influence a range of oncogenic processes, including tumor initiation, progression, metastasis, and resistance to therapy. By directly regulating the expression of oncogenes and tumor suppressor genes, mirtrons serve as key molecular mediators within cellular signaling pathways. What sets mirtrons apart from canonical miRNAs is their unique mode of biogenesis and structural attributes, which reveal alternative regulatory mechanisms that could be exploited in cancer biology. Recent advances in understanding their functions suggest that mirtrons hold significant potential as biomarkers for cancer diagnosis and prognosis. Additionally, their role as modulators of cancer pathways positions them as promising therapeutic targets in precision oncology. This review delves into the growing body of research on mirtrons, focusing on their biogenesis, biological roles, and implications in cancer. By emphasizing their distinct features and clinical relevance, it aims to provide a comprehensive perspective on the potential applications of mirtrons in advancing cancer diagnostics and therapeutics.
]]>Authors: Manav Shah Abdullah Khalid Oliver Standring Neda Amini Lyudmyla Demyan Shruti Koti Emma Gazzara Grace Wu Nandan Vithlani Danielle DePeralta Sepideh Gholami Matthew Weiss
Background/Objectives: Treatment options for advanced HCC are limited. Immunotherapy, a promising new therapeutic, has recently been incorporated as a first-line systemic treatment. This study evaluates immunotherapy uptake and disparities in its adoption prior to first-line approval, which are currently unknown. Methods: Patients diagnosed with stage IV HCC between 2014 and 2019 were identified in the National Cancer Database (NCDB). Multivariable logistic regression analysis was performed for demographic and clinical variables to determine their association with the receipt of immunotherapy. Results: A total of 18,248 patients were diagnosed with stage IV HCC, of which 977 (5.35%) received immunotherapy. From 2014 to 2019, the rate of immunotherapy uptake increased each year, with an approximate 25-fold increase overall. On multivariable analysis, patients with a more recent period of diagnosis (OR: 30.19, 95% CI: 16.47–55.33), with private insurance (OR: 2.56, 95% CI: 1.62–4.04), with treatment at an academic or research center (OR: 1.97, 95% CI: 1.37–2.82), or with an income ≥ USD 63,333 (OR: 1.27, 95% CI: 1.01–1.59) were more likely to receive immunotherapy. Conclusions: Various demographic factors impact the receipt of immunotherapy in the pre-approval setting, such as income, insurance status, and treatment center. As immunotherapy use will likely further expand and these disparities may potentially persist following first-line approval, strategies to mitigate them are especially important.
]]>Authors: Constantin N. Baxevanis Maria Goulielmaki Ourania E. Tsitsilonis Angelos D. Gritzapis
The year of 2024 was successful regarding the scientific performance of Onco [...]
]]>Authors: Guilherme Carlos Beiruth Freire Luiz Eduardo Rodrigues Juliasse Salomão Israel Monteiro Lourenço Queiroz Ruthinéia Diógenes Alves Uchôa Lins Carlos Fernando Mourão Bruno César de Vasconcelos Gurgel
Background/Objectives: Lip cancer represents one of the most prevalent malignant neoplasms in the oral cavity worldwide. This study investigated the prevalence, epidemiological profile, and survival rates of lip squamous cell carcinoma cases at the Liga Norte Riograndense Contra o Câncer (LNRCC) through a 15-year retrospective analysis. Methods: Data collection included sociodemographic characteristics, risk factors, tumor features, staging, and treatment modalities from 348 patient records. Statistical analysis was performed using Stata 12.0 and SPSS 22.0. Results: Results showed a predominance of male patients (70.4%), with a mean age of 65.51 years, mostly brown-skinned, illiterate individuals working in rural areas and residing in the state’s eastern region. Moderately differentiated squamous cell carcinoma (82.8%) affecting the lower lip (89.1%) was most frequent, with a tendency toward advanced staging. The overall survival rate was 88.90%, with lower rates observed among white, illiterate, and substance-using patients, as well as those with advanced-stage disease and chemotherapy treatment. Conclusions: Notably, race emerged as the most significant survival predictor, with white individuals showing consistently lower survival rates regardless of disease characteristics or treatment approach.
]]>Authors: Emma Boydell Maxime Borgeaud Petros Tsantoulis
Tumor dormancy plays a pivotal role in cancer relapse. Dormant tumor cells have been identified in distant sites, even in early-stage tumors, and are associated with worse outcomes. This review explores the current understanding of the molecular and cellular mechanisms behind tumor dormancy, including the role of the immune system and the microenvironment. Targeting dormant tumor cells could be a therapeutic strategy to offer long-term remission and potentially cure cancer. Unfortunately, the translation of this knowledge in clinical practice is lacking. We assess the feasibility of detecting and measuring dormant tumor cells in clinical practice, and give an overview of potential therapeutic targets, both in terms of maintaining tumor cells in a dormant state, and in terms of eradicating this tumor population.
]]>Authors: Carolina Sousa Mafalda Videira
The integration of small interfering RNA (siRNA) with traditional cancer therapies represents a promising frontier in oncology aimed at enhancing treatment effectiveness, reducing side effects, and overcoming drug resistance. This review highlights the potential of siRNA to selectively silence genes that are overexpressed or uniquely expressed in cancer cells, thereby disrupting critical pathways that support tumor growth and survival. Key target genes discussed include survivin, VEGF, EGFR, c-MET, HER2, MUC1, and Bcl-2, all of which play vital roles in tumor proliferation, angiogenesis, and resistance to therapies. Clinical trials investigating various siRNA candidates, such as EZN-3042 and ALN-VSP, indicate that these therapies are generally well-tolerated; however, significant challenges persist, including the effective delivery and stability of siRNA. Recent advancements in nanoparticle-based delivery systems have shown promise in addressing these issues. Future research will focus on optimizing siRNA delivery methods, personalizing therapies based on individual genetic profiles, and establishing clearer regulatory guidelines for approval. As the field evolves, siRNA-based combination therapies are poised to become an integral part of precision oncology, offering new therapeutic options and hope for patients with difficult-to-treat cancers.
]]>Authors: Aaron Y. Mochizuki Trent R. Hummel Timothy Cripe Maryam Fouladi Ian F. Pollack Duane Mitchell Tina Young Poussaint Arzu Onar-Thomas Natasha Pillay-Smiley Mariko DeWire-Schottmiller Charles B. Stevenson
Background/Objectives: Multiple immune-modulatory strategies have been tested in efforts to mitigate the pro-tumor microenvironment in pediatric high-grade glioma. HSV1716 is an oncolytic virus that previously demonstrated evidence of response in adult and pediatric patients. PBTC-037 was a single-center phase I trial developed and performed by the Pediatric Brain Tumor Consortium (PBTC) to estimate the maximum tolerated dose or recommended phase II dose of HSV1716 administered during surgical resection. Methods: Patients aged 12 to 21 years with recurrent or refractory high-grade glioma for whom surgical resection was clinically indicated were eligible. After maximal tumor resection, patients received one intraoperative dose of HSV1716. Results: Two patients were enrolled; one was later deemed ineligible yet was continued in follow up for safety. Both patients underwent complete tumor resection with the administration of HSV1716. Shortly after the enrollment of the two patients, this study was closed to accrual due to a change in the sponsor’s investment focus. One patient completed the 8-week reporting period without toxicity. The second patient who was later deemed ineligible had no evidence of dose-limiting toxicity. The two patients had progressive disease at 1.9 and 2.9 months after enrollment; both eventually died due to progressive disease at 7.5 months. Conclusion: We describe the administration of HSV1716 to two pediatric patients with recurrent high-grade glioma, without evidence of dose-limiting toxicity. Oncolytic viruses are currently being tested in pediatric patients in larger combinatorial trials. Despite the limited numbers, the data presented here will hopefully provide incremental steps toward improved immunovirotherapy of pediatric brain tumors.
]]>Authors: Jesús Peña-López Laura Gutiérrez-Sainz Diego Jiménez-Bou Icíar Ruíz-Gutiérrez Carmen Navas-Jiménez Jorge Ignacio Alonso-Eiras Álvaro García-Zamarriego Darío Sánchez-Cabrero Leticia Ruíz-Giménez Ana Pertejo-Fernández Julia Villamayor-Sánchez Patricia Cruz-Castellanos Oliver Higuera-Gómez Javier de Castro
Background: Patients with lung cancer experience higher rates of hospitalization due to their elevated mortality and associated comorbidities. Hospital admissions among oncology patients often indicate organ vulnerability and are linked to poor prognosis. This study aimed to assess the characteristics and potential prognostic factors of hospitalized lung cancer patients. Methods: We retrospectively analyzed 646 patients admitted from June 2021 to May 2022 to the Medical Oncology Service at La Paz University Hospital (Madrid, Spain). Results: During this period, 158 patients admitted had lung cancer (24.5%). The median overall survival since admission (mOSSA) was 3.3 months (95%CI: 1.86–7.74). In the univariate analysis, poorer mOSSA was associated with admission for tumor-related causes (1.33 vs. 7.30 months, p < 0.001), ECOG ≥ 2 (2.43 vs. 8.50 months, p < 0.001), NLR ≥ 6 (1.87 vs. 7.40 months), PNI ≤ 40 (1.67 vs. 4.97 months), and LDH ≥ 210 (2.27 vs. 7.87 months, p = 0.044). In the multivariate analysis, independent prognostic factors included admission for tumor-related causes (p = 0.032, aHR 1.81, 95%CI: 1.05–3.11) and ECOG ≥ 2 (p = 0.041, aHR 1.80, 95%CI: 1.03–3.16). Conclusions: Hospital admission for lung cancer is a poor prognostic event, particularly when associated with tumor-related causes or a decline in performance status.
]]>Authors: Guillaume Mestrallet
Immune checkpoint blockade (ICB), radiotherapy, chemotherapy and surgery are currently used as therapeutic strategies against melanoma, lung, bladder and renal cancers, but their efficacy is limited. Thus, I need to predict treatment response and resistance to address this challenge. In this study, I analyzed 350 lung cancer, 320 melanoma, 215 bladder cancer, 139 head and neck cancer and 151 renal carcinoma patients treated with ICB to identify tumor mutations associated with response and resistance to treatment. I identified several tumor mutations linked with a difference in survival outcomes following ICB. In lung cancer, missense mutations in ABL1, ASXL1, EPHA3, EPHA5, ERBB4, MET, MRE11A, MSH2, NOTCH1, PAK7, PAX5, PGR, ZFHX3, PIK3C3 and REL genes were indicative of favorable responses to ICB. Conversely, mutations in TGFBR2, ARID5B, CDKN2C, HIST1H3I, RICTOR, SMAD2, SMAD4 and TP53 genes were associated with shorter overall survival post-ICB treatment. In melanoma, mutations in FBXW7, CDK12, CREBBP, CTNNB1, NOTCH1 and RB1 genes predict resistance to ICB, whereas missense mutations in FAM46C and RHOA genes are associated with extended overall survival. In bladder cancer, mutations in HRAS genes predict resistance to ICB, whereas missense mutations in ERBB2, GNAS, ATM, CDKN2A and LATS1 genes, as well as nonsense mutations in NCOR1 and TP53 genes, are associated with extended overall survival. In head and neck cancer, mutations in genes like PIK3CA and KRAS correlated with longer survival, while mutations in genes like TERT and TP53 were linked to shorter survival. In renal carcinoma, mutations such as EPHA5, MGA, PIK3R1, PMS1, TSC1 and VHL were linked to prolonged overall survival, while others, including total splice mutations and mutations in B2M, BCOR, JUN, FH, IGF1R and MYCN genes were associated with shorter overall survival following ICB. Then, I developed predictive survival models by machine learning that correctly forecasted cancer patient survival following ICB within an error between 5 and 8 months based on their distinct tumor mutational attributes. In conclusion, this study advocates for personalized immunotherapy approaches in cancer patients.
]]>Authors: Simon L. Barry Emer Lynch Philip Bredin Sebastian McWilliams Julie McCarthy Orla O’Mahony Linda Feeley Killian Nugent Patrick Sheahan Deirdre O’Hanlon David O’Reilly Seamus O’Reilly
Anaplastic thyroid cancer (ATC) is considered to be one of the most virulent, treatment-refractory malignancies. Recent molecular insights into the biology of thyroid cancer have transformed ATC management, and BRAF/MEK targeted therapy is now incorporated into guideline-based multidisciplinary care. We report visceral perforation in the setting of an extreme response to such therapy in a patient with ATC. Molecularly targeted therapy afforded a dramatic but life-threatening response to treatment. This report highlights the complexities of care for the patient and treating clinicians.
]]>Authors: Hugo C. Temperley Jack Bell Tom O. Cuddihy Niall J. O’Sullivan Benjamin M. Mac Curtain Steven Dolan Niall McEniff Ian Brennan Kevin Sheahan Martin Marshal Michael E. Kelly Zi Q. Ng
Background: Locally advanced rectal cancer (LARC) presents a significant treatment challenge. Transarterial chemoembolization (TACE) has emerged as a potential adjunctive treatment, offering targeted delivery of chemotherapeutic agents to the tumor site, minimizing systemic exposure. This systematic review aims to assess the current literature on this novel technique and evaluate the safety and efficacy profile of TACE in treating this complex cohort of patients. Methods: A comprehensive literature search was conducted across multiple databases, including PubMed, EMBASE, and Cochrane Library, to identify studies evaluating TACE in LARC. Inclusion criteria encompassed clinical trials, cohort studies, and case series reporting on outcomes such as tumor response rate, overall survival (OS), progression-free survival (PFS), and treatment-related adverse events. Results: A total of eight studies involving 543 patients met the inclusion criteria. The studies varied in design, with five prospective and three retrospective studies. A higher prevalence of male participants (68.7%) was noted, with a median age of 60.3 years. The studies primarily evaluated the efficacy and safety of TACE in LARC treatment. Pathological response rates, tumor reduction, and survival outcomes varied across studies, with TACE showing promise in reducing tumor size, improving survival, and controlling metastasis. Major complications were rare, reported in 6.0% of cases. Conclusions: TACE is a promising therapeutic option for patients with LARC, demonstrating favorable tumor response rates and manageable toxicity profiles. Further large-scale, randomized controlled trials are warranted to confirm these findings and better define the role of TACE in the multimodal treatment of LARC.
]]>Authors: Peter Weeber Stephanie Bremer Jonas Haferanke Carla Regina Martin Schönfelder Henning Wackerhage Irene von Luettichau
Background: Exercise has beneficial effects on cancer and its treatment, but the underlying mechanisms are poorly understood. Some studies have linked the positive impact of exercise to catecholamine signaling. In contrast, cancer stress studies have typically reported that catecholamines worsen cancer hallmarks and outcomes. Here, we aimed to investigate whether adrenergic receptor isoform expression can explain the contradictory effects of catecholamines in cancer. Methods: We cultured two pediatric sarcoma cancer cell lines that either express (A673 cell line) or do not express (RD cell line) adrenergic receptors. The cells were treated with a 5× dilution series of noradrenaline to assess the effects of noradrenaline on cell numbers. After these dose-finding experiments, we treated both cancer cell lines with 60 μM noradrenaline to examine its effect on cell proliferation and migration and cAMP signaling. Results: Treatment with 60 μM noradrenaline significantly decreased the cell numbers by 61.89% ± 10.36 (p ≤ 0.001), decreased cell proliferation by 15.88% ± 6.76 (p ≤ 0.05), decreased cell migration after 24 h (p ≤ 0.001), and increased cAMP concentrations 38-fold (p ≤ 0.001) in the A673 cells, which express adrenergic receptors, but not in the RD cells, which do not express adrenergic receptors. Conclusions: Our results indicate, as a proof of principle, that the effects of catecholamines on cancer progression and metastasis might depend on the expressions of the nine adrenergic receptor isoforms. As cancers express adrenergic and other receptors differentially, this has implications for the response of cancers to exercise, stress, and medication and may help to further personalize cancer treatments.
]]>Authors: Samuel McCullough Eliene Albers Akshata Anchan Jane Yu Bronwen Connor E. Scott Graham
Background/Objectives: Brain cancers offer poor prognoses to patients accompanied by symptoms that drastically impact the patient and their family. Brain tumours recruit local non-transformed cells to provide trophic support and immunosuppression within the tumour microenvironment, supporting tumour progression. Given the localisation and supportive role of pericytes at the brain vasculature, we explored the potential for brain pericytes to contribute to the brain cancer microenvironment. Methods: To investigate this, primary brain pericytes were treated with factors commonly upregulated in brain cancers. Immunofluorescent labelling identified changes to brain pericyte cell signalling, cytometric bead array measured inflammatory secretion, and flow cytometry investigated brain pericyte phagocytosis. Results: The TGFβ superfamily cytokines TGFβ and GDF-15 activated SMAD2/3 and inhibited C/EBP-δ, revealing a potential mechanism behind the pleiotropic action of TGFβ on brain pericytes. IL-17 induced secretion of IL-6 without activating NFκB, STAT1, SMAD2/3, or C/EBP-δ signalling pathways. IL-27 and IFNγ induced STAT1 signalling and significantly reduced brain pericyte phagocytosis. The remaining brain cancer-derived factors did not induce a measured response, indicating that these factors may act on other cell types or require co-stimulation with other factors to produce significant effects. Conclusions: We identify several brain cancer-secreted factors which alter relevant brain pericyte functions. This reveals mechanisms through which brain tumours may regulate brain pericyte activity and these data start to uncover the supportive role these cells may play in brain cancers.
]]>Authors: Nishika Karbhari Simon Khagi
Introduction: Glioblastoma is a fatal intracranial neoplasm that is refractory to treatment, with inevitable disease recurrence and progression to death. Marine-derived compounds, including those found in nutraceutical products, may provide therapeutic benefit in the setting of glioblastoma. We present two patient cases whose courses demonstrate a compelling role for marine-derived products in the management of glioblastoma. Cases: Case 1 describes a patient with MGMT promoter unmethylated glioblastoma who went on to complete standard of care chemoradiation along with concurrent use of a majority sea cucumber (MSC) blend known as SeaCare® (SeaCare, Torrington, CT, USA). Her survival of over 2 years significantly exceeds the recognized median survival time of glioblastoma. Case 2 describes a patient with a complicated course who experienced dramatic improvement after the initiation of the MSC blend, with an exceptional survival time of over 4 years post-diagnosis. Discussion: The mechanisms of marine-derived products that underlie these dramatic clinical effects are likely multifaceted but may hinge on the modification of the tumor immune microenvironment and suppression of tumorigenic effects. Specifically, the change in tumor-associated macrophages (TAMs) within the tumor microenvironment is central to this complex interplay. Conclusions: Ultimately, the use of marine products in the treatment of glioblastoma may present a novel and promising therapeutic strategy that warrants further investigation.
]]>Authors: Pemla Jagtiani Mert Karabacak Alejandro Carrasquilla Raymund Yong Konstantinos Margetis
(1) Background: Glioblastoma (GBM) is the most common malignant brain tumor in adults. Due to a lack of level 1 evidence, there is no clear consensus on the optimal extent of resection to improve overall survival. This umbrella review aggregates existing meta-analyses (MAs) to assess overall survival in patients undergoing subtotal resection (STR) versus gross total resection (GTR). (2) Methods: A systematic search of PubMed, Scopus, and Web of Science identified 441 studies, with four MAs meeting inclusion criteria. Data were analyzed using the metaumbrella R package, focusing on overall survival. Quality was assessed using AMSTAR2, with scores ranging from 0 to 11. The Ioannidis criteria were applied to evaluate the credibility of the evidence. (3) Results: The quality assessment rated all four studies highly, with a mean AMSTAR2 score of 10.25. The pooled analysis revealed a significant survival advantage for GTR over STR. However, the Ioannidis classification graded the evidence as Class III, indicating weak credibility. (4) Conclusions: GTR offers a slight survival benefit over STR in GBM patients, but the credibility of the evidence is weak, highlighting the need for further research.
]]>Authors: Pulkit Malhotra Ruman Rahman
Isocitrate dehydrogenase wild-type glioblastoma, a Grade 4 malignant brain neoplasm, remains resistant to multimodal treatment, with a median survival of 16 months from diagnosis with no geographical bias. Despite increasing appreciation of intra-tumour genotypic variation and stem cell plasticity, such knowledge has yet to translate to efficacious molecular targeted therapies in this post-genomic era. Critically, the manifestation of molecular heterogeneity and stem cell biological process within clinically relevant infiltrative disease is little understood. Here, we review the interactions between neural plasticity, intra-tumour heterogeneity and residual infiltrative disease, and we draw upon antibiotic resistance as an insightful analogy to further explain tumour heterogeneity.
]]>Authors: Sathya Narayanan Yuling Wang Howard Gurney
Raman spectroscopy is a technique which involves quantitative and qualitative molecular analysis based on the interaction between incident light and isolation of scattered wavelengths in generating a molecular fingerprint. It has a broad array of potential scientific applications, encompassing areas as diverse as food science and forensics. However, it may also be highly useful in clinical oncology. A recent focus of research in oncology has been in achieving the individualisation of care. Two important strategies to achieve a so-called “precision oncology” approach may include the detection of circulating tumour DNA (ctDNA) in more objectively evaluating treatment response and guiding de-escalation and intensification approaches in systemic therapy and therapeutic drug monitoring (TDM). Therapeutic drug monitoring involves the quantitation of plasma drug levels in order to tailor medication dosing in optimizing outcomes. The existing approaches to characterize small molecules, such as fluorescence-based and chromatographic strategies, may be limited by high costs, long turnaround times, and bulky equipment. Surface-enhanced Raman spectroscopy (SERS) may be deployed by utilizing a handheld device, with the potential for point of care, rapid turnaround, low-cost assessment of clinically relevant parameters, and prompt implementation of attendant changes in treatment. Although there is a growing body of data supporting the implementation of TDM and evaluation of ctDNA in achieving precision medicine, the uptake of such approaches remains relatively limited outside of clinical trials. As stated, the nature of existing analytical methodologies may prove to be a significant barrier to the routine clinic-based implementation of such approaches. Therefore, we provide the existing evidence for SERS in alleviating these barriers. We also provide insights into how SERS could contribute to clinical oncology.
]]>Authors: Karim Hawillo Samira Kemiha Hervé Técher
Chromosomal instability and DNA damage are hallmarks of cancers that can result in the accumulation of micronuclei, cytosolic chromatin fragments (CCFs), or cytosolic DNA species (cytoDNA). The cyclic GMP-AMP synthase (cGAS) is a DNA sensor that recognizes cytosolic DNA and chromatin fragments and subsequently triggers a systemic type I interferon response via the cGAS-STING pathway. Although cancer cells usually contain a high level of chromosomal instability, these cells can avoid the induction of the interferon (IFN) response either by silencing cGAS-STING or the upregulation of the three prime exonuclease 1 (TREX1). TREX1 restricts the spontaneous activation of the cGAS-STING pathway through the degradation of cytoDNA; this in turn limits tumor immunogenicity allowing cancer cells to evade immune detection. Deletion of TREX1 in different cancer types has been shown to decrease tumor growth and increase tumor immune infiltration in pre-clinical mice models. These recent studies also showed the efficacy of TREX1-targeting in combination with anti-PD-1 immune checkpoint blockade. Therefore, targeting TREX1 represents a unique therapeutic strategy to induce an amplified induction of a type I IFN response, promoting the host’s immune response against chromosomally unstable cancer cells. We here discuss these recent advances obtained in preclinical cancer models that pave the way to develop TREX1 inhibitors and to find new avenues to target the broad cGAS-STING pathway signaling in cancer therapy.
]]>Authors: Gerhard Nahler
Cancer, one of the leading causes of death worldwide, is on the rise. The high toxicity of conventional chemotherapy, often applied as drug cocktails, and the development of resistance limit the use of antineoplastic drugs and reduce the quality of life. With easier access, a growing number of patients are using cannabis (cannabinoids) for alleviation of their symptoms, and in the hope of improving survival. This article summarizes results observed with combinations of phytocannabinoids and standard chemotherapeutic agents in animal tumour models and in patients. It is limited to approved phytocannabinoids. Preliminary preclinical data suggest that conventional antineoplastic agents combined with cannabinoids exert enhanced anti-cancer effects, reduce resistance development and improve survival. Corresponding experiences with patients are still very limited and only concern a few patients with glioblastoma and pancreatic cancer. Benefits of combinations containing cannabinoids have also been reported for chemotherapy-induced nausea and vomiting, loss of appetite (dronabinol), and chemotherapy-induced peripheral neuropathic pain and anxiety (cannabidiol). In addition, phytocannabinoids, particularly cannabidiol, may play a role in protecting organs such as the heart, lungs or kidneys from chemotherapy-related toxicity. Although the results are promising, more research is needed to ensure whether the benefits of adjuvant cannabinoids outweigh the potential risks.
]]>Authors: Riccardo Gili Simone Caprioli Paola Lovino Camerino Gianluca Sacco Tommaso Ruelle Daria Maria Filippini Silvia Pamparino Stefania Vecchio Filippo Marchi Lucia Del Mastro Giuseppe Cittadini
Background: For patients with head and neck squamous cell carcinoma (HNSCC), after a single or multi-modality treatment, a specific follow-up strategy is needed, but there is no agreement between the main international societies on the proper methods and timing of follow-up. Methods: We performed a descriptive review to evaluate the available data and compare the main guidelines, giving some practical guidance to perform effective personalized follow-up strategies. Results and Conclusions: While clinical and endoscopic follow-up alone seems to be appropriate for early-stage HNSCCs, the addition of close radiologic follow-up in locally advanced HNSCCs is still debated, as there are no data indicating that an earlier detection of recurrence correlates with increased survival, while it is mandatory in the first three-six months to define the response to treatment. For patients who have undergone conservative surgery or have major pathological risk factors, the incidence of locoregional recurrence is higher, and locoregional radiologic follow-up (magnetic resonance imaging is preferred to computed tomography) should be considered. Positron emission tomography may be useful in cases of suspected locoregional persistence of disease, differentiating it from post-irradiation outcomes. Distant radiological follow-up can be considered in the detection of the second primary in cases of specific risk factors and for virus-related tumors. For the latter, the use of circulating DNA should always be considered. A brain scan is not recommended without specific symptoms. For all patients who do not fall into the above categories, clinical and endoscopic follow-up should be proposed, reserving radiological investigations only at the onset of symptoms.
]]>Authors: Cara Guernsey-Biddle Peyton High Kendra S. Carmon
The epidermal growth factor receptor (EGFR) plays a critical role in regulating essential cellular processes that are frequently hijacked to promote cancer. In colorectal cancer (CRC) in particular, the EGFR signaling pathway is frequently hyperactivated via receptor and/or ligand overexpression and downstream oncogenic mutations. Current EGFR-targeted therapies for metastatic CRC (mCRC) include the mAbs cetuximab and panitumumab. However, intrinsic and acquired resistance to EGFR-targeted mAbs are commonly observed. Thus, additional biomarkers are necessary to better understand patient sensitivity to EGFR-targeted therapies. Furthermore, therapeutic targeting of alternative EGFR pathway components may serve as one mechanism to overcome EGFR-targeted mAb resistance. In this review, we discuss the mounting evidence supporting EGFR ligands epiregulin (EREG) and amphiregulin (AREG), which are overexpressed in CRC with potential key roles in tumor progression, as predictive biomarkers for EGFR-targeted therapy sensitivity, as well as mediators of therapy resistance, though further studies are necessary to validate the prognostic roles and mechanisms by which these ligands contribute to resistance. Additionally, we review recent advances towards therapeutic targeting of EREG and AREG in cancer through the development and use of EREG- and AREG-targeted mAbs as well as antibody–drug conjugates (ADCs). We conclude with a discussion on the roadblocks to clinical implementation of EREG and AREG as biomarkers, as well as approaches to enhance the efficacy of current EREG- and AREG-targeted strategies.
]]>Authors: Michela Perrone Sara Sergio Amalia Tarantino Giuseppina Loglisci Rosella Matera Davide Seripa Michele Maffia Nicola Di Renzo
Background: JAK2 V617F is a somatic mutation associated with myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). In MPNs, this mutation is associated with the germline GGCC (46/1) haplotype. Several studies associated JAK2 haplotype GGCC_46/1 with some MPNs clinical parameters, but not one explore the link between JAK2 haplotype GGCC_46/1 and onco-drug resistance. Thus, we assessed for the JAK2 46/1 haplotype’s correlation with therapy response in JAK2 V617F-positive patients. Methods: Patients with MPN, selected by the Hematology Laboratory of “V. Fazzi” Hospital (LE), were analyzed with RLFP-PCR assay with rs10974944 SNP. Results: Results show how the majority of patients had PV (63%) or PMF (61%) and that 58% of patients who developed drug resistance had the C/G genotype, while only 11% had the G/G allele. While no direct correlation between JAK2 46/1 haplotype variants and drug resistance was found, the G/G allele was associated with disease progression to myelofibrosis and certain resistance-related clinical parameters (p = 0.002449, odds ratio = 3.701209). Conclusions: Although other analyses are required, due to the narrow cardinality of sample, our findings suggest how the G/G allele could be useful for MPNs diagnosis and for the prediction of the disease outcome.
]]>Authors: Jose Alejandro Madrigal José C. Crispín
The use of chimeric antigen receptors (CAR T-cells) for the treatment of patients with malignant haematological diseases has become a well-established application for conditions such as refractory or relapsed B-cell acute lymphoblastic leukaemia (B-ALL), B-cell lymphomas (BCL), and multiple myeloma (MM). Nearly 35,000 patients have received autologous CAR T-cells for the treatment of these conditions only in the USA. Since their approval by the Food and Drug Administration (FDA) in 2017, over 1200 clinical trials have been initiated globally and there are at least 10 different CAR T-cells with approval by different regulatory agencies around the globe. In the USA, the FDA has approved six commercial CAR T-cells that are widely distributed worldwide. At the time of writing, several clinical trials have been performed in patients with solid tumours such as glioblastoma, renal and pancreatic cancer, as well as in patients with autoimmune conditions such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis (IIM), and systemic sclerosis (SS). There are also several studies showing the potential benefit of CAR T-cells for other non-malignant diseases such as asthma and even fungal infections. In this review, without pretending to cover all current areas of treatments with CAR T-cells, we offer a brief summary of some of the most relevant aspects of the use of CAR T-cells for some of these conditions.
]]>Authors: Yina Wang Liangyou Rui
Liver cancer imposes a pervasive global health challenge, ranking among the most prevalent cancers worldwide. Its prevalence and mortality rates are on a concerning upward trajectory and exacerbated by the dearth of efficacious treatment options. The Hippo signaling pathway, originally discovered in Drosophila, comprises the following four core components: MST1/2, WW45, MOB1A/B, and LATS1/2. This pathway regulates the cellular localization of the transcriptional coactivator Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ) through a series of enzymatic reactions. The Hippo-YAP/TAZ pathway maintains a balance between cell proliferation and apoptosis, regulates tissue and organ sizes, and stabilizes the internal environment. Abnormalities of any genes within the Hippo signaling pathway, such as deletion or mutation, disturb the delicate balance between cell proliferation and apoptosis, creating a favorable condition for tumor initiation and progression. Mutations or epigenetic alterations in the Hippo signaling pathway components can lead to its inactivation. Consequently, YAP/TAZ becomes overexpressed and activated, promoting excessive cell proliferation and inhibiting apoptosis. This dysregulation is closely associated with the development of liver cancer. This review discusses the pivotal role of the Hippo signaling pathway in the pathogenesis and progression of liver cancer. By elucidating its mechanisms, we aim to offer new insights into potential therapeutic targets for effectively combating liver cancer.
]]>Authors: Eduarda Maria Rocha Teles de Castro Coelho Helena Isabel Azevedo Mendes Carla Afonso Varajidás Sandra Celina Fernandes Fonseca
Controlled study designs usually report that physical exercise improves the health of women living with breast cancer. However, many of these women are not sufficiently active to experience the benefits of exercise. The main objective was to analyze the effect of a physical exercise program on quality of life, self-esteem, and depression in breast cancer survivors. Thirteen participants (46.54 ± 6.31 years old) completed the exercise intervention. Three patient-reported questionnaires were used: Supplementary Questionnaire Breast Cancer Module (QLQ-BR23), Beck Depression Inventory (BDI), and Rosenberg Self-Esteem Scale (RSES). All participants had significantly improved self-esteem (p = 0.004). Although there were no statistically significant changes in depression, there was a notable decrease in scores (6.39 ± 4.75 vs. 5.00 ± 4.75; p = 0.080). Regarding quality of life, significant improvements were observed in “future perspectives” (p = 0.047) and “arm symptoms” (p = 0.015). No significant changes were noted in the other variables. Our results suggest that physical exercise is an effective strategy that positively affects breast cancer survivors’ quality of life and self-esteem. The results reinforce the need for community-based exercise programs for breast cancer survivors. Healthcare professionals should promote physical exercise to improve health outcomes before, during, and after treatment.
]]>Authors: Guillaume Mestrallet
Strategies for tackling cancer involve surgery, radiotherapy, chemotherapy, and immune checkpoint inhibitors (ICB). However, the effectiveness of ICB remains constrained, prompting the need for a proactive strategy to foresee treatment responses and resistances. This study undertook an analysis across diverse cancer patient cohorts (including melanoma, clear cell renal carcinoma, glioblastoma, bladder, and stomach cancers) subjected to various immune checkpoint blockade treatments. Surprisingly, our findings unveiled that over 38% of patients demonstrated resistance and persistent disease progression despite undergoing ICB intervention. To unravel the intricacies of resistance, we scrutinized the immune profiles of cancer patients experiencing ongoing disease progression and resistance post-ICB therapy. These profiles delineated multifaceted defects, including compromised macrophage, monocyte, and T cell responses, impaired antigen presentation, aberrant regulatory T cell (Tregs) responses, and an elevated expression of immunosuppressive and G protein-coupled receptor molecules (TGFB1, IL2RA, IL1B, EDNRB, ADORA2A, SELP, and CD276). Building upon these insights into resistance profiles, we harnessed machine learning algorithms to construct models predicting the response and resistance to ICB and developed the accompanying software. While previous work on glioblastoma with only one type of algorithm had an accuracy of 0.82, we managed to develop 20 models that provided estimates of future events of resistance or response in five cancer types, with accuracies ranging between 0.79 and 1, based on their distinct immune characteristics. In conclusion, our approach advocates for the personalized application of immunotherapy in cancer patients based on patient-specific attributes and computational models.
]]>Authors: Giulia Pozzati Jinrui Zhou Hananel Hazan Giannoula Lakka Klement Hava T. Siegelmann Jack A. Tuszynski Edward A. Rietman
Whole-genome sequencing has revealed that TP53, NOTCH1, ATM, SF3B1, BIRC3, ABL, NXF1, BCR, and ZAP70 are often mutated in CLL, but not consistently across all CLL patients. This paper employs a statistical thermodynamics approach in combination with the systems biology of the CLL protein–protein interaction networks to identify the most significant participant proteins in the cancerous transformation. Betti number (a topology of complexity) estimates highlight a protein hierarchy, primarily in the Wnt pathway known for aberrant CLL activation. These individually identified proteins suggest a network-targeted strategy over single-target drug development. The findings advocate for a multi-target inhibition approach, limited to several key proteins to minimize side effects, thereby providing a foundation for designing therapies. This study emphasizes a shift towards a comprehensive, multi-scale analysis to enhance personalized treatment strategies for CLL, which could be experimentally validated using siRNA or small-molecule inhibitors. The result is not just the identification of these proteins but their rank-order, offering a potent signal amplification in the context of the 20,000 proteins produced by the human body, thus providing a strategic basis for therapeutic intervention in CLL, underscoring the necessity for a more holistic, cellular, chromosomal, and genome-wide study to develop tailored treatments for CLL patients.
]]>Authors: Chen Yeh Shu-Ti Lin Hung-Chih Lai
As precision medicine such as targeted therapy and immunotherapy often have limited accessibility, low response rate, and evolved resistance, it is urgent to develop simple, low-cost, and quick-turnaround personalized diagnostic technologies for drug response prediction with high sensitivity, speed, and accuracy. The major challenges of drug response prediction strategies employing digital database modeling are the scarcity of labeled clinical data, applicability only to a few classes of drugs, and losing the resolution at the individual patient level. Although these challenges have been partially addressed by large-scale cancer cell line datasets and more patient-relevant cell-based systems, the integration of different data types and data translation from pre-clinical to clinical utilities are still far-fetched. To overcome the current limitations of precision medicine with a clinically proven drug response prediction assay, we have developed an innovative and proprietary technology based on in vitro patient testing and in silico data analytics. First, a patient-derived gene expression signature was established via the transcriptomic profiling of cell-free mRNA (cfmRNA) from the patient’s blood. Second, a gene-to-drug data fusion and overlaying mechanism to transfer data were performed. Finally, a semi-supervised method was used for the database searching, matching, annotation, and ranking of drug efficacies from a pool of ~700 approved, investigational, or clinical trial drug candidates. A personalized drug response report can be delivered to inform clinical decisions within a week. The PGA (patient-derived gene expression-informed anticancer drug efficacy) test has significantly improved patient outcomes when compared to the treatment plans without PGA support. The implementation of PGA, which combines patient-unique cfmRNA fingerprints with drug mapping power, has the potential to identify treatment options when patients are no longer responding to therapy and when standard-of-care is exhausted.
]]>Authors: Fernando Leporace-Jiménez Isabel Portillo-Hernandez Justino Jiménez-Almonacid Ignacio Zubillaga Rodriguez María Mejía-Nieto Pablo Caballero Pedrero Gregorio Sanchez Aniceto
Background: PD1 and its ligand PD-L1 are related to prognosis in many solid tumors; however, their role in oral squamous cell carcinoma (OSCC) remains unclear. Methods: A retrospective monocentric study including all patients with OSCC diagnosed and treated between January 2020 and May 2022 was performed. PD-L1 expression was assessed per a combined positive score (CPS), considering a CPS of > or equal to 1 as positive (1–20 indicating “low expression” and ≥20 indicating “high”). A descriptive analysis of the patient cohort and tumors was performed, including tumor size, stage, lymph node involvement, recurrence, and survival. Results: In total, 65 patients (65 tumors) were analyzed. A total of 66.15% of the tumors were in advanced stages (III-IV), of which 97.67% expressed PD-L1+, compared with 71.42% in the early stages (I–II). T4 tumors expressed PD-L1 in 100% of cases, compared with 54% in T1 tumors. A total of 50.79% of the tumors showed lymph node involvement (pN+), with 100% of the pN+ showing PD-L1+. The prevalence of pN+ was 59.38% vs. 40.63% for high vs. low PD-L1 expression, respectively. Patients’ follow-ups ranged from 2 to 34.5 months. No significant difference was seen between overall survival (OS) and PD-L1 +/− (CPS ≥ 1 vs. CPS < 1) or high (CPS ≥ 20) and low (CPS < 20) PD-L1 expression (p < 0.97 and 0.64, respectively). Conclusions: The method used to measure PD-L1 (a laboratory test with Dako 22C3 anti-PD-L1 primary antibodies) was reliable and accurate, with a correlation coefficient between PD-L1 expression in the biopsy and the surgical piece of 0.83 (p < 0.0001). A CPS of ≥1 was observed in large tumors (p < 0.001) and was correlated with that of lymph node metastases (p < 0.004). Further analysis of PD-L1 expression in OSCC and studies to determine its relevance in tumor biology and prognosis is needed.
]]>Authors: João Martins Gama Paulo Teixeira Rui Caetano Oliveira
Immunotherapy has paved the way for the development of solid tumor new treatments in the last decade. The approval of immune checkpoint inhibitors such as anti PD-1/PD-L1 provided a revolution with optimal results. However, a considerable proportion of patients experience adverse therapeutic effects, and up to 50% may develop secondary resistance in the first three to five years. This has prompted the need for identifying new targets for immunotherapy that have good tolerance and biosafety and, of course, good tumoral response, either alone or in combination. Two of these new targets are the Lymphocyte-activation gene 3 (LAG-3) and the T cell immunoglobulin and ITIM domain (TIGIT). They are responsible for several interactions with the immune system, prompting an immunosuppressive phenotype in the tumor microenvironment. Both LAG-3 and TIGIT can be druggable, alone or in combination with anti-PD-1/PD-L1, with rather safe profiles making them attractive. In this review, we highlight some of the immune mechanisms of TIGIT and LAG-3 and their detection by immunohistochemistry, providing some insight into their use in the clinical setting.
]]>Authors: Ana Filipa Ferreira Tatiana Fernandes Maria do Carmo Carvalho Helena Soares Loureiro
The increase in new cancer diagnoses in the elderly calls for new, accessible, and easy-to-use prognostic tools that contribute to lowering the burden of the disease. Recognising the importance of inflammation and nutritional status in the progression of the disease, the purpose of this systematic review was to synthesise the evidence on the prognostic role of Prognostic Nutritional Index (PNI) and Controlling Nutritional Status (CONUT) in predicting survival of older adult cancer patients. A comprehensive search was conducted in PubMed and Web of Science Core Collection databases until 22 February 2024. The articles included in this review (n = 38) examined the relationships of PNI and CONUT with survival outcomes in elderly cancer patients. Despite high heterogeneity between the studies, most concluded that low PNI values are associated with poor overall survival (OS), particularly in gastric cancer patients. Most studies did not find an association between PNI and cancer-specific survival, progression-free survival, disease-free survival, recurrence-free survival, and mortality. Results regarding the prognostic role of CONUT in predicting survival were inconclusive. This study suggests that PNI could be used to predict OS in elderly cancer patients, while more studies are needed to assess the prognostic role of CONUT.
]]>Authors: Eithar Mohamed Daniel Fletcher Simon Hart Barbara-ann Guinn
Lung cancer (LC) is one of the leading causes of cancer-related deaths. Pulmonary nodules are one of the risk factors, and their discovery rate has been increasing due to enhanced performance of chest CT scans, but more than 90% are non-malignant, causing unnecessary stress to patients and costs to healthcare providers. Early diagnosis of LC is associated with a 5-year survival rate of up to 75% following surgical resection, but LC is often diagnosed late due to a lack of symptoms and poor 5-year survival rates as low as 10%. The cost of LC diagnosis is high, with 40% of it associated with benign lesions, which are difficult to differentiate from malignant lesions. Tumour-associated antigens (TAAs) may provide one way in which LC could be diagnosed early using minimally-invasive techniques, under their association with immune responses and specificity for disease. Here we discuss the potential of cancer-testis antigens (CTAs) to act as non-invasive biomarkers for the early detection of non-small cell lung cancer.
]]>Authors: Shogo Maruzen Seiichi Munesue Mitsuyoshi Okazaki Satoshi Takada Shinichi Nakanuma Isamu Makino Linxiang Gong Susumu Kohno Chiaki Takahashi Hidehiro Tajima Yasuhiko Yamamoto Shintaro Yagi
Although pancreatic neuroendocrine neoplasms (panNENs) are much less common and have a better prognosis than exocrine pancreatic cancers, their recurrence rate is not low, even in Grade 1 (World Health Organization classification) panNEN. Recently, there have been several reports that the progression-free survival in patients with unresectable panNEN could be improved by an antidiabetic drug, metformin, with the co-treatment of everolimus or a somatostatin analog. In this study, we aimed to evaluate the effects of metformin on cell metabolism and viability using the panNEN cell line, QGP-1, and RIN-m in culture. We observed an inhibitory effect of metformin on QGP-1 cell proliferation in a dose-dependent manner. Metformin was found to decrease the oxygen consumption rate in QGP-1 and RIN-m cells after metformin 48 h treatment and immediately after exposure. Cell proliferation was suppressed after metformin treatment. Phosphorylated adenosine monophosphate-activated protein kinase (AMPK) expression was increased, and cyclin D1 expression was decreased in RIN-m cells 24 h after metformin treatment by Western blotting in a dose-dependent manner. In conclusion, suppressive mitochondrial respiration and AMPK activation by metformin are, thus, suggested to inhibit panNEN cell viability and cell survival.
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