Cancers

16 pages, 1270 KB

Open AccessArticle

Clinical and Biological Factors Associated with Pseudoprogression Under Immune Checkpoint Inhibitors: A Retrospective Pan-Tumor Cohort Study

by Amélie Toulet, Valérie Seegers, Frédéric Bigot, Sylvère Guillemois, Damien Vansteene, Rémy Delva and Manon de Vries-Brilland

Cancers 2026, 18(18), 3040; https://doi.org/10.3390/cancers18183040 (registering DOI) - 19 Sep 2026

Abstract

Background: Immune checkpoint inhibitors (ICIs) have transformed cancer treatment but may induce pseudoprogression (PP), an atypical response pattern that may mimic progressive disease (PD). Although iRECIST criteria were developed to characterize such atypical responses, distinguishing PP from PD when progression is first [...] Read more.

Background: Immune checkpoint inhibitors (ICIs) have transformed cancer treatment but may induce pseudoprogression (PP), an atypical response pattern that may mimic progressive disease (PD). Although iRECIST criteria were developed to characterize such atypical responses, distinguishing PP from PD when progression is first observed remains challenging. We aimed to characterize patients with clinically suspected PP and explore clinical and biological factors associated with subsequent classification as PP versus PD. Methods: We conducted a retrospective single-center study including patients with metastatic cancer treated with ICIs at the Institut de Cancérologie de l’Ouest (ICO) in whom PP was clinically suspected. Clinical, biological, treatment, and outcome data were collected at ICI initiation, PP suspicion, and subsequent PP/PD classification. Associations with PP versus PD were explored using univariable and multivariable logistic regression. Results: Among 123 patients with clinically suspected PP, 56 were subsequently classified as PP and 67 as PD. The most frequent primary tumors were lung (38%), kidney (24%), and bladder (11%) cancers. Median time from ICI initiation to PP suspicion was 79 days. ECOG performance status of 0 at ICI initiation was more frequent in the PP than in the PD group (55% vs. 32%; p = 0.046). At PP suspicion, median LDH levels were lower in the PP than in the PD group (189 vs. 232.5 U/L; p = 0.003). After multivariable adjustment, higher LDH levels at PP suspicion remained associated with PD (adjusted OR 2.78 per 100 U/L increase; 95% CI, 1.19–6.52; p = 0.019). Conclusions: In patients with clinically suspected PP, LDH may provide complementary information but cannot reliably distinguish PP from PD when considered alone. Confirmatory imaging therefore remains essential for treatment decision-making. Full article

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

► Show Figures

Figure 1

21 pages, 1009 KB

Open AccessReview

Therapeutic Time Migration in Hepatocellular Carcinoma: Rethinking the Timing of Systemic Therapy Across the Disease Continuum

by Fausto Meriggi, Ester Oneda, Sara Cherri and Alberto Zaniboni

Cancers 2026, 18(18), 3039; https://doi.org/10.3390/cancers18183039 (registering DOI) - 19 Sep 2026

Abstract

The management of hepatocellular carcinoma has traditionally followed a stage-dependent sequence in which surgery or thermal ablation is prioritized for early disease, transarterial approaches are used for intermediate-stage tumors, and systemic treatment is introduced after progression to advanced disease or loss of suitability [...] Read more.

The management of hepatocellular carcinoma has traditionally followed a stage-dependent sequence in which surgery or thermal ablation is prioritized for early disease, transarterial approaches are used for intermediate-stage tumors, and systemic treatment is introduced after progression to advanced disease or loss of suitability for locoregional therapy. This paradigm was developed when systemic treatments had limited antitumor activity. Modern immune checkpoint inhibitors and immune–antiangiogenic combinations have substantially changed these premises. Randomized trials now demonstrate clinical benefit when systemic treatment is integrated with transarterial chemoembolization before conventional locoregional failure, while perioperative studies suggest that systemic treatment can also be moved into selected high-risk resectable disease. Conversely, updated adjuvant data indicate that simply administering systemic therapy at an earlier stage does not necessarily improve outcome after complete tumor eradication. We propose the concept of therapeutic time migration, whereby systemic treatment is introduced at an earlier biological point in selected patients, while hepatic reserve is preserved, occult systemic risk is becoming clinically relevant, and effective local treatment remains feasible. We explicitly distinguish this framework from the established concept of treatment stage migration and therapeutic hierarchy. This framework emphasizes treatment sequence rather than treatment escalation and suggests that timing itself may function as a dynamic therapeutic biomarker. Prospective studies should determine whether changing the order of systemic and locoregional therapy can modify immune activation, preserve liver function, increase conversion to definitive local treatment, and ultimately improve survival. Full article

(This article belongs to the Section Cancer Therapy)

► Show Figures

Figure 1

16 pages, 307 KB

Open AccessReview

Primary Cutaneous Lymphomas and Lymphoproliferative Disorders: Current Insights for Classification and Management

by Uğur Hatipoğlu, Mert Seyhan, Hakan Eminoglu, Turgay Ulaş and Mehmet Sinan Dal

Cancers 2026, 18(18), 3038; https://doi.org/10.3390/cancers18183038 (registering DOI) - 19 Sep 2026

Abstract

Background: Primary cutaneous lymphomas (PCLs) represent a heterogeneous group of extranodal non-Hodgkin lymphomas with distinct clinical, histological, and molecular profiles. Recent advancements in genomic profiling have led to significant revisions in diagnostic frameworks and therapeutic paradigms. Objective: This review aims to summarize the [...] Read more.

Background: Primary cutaneous lymphomas (PCLs) represent a heterogeneous group of extranodal non-Hodgkin lymphomas with distinct clinical, histological, and molecular profiles. Recent advancements in genomic profiling have led to significant revisions in diagnostic frameworks and therapeutic paradigms. Objective: This review aims to summarize the current landscape of primary cutaneous B-cell and T-cell lymphomas and lymphoproliferative disorders (LPDs), focusing on the diagnostic updates in the WHO 5th edition and the International Consensus Classification (ICC 2022), alongside evolving risk-adapted treatment strategies. Methods: A comprehensive review of the recent literature and major international consensus guidelines was conducted, evaluating diagnostic shifts, disease reclassifications, and novel therapeutic interventions across various PCL subtypes. Results: The latest WHO 5th and ICC 2022 classifications emphasize the clinical behavior of indolent entities, shifting terminology from “lymphoma” to “lymphoproliferative disorder” for conditions such as primary cutaneous acral CD8+ T-cell LPD and primary cutaneous CD4+ small/medium T-cell LPD to prevent overtreatment. Several previously provisional categories (e.g., primary cutaneous gamma/delta T-cell lymphoma and EBV-positive mucocutaneous ulcer) have achieved definitive diagnostic status. Parallel to these revisions, therapeutic management has shifted toward toxicity-reducing, risk-adapted strategies. For indolent subtypes, ultra-low-dose radiotherapy (4 Gy) and skin-directed therapies remain highly effective. In aggressive or refractory subtypes, such as Mycosis Fungoides and primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT), precision oncology—utilizing targeted agents (e.g., brentuximab vedotin, mogamulizumab, lenalidomide, ibrutinib) and cellular/immunotherapies—is rapidly changing outcomes. Conclusions: Integrating the updated diagnostic classifications with modern risk-stratified and targeted treatment paradigms is crucial for optimizing clinical management and avoiding overtreatment in indolent PCLs while improving survival in aggressive subtypes. Full article

(This article belongs to the Section Cancer Therapy)

16 pages, 1643 KB

Open AccessArticle

CD84 Expression Across Disease Stages and Leukemic Subpopulations in Acute Myeloid Leukemia

by Beatriz Martín-Herreros, Lourdes Cordón, Rebeca Rodríguez-Veiga, Isabel Cano-Ferri, Evelyn Acuña-Cruz, Laura Torres-Miñana, Irene Navarro, Pilar Lloret-Madrid, Amparo Sempere, María Dolores Linares, Sara Torres-Sánchez, Elisa González-Romero, Nela Klein-González, Lorena Pérez-Amill, Leonor Senent, José Luis Poveda-Andrés, Javier De La Rubia, Pau Montesinos and Manuel Guerreiro

Cancers 2026, 18(18), 3037; https://doi.org/10.3390/cancers18183037 (registering DOI) - 18 Sep 2026

Abstract

Background/Objectives: In recent years, increasing evidence has supported CD84 as a promising therapeutic target in acute myeloid leukemia (AML), including its potential application in CAR T-cell therapy. CD84 is consistently reported to be highly expressed on AML cells in both adult and pediatric [...] Read more.

Background/Objectives: In recent years, increasing evidence has supported CD84 as a promising therapeutic target in acute myeloid leukemia (AML), including its potential application in CAR T-cell therapy. CD84 is consistently reported to be highly expressed on AML cells in both adult and pediatric patients, providing a strong biological rationale for the development of CD84-directed immunotherapies. Methods: We characterized CD84 expression in bone marrow and peripheral blood samples from 61 adult patients with AML at diagnosis, relapse, and refractory disease using multiparametric flow cytometry. Results: Our results demonstrate that CD84 is highly expressed on AML cells throughout the course of the disease. More than 80% of leukemic populations showed CD84 expression above 80%, with median expression levels remaining consistently high at diagnosis (98%), relapse (96.5%), and refractory disease (96%). A novel aspect of our study is the evaluation of CD84 expression across distinct leukemic subpopulations within individual samples; only three of the 94 leukemic populations analyzed showed CD84 expression below 20%. Similarly, CD84 expression remained consistently high across the major AML subtypes analyzed, including AML with NPM1 mutation, AML with myelodysplasia-related gene mutations, and TP53-mutated AML. Comparable median CD84 expression was observed in bone marrow and peripheral blood; however, paired analysis identified significant differences between both compartments. CD84 expression assessed with antibody clone 153-4D9 was significantly lower than that detected with clone CD84.1.21 across AML leukemic populations (median, 75% vs. 98%; p < 0.0001). When compared with CD33 and CD123, CD84 showed a similarly broad prevalence of expression across AML leukemic populations. Healthy bone marrow samples were additionally evaluated to characterize the physiological distribution of CD84 expression across normal hematopoietic populations and provide a framework for the assessment of CD84-targeted therapeutic strategies. Conclusions: Together with the available preclinical and clinical evidence, these findings support the continued evaluation of CD84-directed immunotherapies, including CAR T-cell therapy, in AML. Full article

(This article belongs to the Special Issue Advances in Immunotherapy for Acute Myeloid Leukemia)

► Show Figures

Figure 1

27 pages, 9851 KB

Open AccessReview

Ovarian Precancerous Lesions and Their Molecular Landscape: A Structured Scoping Review Focused on STIC and Related Precursors of Epithelial Ovarian Cancer

by Katarzyna Kwas-Sarnacka, Wiktoria Lisińska, Edward Koziróg, Kinga Stanek, Daniel Wolder, Maria Szubert and Jacek Wilczyński

Cancers 2026, 18(18), 3036; https://doi.org/10.3390/cancers18183036 (registering DOI) - 18 Sep 2026

Abstract

Ovarian cancer remains one of the deadliest gynecologic malignancies because of late-stage diagnosis, biological heterogeneity, and the lack of effective early detection strategies. Epithelial ovarian cancer (EOC) comprises several histotypes, including high-grade serous carcinoma (HGSC), low-grade serous carcinoma (LGSC), endometrioid ovarian carcinoma (ENOC), [...] Read more.

Ovarian cancer remains one of the deadliest gynecologic malignancies because of late-stage diagnosis, biological heterogeneity, and the lack of effective early detection strategies. Epithelial ovarian cancer (EOC) comprises several histotypes, including high-grade serous carcinoma (HGSC), low-grade serous carcinoma (LGSC), endometrioid ovarian carcinoma (ENOC), clear cell ovarian carcinoma (CCOC), and mucinous ovarian carcinoma (MOC), each with distinct molecular pathways and precursor lesions. In recent years, serous tubal intraepithelial carcinoma (STIC) has emerged as the principal precursor lesion of HGSC, supporting the fallopian tube origin paradigm of ovarian carcinogenesis. This structured scoping review summarizes current evidence on the molecular and cellular origins of epithelial ovarian cancer, with particular emphasis on precursor lesions, including p53 signatures, SCOUTs, STILs, cortical inclusion cysts, endometriosis-associated lesions, and borderline ovarian tumors. Particular attention is given to the molecular events that drive progression toward invasive carcinoma, including TP53 mutations, BRCA1/2 dysfunction, homologous recombination deficiency, chromosomal instability, telomere shortening, cell-cycle dysregulation, stemness-associated pathways, and inflammatory signaling. A structured literature search was conducted in PubMed/MEDLINE, Scopus, and Web of Science to identify studies published from 2000 to 2026 that addressed ovarian cancer precursor lesions, molecular pathogenesis, and early carcinogenic mechanisms. Articles were selected for relevance to epithelial ovarian carcinogenesis, precursor biology, and translational implications. Current evidence supports substantial biological heterogeneity among precursor lesions, particularly STICs, with only a subset likely to progress to invasive HGSC. Emerging molecular approaches, including genome-wide aneuploidy profiling and integrated genomic classifiers, may improve risk stratification and facilitate earlier detection of clinically significant precursor lesions. A better understanding of precursor biology may ultimately contribute to personalized prevention strategies and improved clinical outcomes in ovarian cancer. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Pathology Diagnosis of Gynecologic Cancers)

► Show Figures

Figure 1

34 pages, 3909 KB

Open AccessReview

Circulating microRNAs at the Interface of Obesity and Breast Cancer: From Molecular Machinery, Diagnostic Potential, and Therapeutic Perspectives

by Georgina Victoria-Acosta, Stephanie I. Núñez-Olvera, María Elizbeth Alvarez-Sánchez, Yarely M. Salinas-Vera and Jonathan Puente-Rivera

Cancers 2026, 18(18), 3035; https://doi.org/10.3390/cancers18183035 (registering DOI) - 18 Sep 2026

Abstract

Obesity influences breast cancer risk, progression, and therapeutic response through endocrine, inflammatory, metabolic, stromal, and vesicular mechanisms. Circulating and extracellular vesicle (EV)-associated microRNAs are attractive liquid biopsy candidates; however, in obesity-associated breast cancer, they should not be interpreted as tumor-only biomarkers. This narrative [...] Read more.

Obesity influences breast cancer risk, progression, and therapeutic response through endocrine, inflammatory, metabolic, stromal, and vesicular mechanisms. Circulating and extracellular vesicle (EV)-associated microRNAs are attractive liquid biopsy candidates; however, in obesity-associated breast cancer, they should not be interpreted as tumor-only biomarkers. This narrative review analyzes circulating/EV-miRNAs as mixed host–tumor signals and separates association-based biomarker evidence from functional EV-mediated transfer. We performed a narrative and integrative review of studies on miRNA biogenesis, circulating miRNA transport, EV biology, adipose tissue dysfunction, adipose-tumor communication, biomarker development, therapy response, and methodological reporting standards. The current literature is read along two independent axes: human relevance and source attribution, from non-breast models to obesity-stratified human cohorts, and mechanistic causality, from association only to EV-level function, miRNA-level function, and causality with rescue; clinical validation is treated as a separate qualifier rather than as the top of a single scale. For example, EV-let-7a in overweight/obese breast cancer patients mainly supports an obesity-stratified biomarker candidate. Breast adipose tissue-derived EV cargoes enriched in miR-155-5p, miR-10a-3p, and miR-30a-3p provide stronger functional support for metabolic reprogramming, whereas EV-associated miR-221/222 has mediator-level evidence in endocrine resistance but is not obesity specific. Conclusions: The main contribution of this review is an operational interpretation framework in which circulating miRNAs are evaluated according to probable source, evidence level, and clinical purpose. Future studies should report EV workflow quality, sample type, hemolysis and platelet control, normalization strategy, external validation, tumor subtype, and obesity phenotyping beyond BMI, including waist circumference or waist-to-hip ratio, insulin resistance, diabetes, menopausal status, and inflammatory markers. Full article

(This article belongs to the Special Issue Breast Cancer Microenvironment: Molecular Mechanisms and Therapeutic Targeting)

► Show Figures

Graphical abstract

20 pages, 4491 KB

Open AccessArticle

Somatic Mutation Profile in Normal Tissue Adjacent to Tumor in Colorectal Carcinoma Patients: Functional Effect on Gene Expression and Potential Implications for Precision Medicine

by Farzana Jasmine, Daniil Vasiljevs, Armando Almazan, Habibul Ahsan and Muhammad G. Kibriya

Cancers 2026, 18(18), 3034; https://doi.org/10.3390/cancers18183034 (registering DOI) - 18 Sep 2026

Abstract

Background: The somatic mutation (SM) profile of normal colon tissue in colorectal carcinoma (CRC) patients is not well-known. We examined (a) SMs in resected normal colonic tissue adjacent to tumors from non-metastatic CRC patients, (b) identified potentially malignant mutations, and (c) their functional [...] Read more.

Background: The somatic mutation (SM) profile of normal colon tissue in colorectal carcinoma (CRC) patients is not well-known. We examined (a) SMs in resected normal colonic tissue adjacent to tumors from non-metastatic CRC patients, (b) identified potentially malignant mutations, and (c) their functional effects and utility for precision medicine. Materials and Methods: Surgically resected fresh paired tumor and adjacent normal colon tissues from 61 patients were used as sources of tissue DNA. Whole blood (WB) DNA was used as a germline reference. Next-generation sequencing using a custom hybridization capture panel was performed on each. Differential gene expression was assessed and stratified by mutation status in normal tissue. Results: Compared to WB DNA, similar numbers of SMs were detected in tumor and adjacent normal colon tissue. Of all SMs found in adjacent tissue, more than 23% of those same mutations were also detected in the matched tumor. Of the 61 patients, 57 (93.4%) had at least one potentially malignant non-synonymous SM in their normal tissue. The most frequently involved genes were BRCA2 (67% of the patients), KMT2C (64%), DHFR (49%), APC (41%), MAP3K1 (41%), PIK3CA (39%), PTEN (39%), ARID1A (38%), and MSH6 (38%). The use of WB as a germline reference was important, as using only adjacent normal tissue as a reference caused false negatives for mutations shared between tumor and normal tissue. Mutation status in normal tissue was associated with differential gene expressions in matched tumors. APC mutations were associated with more marked down-regulation of APC, SLC26A3, SELENBP1, KRT20, and CXCL14, and more marked up-regulation of MMP1, MMP12, MTHFD1L and MTHFD2, the latter two suggesting the folate pathway as a potential therapeutic target. Conclusions: For the first time, we document a comprehensive SM profile of normal colon tissue adjacent to tumors in CRC patients and observe its functional effect on differential gene expression in matched tumor tissue to identify potential therapeutic applications in precision medicine. Full article

(This article belongs to the Special Issue Oncogenetics of Colorectal Cancer (2nd Edition))

► Show Figures

Figure 1

19 pages, 2170 KB

Open AccessArticle

Early Longitudinal Changes in Radiomic Tumor Heterogeneity Predict Progression-Free Survival in Advanced Non-Small Cell Lung Cancer

by Zachary Thompson, Junmin Whiting, Olyo Stringfield, Mahmoud Abdalah, Sebastian Viracacha, Jhanelle Gray, Andreas Saltos and Dung-Tsa Chen

Cancers 2026, 18(18), 3033; https://doi.org/10.3390/cancers18183033 (registering DOI) - 18 Sep 2026

Abstract

Radiomic features derived from longitudinal imaging offer a non-invasive approach to quantify tumor heterogeneity, but their integration with clinical variables in small cohorts remains methodologically challenging. We analyzed 23 patients with advanced non-small cell lung cancer (NSCLC) enrolled in a Phase I study [...] Read more.

Radiomic features derived from longitudinal imaging offer a non-invasive approach to quantify tumor heterogeneity, but their integration with clinical variables in small cohorts remains methodologically challenging. We analyzed 23 patients with advanced non-small cell lung cancer (NSCLC) enrolled in a Phase I study of pembrolizumab and vorinostat. Radiomic features were extracted from baseline and two-month follow-up computed tomography scans, aggregated to the patient level, and transformed into delta features representing early changes over time. A unified modeling framework was implemented using strict leave-one-out cross-validation (LOOCV), incorporating both radiomic and clinical variables. Within each training fold, outcome-guided feature screening was performed using elastic net penalized Cox regression, followed by category-aware principal component analysis and ridge-penalized Cox modeling. Model performance was evaluated using out-of-fold concordance indices for overall survival (OS) and progression-free survival (PFS). Radiomics-only models demonstrated moderate discrimination for OS (C-index 0.609) and favorable discrimination for PFS (C-index 0.770), whereas clinical-only models showed weaker performance (OS 0.605; PFS 0.571). The combined radiomics and clinical model demonstrated numerically higher discrimination without statistically distinguishable differences for OS (C-index 0.648) while maintaining favorable discrimination for PFS (C-index 0.718). Stable features were predominantly texture-based and included Laws filter and co-occurrence-derived metrics associated with spatial heterogeneity. In this exploratory analysis, early changes in radiomic features reflecting tumor heterogeneity suggest potential associations with survival outcomes in advanced NSCLC. Integration of radiomic and clinical variables showed trends toward improved performance for overall survival while maintaining favorable discrimination for progression-free survival. These findings support further investigation of longitudinal radiomic features as candidate imaging biomarkers in larger, independently validated cohorts. Full article

(This article belongs to the Section Cancer Biomarkers)

► Show Figures

Figure 1

13 pages, 1468 KB

Open AccessArticle

Circulating Tumor DNA (ctDNA) Clearance After Immune Checkpoint Inhibition (ICI) with Radiotherapy (RT) as a Prognostic Biomarker for Advanced Melanoma

by Alyssa K. Steimle, Amir M. Forati, Alice Y. Zhou, Trevor McCracken, Meena M. Hosny, Golbarg Rahimi, Janmesh D. Patel, Caroline Burkey, Jessica Caraway, Taylor Huppe, Andrew Wood, Madison S. Harris, Alexander Birbrair, Jose M. Ayuso, Deepak M. Sahasrabudhe, Fauzia Hollnagel, Gary C. Doolittle, Adam R. Burr, Nina S. Mathew, Gino K. In, Adrienne Victor and Vincent T. Ma Show full author list Hide full author list

Cancers 2026, 18(18), 3032; https://doi.org/10.3390/cancers18183032 (registering DOI) - 18 Sep 2026

Abstract

Background/Objectives: ctDNA is evolving as an important biomarker for prognostic assessment in advanced melanoma. However, the utility of ctDNA monitoring during concurrent ICI with RT remains incompletely explored. Methods: In this multicenter retrospective study, patients with unresectable stage III/IV melanoma treated with ICI [...] Read more.

Background/Objectives: ctDNA is evolving as an important biomarker for prognostic assessment in advanced melanoma. However, the utility of ctDNA monitoring during concurrent ICI with RT remains incompletely explored. Methods: In this multicenter retrospective study, patients with unresectable stage III/IV melanoma treated with ICI and palliative RT were identified. Patients had retrospectively collected, tumor-informed, exome-based, ctDNA monitoring within 3 months following RT. Results: A total of 50 patients treated with ICI and palliative RT were analyzed. Compared with ctDNA clearance, ctDNA detectable and increasing was associated with worse OS (adjusted HR 2.52, 95% CI 1.20–5.29; p = 0.015), whereas ctDNA detectable and decreasing was not significantly different from ctDNA clearance (adjusted HR 1.58, 95% CI 0.69–3.65; p = 0.282). One-year OS was 87.5% with persistently undetectable ctDNA, 83.3% for ctDNA clearance, 46.3% for detectable and decreasing ctDNA, and 21.4% for detectable and increasing ctDNA. In a multivariable analysis, detectable and increasing ctDNA was associated with worse OS compared with ctDNA clearance (HR 2.52, 95% CI, 1.20–5.29, p = 0.015). Conclusions: Among patients with advanced melanoma treated with ICI and palliative RT, ctDNA clearance is associated with significantly improved OS compared to patients with detectable and increasing ctDNA within 3 months following RT. Ongoing prospective studies are needed to understand the role of ctDNA in this population. Full article

(This article belongs to the Special Issue Melanoma Combination Therapy: New Horizons, Challenges and Clinical Breakthroughs)

► Show Figures

Figure 1

13 pages, 1368 KB

Open AccessArticle

External Validation of the ARCAD Nomogram in a Real-World Cohort with Stage 4 Colorectal Cancer

by James Yu, Jiannong Li, Michael J. Schell, Pablo Gonzalez Ginestet, John Raymond Zalcberg, R John Simes, Ian Marschner, Richard D. Kim and Katrin Marie Sjoquist

Cancers 2026, 18(18), 3031; https://doi.org/10.3390/cancers18183031 (registering DOI) - 18 Sep 2026

Abstract

Introduction: The ARCAD-CRC nomogram predicts 1-year survival in clinical trial populations with stage 4 colorectal cancer (CRC). This study evaluated its performance in a real-world cohort. Methods: Patients with stage 4 CRC were identified from the Flatiron database. A multivariable Cox proportional hazards [...] Read more.

Introduction: The ARCAD-CRC nomogram predicts 1-year survival in clinical trial populations with stage 4 colorectal cancer (CRC). This study evaluated its performance in a real-world cohort. Methods: Patients with stage 4 CRC were identified from the Flatiron database. A multivariable Cox proportional hazards model for overall survival was applied to fit the reduced model derived from the published full ARCAD nomogram, as some variables were unavailable in the database. Validation of the reduced model used C-index, while predictive performance was assessed using time-dependent ROC analysis and calibration in the Flatiron real-world cohort (FRWC). Results: A total 9710 patients, including 5740 deceased, were analyzed. The FRWC was older (64 vs. 62 years) and had poorer ECOG-PS (15% vs. 4% with ECOG 2+) compared to the ARCAD cohort. The reduced nomogram’s calibration was comparable to the full model (C-index 0.67 vs. 0.68). In the FRWC, the reduced nomogram showed good discrimination, with time-dependent AUROC at the 12-month time horizon of 0.741 (95% CI 0.729–0.753). Calibration plots indicated the reduced ARCAD-CRC nomogram performed quantitively well with a calibration slope of 1.010 (95% CI 0.966–1.054). The calibration intercept was −0.160 (95% CI −0.189, −0.131), indicating systematic underestimation of 1-year survival in the FRWC. The predicted and observed 1-year OS using the reduced ARCAD nomogram in the FRWC were 0.640 (95% CI 0.637, 0.644) and 0.694 (95% CI 0.684–0.703), respectively. Conclusions: Our findings show that the ARCAD-CRC nomogram is a useful tool for predicting 1-year survival in a real-world cohort. The observed underestimation of survival may be due to advances in CRC treatments, as the FRWC cohort (2013–2020) was collected later than the original ARCAD cohort (1997–2012). Full article

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

► Show Figures

Figure 1

19 pages, 2729 KB

Open AccessArticle

Tumor Inflammation Confounds Radiographic Determination of Extranodal Extension in HPV-Associated Head and Neck Squamous Cell Carcinoma

by Sri Vemulamanda, Yasine Mirmozaffari, Alan H. Zhao, Noman Khan, Wendell G. Yarbrough, Natalia Issaeva, Benjamin Y. Huang and Travis P. Schrank

Cancers 2026, 18(18), 3030; https://doi.org/10.3390/cancers18183030 (registering DOI) - 18 Sep 2026

Abstract

Background/Objectives: Pathologically identified extranodal extension (pENE) predicts outcome and guides the intensity of adjuvant therapy in HPV-associated HNSCC. ENE determined by imaging (iENE) is a criterion for upstaging HPV+ HNSCC in the AJCC Cancer Staging System, 9th edition; however, its prognostic value [...] Read more.

Background/Objectives: Pathologically identified extranodal extension (pENE) predicts outcome and guides the intensity of adjuvant therapy in HPV-associated HNSCC. ENE determined by imaging (iENE) is a criterion for upstaging HPV+ HNSCC in the AJCC Cancer Staging System, 9th edition; however, its prognostic value is less than that of pENE, varies between studies, and the correlation between pENE and iENE is less than optimal. This study explores biological characteristics of tumors that can decrease the predictive value of iENE. Methods: Pre-treatment CT scans from patients with HPV-associated HNSCC were evaluated for iENE status. RNA-Seq data from primary tumor samples were analyzed using edgeR v4.6.2 and transcriptional differences were categorized by ssGSEA. Machine learning was applied to refine gene expression changes associated with iENE and survival was analyzed with log-rank tests. Results: Recurrence-free survival did not differ between patients with and without iENE. Both ML-ENE status and enrichment for inflammatory signaling were associated with improved RFS (p < 0.01 and p < 0.0001). When stratified by the ML-ENE signature or the inflammatory signature, iENE status did not further separate outcomes, indicating that its prognostic information was largely captured by these gene sets. These stratified comparisons were exploratory and limited by subgroup size. Conclusions: These analyses suggest that tumor biology associated with an inflamed tumor microenvironment may confound determination of ENE by imaging and that accounting for tumors with inflammatory signaling could improve the correlation of iENE with outcomes. Full article

(This article belongs to the Special Issue Surgery and Clinical Outcomes in Head and Neck Squamous Cell Carcinoma)

► Show Figures

Figure 1

20 pages, 584 KB

Open AccessReview

Contemporary Multimodal Management of Cutaneous Malignancies: Surgery, Radiotherapy, Systemic Therapy, Molecular Targeting and Immunotherapy

by Dariusz Kowalczyk, Jolanta Jaworek, Andrzej Ciborek, Pawel Antoni Kolodziejski, Ewa Pruszyńska-Oszmałek and Hanna Krauss

Cancers 2026, 18(18), 3029; https://doi.org/10.3390/cancers18183029 (registering DOI) - 18 Sep 2026

Abstract

Background: The therapeutic management of cutaneous malignancies—cutaneous melanoma, cutaneous squamous-cell carcinoma (cSCC), basal-cell carcinoma (BCC) and Merkel-cell carcinoma (MCC)—has shifted toward multimodal, stage-adapted treatment integrating surgery, radiotherapy, molecularly targeted therapy and immune checkpoint inhibition. Methods: We conducted a structured narrative review with a [...] Read more.

Background: The therapeutic management of cutaneous malignancies—cutaneous melanoma, cutaneous squamous-cell carcinoma (cSCC), basal-cell carcinoma (BCC) and Merkel-cell carcinoma (MCC)—has shifted toward multimodal, stage-adapted treatment integrating surgery, radiotherapy, molecularly targeted therapy and immune checkpoint inhibition. Methods: We conducted a structured narrative review with a structured literature search of PubMed/MEDLINE, Scopus and Web of Science (January 2015–6 September 2026), prioritising current clinical practice guidelines, randomised controlled trials and phase II–III studies; landmark older trials were included separately. Synthesis: Surgery with adequate histological margins, including Mohs micrographic surgery where appropriate, remains definitive for localised disease. In resectable macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab with response-driven postoperative management improved event-free survival versus adjuvant nivolumab in NADINA. SWOG S1801 independently demonstrated an event-free-survival advantage for perioperative pembrolizumab over adjuvant-only pembrolizumab in resectable stage III–IV melanoma. In advanced melanoma, dual immune-checkpoint strategies and BRAF/MEK inhibition require patient-specific sequencing; in the European Union, nivolumab plus relatlimab is authorised for first-line advanced melanoma with tumour-cell PD-L1 expression <1%. In high-risk cSCC after surgery and radiotherapy, adjuvant cemiplimab improved disease-free survival. In advanced BCC, Hedgehog-pathway inhibitors remain the principal first systemic option, with anti-PD-1 therapy after HHI failure or intolerance. Clinical implications: Molecular testing should be indication-driven: BRAF V600 is a validated treatment-selecting biomarker, while broader NGS profiling (including NRAS, KIT, NF1, TERT and co-occurring alterations), PD-L1, tumour mutational burden and circulating tumour DNA have context-dependent, supportive or investigational roles. Conclusions: The major unresolved issues are optimal sequencing, response-adapted perioperative treatment, resistance, biomarker validation and treatment of transplant, frail and other under-represented populations. Full article

(This article belongs to the Section Cancer Therapy)

► Show Figures

Figure 1

12 pages, 4871 KB

Open AccessArticle

Standardized Upstream Processing of Ovarian Cancer Surgical Specimens for TIL-Oriented Cellular Workflows

by Anna Biernacka, Joanna Kacperczyk-Bartnik, Ewa Witkowska, Julia Foremniak, Mariusz Bidziński, Paweł Derlatka and Justyna Marynowska

Cancers 2026, 18(18), 3027; https://doi.org/10.3390/cancers18183027 (registering DOI) - 18 Sep 2026

Abstract

Background: Fresh ovarian cancer tissue is a demanding starting material for cellular workflows, particularly when the aim is to obtain tumor-derived suspensions suitable for further TIL-oriented procedures. In this study, we evaluated post-isolation cell concentration and viability in ovarian cancer specimens processed according [...] Read more.

Background: Fresh ovarian cancer tissue is a demanding starting material for cellular workflows, particularly when the aim is to obtain tumor-derived suspensions suitable for further TIL-oriented procedures. In this study, we evaluated post-isolation cell concentration and viability in ovarian cancer specimens processed according to a standardized mechanical–enzymatic protocol. Methods: Biological material was collected from 24 patients undergoing routine surgery for ovarian cancer or suspected advanced ovarian malignancy. After macroscopic assessment and exclusion of extensively necrotic tissue, 19 specimens were included in the final analysis. The cohort was dominated by high-grade serous ovarian carcinoma, which accounted for 15 of 19 analyzed cases. Tissue specimens varied markedly in mass, with a median processed tissue weight of 2.05 g and a range from 0.11 to 14.93 g. Results: The median final cell concentration was 8.10 × 10⁶ cells/mL, with values ranging from 6.40 × 10³ to 9.26 × 10⁸ cells/mL. Median viability was 80.8%, although individual results ranged widely from 2.3% to 98.7%. The calculated median concentration of viable cells was 6.17 × 10⁶ viable cells/mL. Tissue mass showed a moderate positive association with final cell concentration (Spearman’s rho = 0.50, p = 0.028), but not with viability. Conclusions: These findings show that standardized processing of ovarian cancer surgical specimens can generate cell suspensions suitable for post-isolation quality assessment, even when the input material is highly variable. The present study focused on early post-isolation quality-control readouts obtained after tumor dissociation and did not evaluate TIL expansion capacity, detailed TIL phenotype, or antitumor function. The wide range of final cell concentrations underlines the biological and practical heterogeneity of ovarian cancer tissue and supports the need for careful reporting of early tissue-processing parameters in TIL-oriented workflows. Full article

(This article belongs to the Special Issue Gynecological Cancer: Prevention, Diagnosis, Prognosis and Treatment (2nd Edition))

► Show Figures

Figure 1

20 pages, 3992 KB

Open AccessArticle

Payload-Free Epitope Imprinted Polymer Nanoparticles Selectively Targeting IL-13Rα2 and Inhibition of Diffuse Midline Glioma Cells

by Damla Ulker, Adem Ozleyen, Dmitry Pshezhetskiy, Elena Piletska, Salvador Macip, Nikolai A. Barlev and Sergey Piletsky

Cancers 2026, 18(18), 3028; https://doi.org/10.3390/cancers18183028 (registering DOI) - 17 Sep 2026

Abstract

Background/ Objectives: Diffuse midline gliomas (DMGs), including diffuse intrinsic pontine glioma (DIPG), present a significant medical challenge due to their aggressive nature and poor prognosis. Widespread overexpression of the interleukin-13 receptor subunit alpha-2 (IL-13Rα2) across gliomas makes it a promising therapeutic target. Method: [...] Read more.

Background/ Objectives: Diffuse midline gliomas (DMGs), including diffuse intrinsic pontine glioma (DIPG), present a significant medical challenge due to their aggressive nature and poor prognosis. Widespread overexpression of the interleukin-13 receptor subunit alpha-2 (IL-13Rα2) across gliomas makes it a promising therapeutic target. Method: Using epitope mapping through a molecular imprinting (EMMI) technique, we developed nanosized molecularly imprinted polymers (nanoMIPs) that specifically recognize different IL-13Rα2 domains. Results: Functional assays showed that nanoMIPs binding to the surface of IL-13Rα2 reduced glioma cell viability, while sparing non-tumor cells. Consistent with receptor-mediated interactions, these nanoMIPs were selectively accumulated onto glioma cells, a specificity validated using a reverse-epitope nanoMIP negative control (nanoMIP-1*). IL-13Rα2-specific nanoMIPs suppressed phosphorylation of ERK1/2, AKT, and STAT3, disrupting major survival pathways. Moreover, these nanoMIPs activated the pro-apoptotic caspase-3/7 pathway, confirming apoptosis induction. Conclusions: Our findings demonstrate that IL-13Rα2-specific nanoMIPs, without a pharmacological payload, exert strong anti-proliferative and pro-apoptotic effects on DMG cells. Collectively, nanoMIPs represent a robust, reproducible synthetic antibody nanoplatform for targeted therapies in cancer and other diseases characterized by cell-surface protein dysregulation. Full article

(This article belongs to the Section Methods and Technologies Development)

► Show Figures

Graphical abstract

16 pages, 1043 KB

Open AccessArticle

Integrin αvβ6 Expression in Parathyroid Adenomas and Adjacent Non-Neoplastic Parathyroid Tissue: Immunohistochemical Rationale for Integrin αvβ6-Targeted PET Imaging

by Amro Tuffaha, Wael Hananeh, Mario Liese, Dai Que Vu, Muin Tuffaha and Michael Starke

Cancers 2026, 18(18), 3026; https://doi.org/10.3390/cancers18183026 (registering DOI) - 17 Sep 2026

Abstract

Background: Accurate preoperative localization of hyperfunctioning parathyroid tissue is essential for focused parathyroid surgery; however, localization remains challenging in a subset of patients with small, ectopic, multiglandular, or conventionally occult lesions. ⁶⁸Ga-Trivehexin targets integrin αvβ6 and has shown promising clinical performance in [...] Read more.

Background: Accurate preoperative localization of hyperfunctioning parathyroid tissue is essential for focused parathyroid surgery; however, localization remains challenging in a subset of patients with small, ectopic, multiglandular, or conventionally occult lesions. ⁶⁸Ga-Trivehexin targets integrin αvβ6 and has shown promising clinical performance in primary hyperparathyroidism; however, the immunohistochemical distribution of the integrin αvβ6 in parathyroid adenomas and non-neoplastic parathyroid tissue remains insufficiently characterized. Methods: Integrin αvβ6 expression was assessed immunohistochemically in 56 surgically resected parathyroid adenomas. Adjacent morphologically non-neoplastic parathyroid tissue was available in 51 cases and served as a paired comparator. Only membranous staining was scored. Staining intensity was categorized as 0, 1+ (weak), 2+ (moderate), or 3+ (strong), and the percentage of cells at each intensity was recorded. A weighted integrin αvβ6 expression score was calculated as (1 ×% weak) + (2 ×% moderate) + (3 ×% strong), yielding a range of 0–300. Paired comparisons were performed, and correlations with adenoma dimensions were assessed. Results: Forty-five of 56 adenomas (80.4%) and 48 of 51 adjacent non-neoplastic samples (94.1%) met the predefined positivity criterion. The median integrin αvβ6-positive cell fraction and weighted score were 42.5% (interquartile range (IQR) 9.5–90.0%) and 60 (IQR, 10–140), respectively. The corresponding values in adjacent tissue were 50% (IQR, 20–80%) and 60 (IQR, 30–115), respectively. Neither the weighted score nor the total positive-cell fraction differed significantly in paired analyses (Wilcoxon p = 0.902 and p = 0.442, respectively). Categorical positivity also did not differ significantly (exact McNemar p = 0.065). Crucially, the distribution of staining intensity differed between the compartments: a strong (3+) component was present in 19/56 adenomas (33.9%), but in only 3/51 adjacent samples (5.9%). In exploratory paired analysis, the proportion of strongly stained cells was higher in adenomas (Wilcoxon p = 0.0015). Integrin αvβ6 expression was not significantly associated with adenoma dimension. Conclusions: Integrin αvβ6 is a common membranous phenotype in both parathyroid adenomas and adjacent non-neoplastic parathyroid tissue and therefore should not be regarded as adenoma-specific. Nevertheless, adenomas more frequently contain strongly integrin αvβ6-positive cell populations, indicating a redistribution of expression intensity rather than a simple increase in overall positivity or weighted expression. These findings provide tissue-level support for integrin αvβ6-targeted parathyroid imaging and offer a plausible histopathological framework for the encouraging clinical performance of ⁶⁸Ga-Trivehexin PET/CT. Prospective, lesion-matched studies integrating immunohistochemistry, PET metrics, lesion volume, operative findings, and histological confirmation are now required to validate these observations. Full article

(This article belongs to the Section Cancer Pathophysiology)

20 pages, 2557 KB

Open AccessArticle

Integrating Gold Nanoparticles with Brachytherapy: In Vitro Insights into Radiosensitization in Cervical Cancer

by Maria Anthi Kouri, Maria-Eleni Kalkou, Kalliopi Platoni, Nikos Kollaros, Kyveli Zourari, Marina Chalkia, George Patatoukas, Aris Spathis, Vassilis Kouloulias and Efstathios Efstathopoulos

Cancers 2026, 18(18), 3025; https://doi.org/10.3390/cancers18183025 (registering DOI) - 17 Sep 2026

Abstract

Background/Objectives: Cervical cancer treatment relies heavily on high-dose-rate (HDR) ¹⁹²Ir brachytherapy; however, therapeutic efficacy remains limited by tumor radioresistance and the inability to escalate dose without increasing toxicity to surrounding healthy tissues. The present study investigates the potential of gold nanoparticles (AuNPs) [...] Read more.

Background/Objectives: Cervical cancer treatment relies heavily on high-dose-rate (HDR) ¹⁹²Ir brachytherapy; however, therapeutic efficacy remains limited by tumor radioresistance and the inability to escalate dose without increasing toxicity to surrounding healthy tissues. The present study investigates the potential of gold nanoparticles (AuNPs) to enhance radiosensitivity under clinically relevant ¹⁹²Ir brachytherapy conditions through the combined action of physical dose amplification and radiobiological modulation. Particular emphasis is placed on the unique radiophysical interactions generated by the mixed gamma and secondary beta emissions of ¹⁹²Ir, which, in the presence of high atomic number nanoparticles, promote localized photoelectric absorption and the emission of low-range secondary electrons, including Auger electrons. The study further aims to determine how AuNPs size and post-irradiation temporal evolution influence radiation-induced cytotoxicity and apoptosis in cervical cancer cell lines, thereby providing a biologically representative model of nanoparticle-assisted brachytherapy. Methods: Clonogenic survival, dose enhancement factor (DEF), and apoptosis were evaluated following irradiation in the presence of 10 nm and 50 nm AuNPs in two independent biological experiments (n = 2). Results: A clear dose-dependent reduction in survival fraction and increase in apoptosis were observed in nanoparticle-treated groups compared with irradiation alone. Radiosensitization demonstrated strong size dependence, with 50 nm AuNPs producing the greatest enhancement, a finding that may reflect size-dependent differences in cellular internalization, intracellular distribution, and nanoscale energy deposition previously established in AuNP studies. Importantly, biological effects intensified at later post-irradiation intervals, demonstrating a sustained temporal evolution of the radiobiological response beyond the initial irradiation event, potentially involving oxidative and other delayed cellular stress mechanisms described in AuNP radiosensitization. Conclusions: These findings demonstrate the capacity of AuNPs to enhance the radiobiological response of cervical cancer cells to ¹⁹²Ir brachytherapy and identify nanoparticle size and post-irradiation time as important determinants of this effect. They therefore support AuNP-assisted brachytherapy as a promising strategy for further development toward biologically optimized radiotherapy capable of improving tumor response without escalation of the prescribed radiation dose. Full article

(This article belongs to the Special Issue Nanotechnology in Radiation Oncology)

29 pages, 16318 KB

Open AccessArticle

NCX2 Targeting as a Neuroprotective Strategy Against Oxaliplatin-Induced Peripheral Neurotoxicity

by Sara Di Girolamo, Chiara Invernizzi, Margherita Francesca Kraus, Elisa Ballarini, Alessio Malacrida, Mario Mauri, Virginia Rodriguez-Menendez, Stephen N. Housley and Paola Alberti

Cancers 2026, 18(18), 3024; https://doi.org/10.3390/cancers18183024 - 17 Sep 2026

Abstract

Background/Objectives: Oxaliplatin (OHP) is a key component of colorectal cancer chemotherapy, but OHP-induced peripheral neurotoxicity (OIPN) is a major dose-limiting adverse effect. OHP-related sodium-channel dysfunction could increase intracellular Na⁺ and sustain depolarization, conditions that may theoretically favor reverse-mode NCX activity, in [...] Read more.

Background/Objectives: Oxaliplatin (OHP) is a key component of colorectal cancer chemotherapy, but OHP-induced peripheral neurotoxicity (OIPN) is a major dose-limiting adverse effect. OHP-related sodium-channel dysfunction could increase intracellular Na⁺ and sustain depolarization, conditions that may theoretically favor reverse-mode NCX activity, in which the exchanger promotes Ca²⁺ entry rather than Ca²⁺ extrusion. This study evaluated whether NCX2 targeting could reduce OHP-induced sensory neuron injury. Methods: Primary mouse dorsal root ganglion neurons were exposed to OHP, with or without SEA0400 (NCX modulator) pretreatment or siRNA-mediated NCX2 knockdown. Neuronal viability, neurite elongation, live-cell morphology, NCX2 fluorescence, and lipid droplet accumulation were quantified. Results: OHP reduced neuronal survival and neurite elongation and induced stress-related morphological changes and lipid droplet accumulation. NCX2-associated fluorescence varied by neuronal subtype, dose, and time. SEA0400 and partial NCX2 knockdown attenuated selected injury endpoints, mainly under low-dose conditions. Conclusions: These findings suggest that NCX2 may be involved in selected OHP-induced sensory neuron injury endpoints and support further investigation of NCX2 as a potential preventive target. However, reverse-mode NCX activity, Na⁺/Ca²⁺ fluxes, NCX2 directionality, and translational relevance require direct validation. Full article

(This article belongs to the Special Issue Translational Insights into the Prevention and Treatment of Chemotherapy-Induced Peripheral Neuropathy: Integrating Mechanistic, Clinical and Therapeutic Advances)

► Show Figures

Figure 1

27 pages, 4906 KB

Open AccessReview

Developmental Sialylation in Neuroblastoma and Neural-Crest-Derived Tumors

by Laxmi Swami, Megha Sharma, Pracheta Janmeda, Punarvi Mandadapu, Fauzia Jamal, Pradeep Kumar, Karin M. Hardiman and Laura L. Stafman

Cancers 2026, 18(18), 3023; https://doi.org/10.3390/cancers18183023 - 17 Sep 2026

Abstract

Pediatric malignancies are often closely linked to developmental cell states, differentiation trajectories, and restricted developmental windows. This relationship is especially evident in neural-crest-derived tumors, where malignant cells may retain, remodel, or reacquire glycosylation programs that normally regulate embryonic migration and lineage maturation. Using [...] Read more.

Pediatric malignancies are often closely linked to developmental cell states, differentiation trajectories, and restricted developmental windows. This relationship is especially evident in neural-crest-derived tumors, where malignant cells may retain, remodel, or reacquire glycosylation programs that normally regulate embryonic migration and lineage maturation. Using a pediatric developmental perspective, we consider tumor-associated sialylation as potentially reflecting retention of the developmental cell-of-origin glycome, reacquisition during malignant cell state plasticity, or cancer-specific remodeling. Neuroblastoma provides the strongest evidence linking these mechanisms to tumor biology and therapy. Polysialylated NCAM can support migratory and plastic phenotypes, ganglioside biosynthesis is coupled to adrenergic-mesenchymal cell state through cell state-dependent regulation of glycosyltransferases including ST8SIA1, and the developmentally enriched ganglioside GD2 creates an actionable therapeutic vulnerability. Selected neural-crest-derived tumors that also occur outside childhood are included as they may help distinguish lineage-associated mechanisms from features specific to pediatric malignancy. We examine sialoglycan-Siglec immune regulation, emerging glycan-directed therapies, and approaches for resolving sialylation across developmental and malignant cell states. This framework argues that pediatric neural-crest-derived tumors do not simply recapitulate embryonic glycosylation but selectively retain, remodel, or reacquire developmental sialylation programs that can influence plasticity, migration, immune evasion, and therapeutic response. Full article

(This article belongs to the Section Pediatric Oncology)

► Show Figures

Figure 1

12 pages, 4313 KB

Open AccessCommunication

Primary Pap Smear Cytological Diagnosis of ASC-US: HR-HPV Genotyping and Follow-Up of HPV-Positive Patients

by Tiziana Pisani, Maria Cenci and Ettore Domenico Capoluongo

Cancers 2026, 18(18), 3022; https://doi.org/10.3390/cancers18183022 - 17 Sep 2026

Abstract

ASC-US refers to cytological abnormalities suggestive of squamous intraepithelial lesions (SILs) that are qualitatively or quantitatively insufficient for a definitive diagnosis. In addition to HPV infection, which is the etiological agent of preneoplastic and neoplastic cervical lesions, several other conditions may induce cytological [...] Read more.

ASC-US refers to cytological abnormalities suggestive of squamous intraepithelial lesions (SILs) that are qualitatively or quantitatively insufficient for a definitive diagnosis. In addition to HPV infection, which is the etiological agent of preneoplastic and neoplastic cervical lesions, several other conditions may induce cytological changes classified as ASC-US, including inflammation, atrophy with degeneration, hormonal effects, and technical artifacts. The aim of this study was to evaluate the incidence of primary Pap tests diagnosed as ASC-US that also tested positive for HR-HPV genotypes. In this retrospective study, 6181 primary Pap tests collected between 21 July 2021 and 9 January 2024 from the Roma 2 Local Health District were reviewed. ThinPrep containers (Hologic) were used for liquid-based cytology, allowing both cytological examination and molecular testing for HR-HPV detection. The Anyplex™ II HR HPV Detection assay (Seegene) was used for the identification, by real-time PCR, of 14 HR-HPV genotypes (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68). Among the 6181 Pap tests analyzed, 202 cases (3.3%) were diagnosed as ASC-US and subsequently underwent HR-HPV molecular testing. Of these, 107 cases (53.0%) were negative, while 95 (47.0%) were positive for HR-HPV. In HPV-positive samples, single-genotype infections were detected in 65 cases (68.4%), while multiple genotypes were identified in 30 cases (31.6%). A total of 135 HR-HPV genotypes were detected. HPV 16 was identified in nine cases (6.7%), HPV 18 in six (4.4%), HPV 31 in nine (6.7%), HPV 33 in five (3.7%), HPV 35 in two (1.5%), HPV 39 in 10 (7.4%), HPV 45 in four (3.0%), HPV 51 in 20 (14.8%), HPV 52 in seven (5.2%), HPV 56 in 15 (11.1%), HPV 58 in eight (5.9%), HPV 59 in 17 (12.6%), HPV 66 in 12 (8.9%), and HPV 68 in 11 cases (8.1%). Our findings indicate that approximately half of ASC-US diagnoses are associated with HR-HPV infection. Interestingly, the detected viral genotypes mainly belonged to less common HR-HPV strains. HR-HPV testing following an ASC-US cytological diagnosis is essential for colposcopy triage, while extended genotyping enables the monitoring of genotype persistence over time, a key factor in the development of cervical dysplastic and neoplastic lesions. Full article

(This article belongs to the Special Issue Feature Papers in Section “Infectious Agents and Cancer”)

► Show Figures

Figure 1

Journal Description

Cancers

Latest Articles

Journal Menu

Journal Browser

Highly Accessed Articles

Latest Books

E-Mail Alert

News

Topics

Conferences

Special Issues

Topical Collections

Further Information

Guidelines

MDPI Initiatives

Follow MDPI