Cancers

21 pages, 1385 KB

Open AccessArticle

Clinical and LAT1 Biomarker Correlates of Clinical Benefit from Nanvuranlat (JPH203) in Advanced Biliary Tract Cancer: A Post Hoc Analysis

by Eric K. Rowinsky, Ghassan K. Abou-Alfa, Junji Furuse, Makoto Ueno, Masafumi Ikeda, Hiroko Tabuchi, Kazuo Sekiguchi and Michael Szarek

Cancers 2026, 18(15), 2492; https://doi.org/10.3390/cancers18152492 (registering DOI) - 4 Aug 2026

Abstract

Background/Objectives: This exploratory post hoc analysis evaluated clinical and biomarker-defined treatment effects and accumulated nanvuranlat exposure in advanced biliary tract cancer (BTC). Methods: BICR-assessed progression-free survival (PFS) and overall survival (OS) were analyzed in the randomized Phase 2 full analysis set of 104 [...] Read more.

Background/Objectives: This exploratory post hoc analysis evaluated clinical and biomarker-defined treatment effects and accumulated nanvuranlat exposure in advanced biliary tract cancer (BTC). Methods: BICR-assessed progression-free survival (PFS) and overall survival (OS) were analyzed in the randomized Phase 2 full analysis set of 104 patients (nanvuranlat, n = 69; placebo, n = 35). Formal treatment-by-subgroup interaction tests assessed prior primary tumor resection status, LAT1 expression, and anatomical BTC subtype, evaluated both as a four-category variable and as pooled IHC/EHC/GBC versus AVC. Accumulated-exposure analyses pooled Phase 1 and Phase 2 data and were descriptive. Results: Median PFS was 46 versus 43 days (HR, 0.557; 95% CI, 0.344–0.903), and median OS was 155 versus 144 days (HR, 0.875; 95% CI, 0.551–1.390). Interaction tests were nominally significant for resection status with OS (p = 0.028) and for the four-category BTC-subtype variable with PFS (global p = 0.035), but not for LAT1 expression (PFS, p = 0.157; OS, p = 0.586) or pooled IHC/EHC/GBC versus AVC (PFS, p = 0.511; OS, p = 0.208). The binary and four-category subtype analyses addressed different hypotheses and were not considered contradictory. Higher accumulated-exposure quartiles showed numerically longer survival, but these analyses were susceptible to immortal-time bias, reverse causation, and time-dependent confounding. Conclusions: Nanvuranlat was associated with a lower hazard of progression or death than placebo, whereas the OS estimate was less conclusive. The subgroup and exposure findings remain exploratory but support prospective evaluation of resection status, anatomical subtype, and LAT1 expression. Full article

(This article belongs to the Section Cancer Therapy)

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2 pages, 317 KB

Open AccessCorrection

Correction: Gresseau et al. A Signaling Crosstalk Links SNAIL to the 37/67 kDa Laminin-1 Receptor Ribosomal Protein SA and Regulates the Acquisition of a Cancer Stem Cell Molecular Signature in U87 Glioblastoma Neurospheres. Cancers 2022, 14, 5944

by Loraine Gresseau, Marie-Eve Roy, Stéphanie Duhamel and Borhane Annabi

Cancers 2026, 18(15), 2491; https://doi.org/10.3390/cancers18152491 (registering DOI) - 4 Aug 2026

Abstract

In the original publication [...] Full article

(This article belongs to the Section Molecular Cancer Biology)

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18 pages, 4968 KB

Open AccessSystematic Review

Fertility-Sparing Management of Atypical Hyperplasia and Endometrial Cancer from the Perspective of Molecular and Hormonal Profiles: A Meta-Analysis-Driven Framework

by Myriam Jerbaka, Radwa Hablase, Alexander Shushkevich, Martin Koskas, Christopher El Hadi, Nadine El Kassis, Wissam Arab, David Atallah and Jayanta Chatterjee

Cancers 2026, 18(15), 2490; https://doi.org/10.3390/cancers18152490 (registering DOI) - 4 Aug 2026

Abstract

Background/Objectives: The prognostic and predictive values of biomarkers in fertility-sparing management of atypical hyperplasia (AH) and endometrial cancer (EC) remain ill-defined. We aimed to identify the impact of tumour profiles on oncologic and reproductive outcomes to inform clinical decision-making. Methods: We [...] Read more.

Background/Objectives: The prognostic and predictive values of biomarkers in fertility-sparing management of atypical hyperplasia (AH) and endometrial cancer (EC) remain ill-defined. We aimed to identify the impact of tumour profiles on oncologic and reproductive outcomes to inform clinical decision-making. Methods: We conducted a systematic review and meta-analysis by searching MEDLINE, PubMed, Embase, Cochrane Library, Scopus, Google Scholar, and ClinicalTrials.gov, up to July 2026. We intended to include comparative studies or clinical trials, in English or French, assessing outcomes according to molecular or hormonal profiles in reproductive-aged women diagnosed with AH or EC. The primary outcome was the best overall complete remission (CR). Pooled odds ratios (ORs) were calculated using a random-effects model with logit transformation and restricted maximum likelihood estimation. Risk of bias was assessed using the Newcastle–Ottawa scale (NOS). The study protocol was registered in PROSPERO (CRD42025632885). Results: Eighteen retrospective studies comprising 965 patients were included. No specific molecular profile (NSMP) tumours demonstrated significantly higher odds of CR (OR 2.04, 95% CI 1.33–3.11). p53-abnormal (p53abn) and deficient mismatch repair (dMMR) tumours were significantly less likely to achieve CR compared to NSMP (OR 3.87, 95% CI 1.80–8.29 and OR 2.48, 95% CI 1.44–4.29, respectively). POLE-mutated (POLEmut) tumours showed CR comparable to NSMP (OR 1.39, 95% CI 0.60–3.24). Progesterone receptor (PR) positivity was strongly associated with CR (OR 7.73, 95% CI 2.77–21.63). Conclusions: NSMP and PR-positivity represented a favourable prognosis and potential prediction of CR. POLEmut tumours demonstrated CR rates comparable to NSMP, whereas p53abn and dMMR demonstrated unfavourable outcomes. These findings support a biologically tailored approach to patient selection for fertility-sparing management. Full article

(This article belongs to the Special Issue Advancements in “Cancer Biomarkers” for 2025–2026)

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25 pages, 288 KB

Open AccessArticle

Public Awareness of Cancer Symptoms, Risk Factors, and Prevention Strategies Among Adults in Poland: A Nationwide Cross-Sectional Survey

by Kuba Sękowski, Mateusz Jankowski, Stanisław Surma, Agata Olearczyk, Wojciech S. Zgliczyński and Justyna Grudziąż-Sękowska

Cancers 2026, 18(15), 2489; https://doi.org/10.3390/cancers18152489 - 3 Aug 2026

Abstract

Background/Objectives: Cancer remains a major public health challenge, and public awareness of warning signs, risk factors, and prevention methods is essential for early detection and primary prevention. This study aimed to assess cancer knowledge among adults in Poland and identify sociodemographic factors [...] Read more.

Background/Objectives: Cancer remains a major public health challenge, and public awareness of warning signs, risk factors, and prevention methods is essential for early detection and primary prevention. This study aimed to assess cancer knowledge among adults in Poland and identify sociodemographic factors associated with self-reported awareness. Methods: A nationwide cross-sectional survey was conducted in January 2026 among 1087 adults in Poland using computer-assisted web interviewing (CAWI). Non-probability quota sampling was applied based on sex, age, and place of residence. Results: Only 12.7% of respondents reported rather high or very high cancer knowledge. The most frequently recognized warning sign was a lump, mass, or thickening (66.9%). Tobacco use (64.9%) and genetic or familial predisposition (61.8%) were the most commonly identified risk factors, whereas 41.9% recognized overweight or obesity as a cancer risk factor. Smoking cessation and participation in cancer screening programs were each identified as preventive measures by 57.5%. However, 20.8% incorrectly believed that dietary supplements protect against cancer, and 16.2% endorsed “detox” beverages as cancer-preventive. In multivariable analysis, higher education (aOR: 1.67; 95% CI: 1.13–2.46), occupational activity (aOR: 1.56; 95% CI: 1.02–2.37), personal history of cancer (aOR: 4.27; 95% CI: 2.75–6.64), and family history of cancer (aOR: 1.85; 95% CI: 1.25–2.73) were independently associated with higher self-reported cancer knowledge. Conclusions: The findings indicate insufficient cancer awareness among the surveyed sample of Polish adults, particularly among men, younger adults, and individuals with lower educational attainment. Targeted educational initiatives may help improve knowledge of cancer symptoms, risk factors, and prevention strategies. Full article

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

29 pages, 522 KB

Open AccessReview

Predictive Biomarkers of Metronomic Chemotherapy Response in Solid Tumors: Chasing an Elusive Signal

by Piotr Jan Wysocki, Łukasz Kwinta and Ewa Wysocka

Cancers 2026, 18(15), 2488; https://doi.org/10.3390/cancers18152488 - 3 Aug 2026

Abstract

Background: Metronomic chemotherapy (MCT), understood as continuous, low-dose cytotoxic administration without prolonged drug-free intervals, has become an established strategy in several solid tumors, acting primarily through antiangiogenic, immunomodulatory, and direct cytostatic mechanisms rather than replication-dependent cytotoxicity. Despite an expanding evidence base, including positive [...] Read more.

Background: Metronomic chemotherapy (MCT), understood as continuous, low-dose cytotoxic administration without prolonged drug-free intervals, has become an established strategy in several solid tumors, acting primarily through antiangiogenic, immunomodulatory, and direct cytostatic mechanisms rather than replication-dependent cytotoxicity. Despite an expanding evidence base, including positive randomized trials, validated predictive biomarkers of response remain unavailable. Methods: We searched PubMed/MEDLINE, Embase, and ClinicalTrials.gov (January 2000 to July 2026) for phase II/III randomized trials, prospective cohorts, and selected retrospective analyses of MCT in breast cancer, head and neck squamous cell carcinoma, NSCLC, and mCRC, and extracted biomarker data from embedded translational substudies of eligible trials. Results: In breast cancer, phase III SYSUCC-001 (adjuvant metronomic capecitabine, improved DFS in TNBC) and MECCA (metronomic capecitabine plus aromatase inhibitor in HR+/HER2− disease) provide the strongest evidence, supported by randomized phase II data for the VEX regimen (METEORA-II) and MCT-anti-PD-1 combinations. TEMPO LUNG established metronomic vinorelbine as effective in platinum-unfit NSCLC, while CAIRO3 confirmed metronomic capecitabine–bevacizumab as an effective mCRC maintenance therapy. Most recently, the phase III TMC-I trial extended positive randomized evidence to head and neck cancer. Candidate biomarkers span angiogenic, immune, tumor proliferative, molecular, pharmacodynamic cytokine, on-treatment clinical (adverse-event-based), and gut–microbiome domains, with FOXC1, circulating endothelial cell kinetics, VEGF pathway markers, and regulatory T-cell dynamics among the most promising; however, none has been prospectively validated in a dedicated confirmatory trial. Conclusions: MCT has moved from empirical use to an evidence-based strategy across multiple tumor types, but the lack of validated predictive biomarkers limits informed patient selection. Future trials should incorporate biomarker-driven designs, particularly FOXC1, endothelial cell kinetics, and immune profiling as co-primary objectives. Defining an MCT-sensitive biological phenotype remains the key translational challenge for the field. Full article

(This article belongs to the Special Issue From Metronomic Chemotherapy to Time-Optimized Cancer Treatments)

26 pages, 987 KB

Open AccessReview

Predictive Biomarkers of Systemic Therapy Response in Cutaneous Melanoma

by U Sin Wong and Dajiang Guo

Cancers 2026, 18(15), 2487; https://doi.org/10.3390/cancers18152487 - 3 Aug 2026

Abstract

Late-stage cutaneous melanoma management has already evolved into systemic therapy thanks to the fast development of novel targeted inhibitors and immune checkpoint blockers. Therefore, a reliable prediction of systemic therapy response became crucial for making a personalised management plan for melanoma patients. Although [...] Read more.

Late-stage cutaneous melanoma management has already evolved into systemic therapy thanks to the fast development of novel targeted inhibitors and immune checkpoint blockers. Therefore, a reliable prediction of systemic therapy response became crucial for making a personalised management plan for melanoma patients. Although there are multiple biomarkers already available, the overall predictive confidence remains low due to heterogeneous responses among patients. Therefore, novel solid predictive biomarkers are still greatly needed. With the development of new technologies and artificial intelligence, new predictive models are being proposed and generated. In this review, we thoroughly evaluated the established biomarkers that are already in use for clinical practice. In addition, we proposed the emerging new markers with great potential by critically reviewing the literature. Furthermore, we proposed a future framework for making a tailored clinical management plan for melanoma patients. Full article

(This article belongs to the Special Issue Clinical, Immune, and Microbial Markers of Response to Systemic Therapy in Skin Cancer)

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31 pages, 657 KB

Open AccessReview

Postbiotics Against Breast Cancer: A Narrative Review Bridging Preclinical Evidence with Potential Clinical Application

by Chiara Luongo, Roberta Di Santillo, Alessia Cadavere, Franca Oglio, Laura Pisapia, Alessia Gaeta, Chiara Scocco, Juan Luis López-Cánovas, Marco Michelini, Monia De Aloe, Anna Lintura, Saranya Chumsri and Roberto Berni Canani

Cancers 2026, 18(15), 2486; https://doi.org/10.3390/cancers18152486 - 3 Aug 2026

Abstract

Breast cancer is the most common cancer in women, causing more than 600,000 deaths every year. The human microbiome is increasingly recognized as a key regulator of cancer initiation, progression, and therapeutic response. Postbiotics—defined as non-viable microbial cells and/or their structural components and [...] Read more.

Breast cancer is the most common cancer in women, causing more than 600,000 deaths every year. The human microbiome is increasingly recognized as a key regulator of cancer initiation, progression, and therapeutic response. Postbiotics—defined as non-viable microbial cells and/or their structural components and metabolites that confer health benefits—are emerging as promising and safer alternatives to live probiotics in oncology. This review provides a comprehensive mechanistic overview of the potential role of postbiotics against cancer, with a specific focus on breast cancer. Preclinical evidence demonstrates that selected postbiotics exert dose- and time-dependent anticancer effects against multiple breast cancer subtypes by modulating key oncogenic pathways (such as PI3K/AKT and NF-κB) and inducing epigenetic regulation through histone deacetylase inhibition. Beyond direct effects on tumor cell proliferation and apoptosis, postbiotics influence the breast cancer microenvironment by reshaping cytokine networks, suppressing pro-metastatic inflammation, and enhancing antitumor immune responses through the activation of NK cells and T cells. We also provide emerging links between microbiome composition, estrobolome activity, and breast cancer subtype-specific biology. Despite these encouraging findings, the clinical translation of postbiotics in oncology remains limited. Currently, only one registered clinical trial investigates postbiotics in the oncology setting (melanoma), and no clinical trials have specifically evaluated postbiotics in breast cancer patients. This highlights a substantial translational gap between preclinical evidence and clinical application. Accordingly, well-designed, tumor-specific clinical trials are urgently needed to validate the safety, efficacy, and therapeutic potential of postbiotics as novel strategies in personalized breast cancer management. Full article

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

4 pages, 178 KB

Open AccessReply

Reply to Jin, H. Comment on “Yoon et al. Heterogeneous Colorectal Cancer Risk in Women with Metabolic Dysfunction-Associated Steatotic Liver Disease by Age, Lipid, and Waist-Circumference: A Nationwide Cohort Study. Cancers 2026, 18, 125”

by Chang Ik Yoon, Hye Sun Lee, Soyoung Jeon, Jin Ah Lee, Dooreh Kim and Jong Min Lee

Cancers 2026, 18(15), 2485; https://doi.org/10.3390/cancers18152485 - 3 Aug 2026

Abstract

We thank Jin [...] Full article

15 pages, 1724 KB

Open AccessArticle

Clinical Characteristics and Prognostic Analysis of Extramedullary Disease in Multiple Myeloma: A 15-Year Retrospective Cohort Study

by Jingliang Zhao, Qirui Bai, Qile Qiu, Jiaying Song, Siyu Kong, Kun Zhu, Yifan Zhang, Shengtao Li, Yanping Ma, Lin Zhang and Xiaoqi Qin

Cancers 2026, 18(15), 2484; https://doi.org/10.3390/cancers18152484 - 3 Aug 2026

Abstract

Background: Extramedullary disease (EMD) in multiple myeloma (MM) is associated with poor prognosis, yet the clinical distinctions between bone-related EMD (bEMD) and soft tissue-associated EMD (sEMD) remain incompletely characterized. This study aimed to compare the clinical features and outcomes of bEMD versus sEMD [...] Read more.

Background: Extramedullary disease (EMD) in multiple myeloma (MM) is associated with poor prognosis, yet the clinical distinctions between bone-related EMD (bEMD) and soft tissue-associated EMD (sEMD) remain incompletely characterized. This study aimed to compare the clinical features and outcomes of bEMD versus sEMD and to develop a simple pre-treatment risk stratification tool using baseline clinical parameters. Methods: We retrospectively analyzed 118 patients with MM and EMD treated at a single center from 2011 to 2025, including 72 bEMD and 46 sEMD cases. Baseline characteristics, laboratory parameters, cytogenetic abnormalities, and survival outcomes were compared. Results: Patients with sEMD had significantly higher serum β2-microglobulin (β2-MG) levels (6.4 mg/L vs. 4.5 mg/L, p = 0.007) and a higher proportion of relapsed/refractory disease (41.3% vs. 15.3%, p = 0.002) compared to bEMD. Median progression-free survival (PFS) and overall survival (OS) were markedly shorter in patients with sEMD than in those with bEMD (PFS: 12.0 vs. 29.0 months, p < 0.001; OS: 25.0 vs. 67.0 months, p = 0.009). Multivariate analysis identified thrombocytopenia (PLT < 100 × 109/L), elevated β2-MG, multisite extramedullary involvement, and TP53 deletion as independent adverse prognostic factors. A risk scoring system incorporating β2-MG (0–2 points), thrombocytopenia (1 point), and multisite involvement (1 point) stratified patients into low-risk (0–2 points) and high-risk (3–4 points) groups with significantly different PFS (27.0 vs. 10.0 months, p < 0.001) and OS (54.0 vs. 22.0 months, p = 0.008). Conclusions: sEMD represents a more aggressive subtype of MM with inferior outcomes. The proposed risk score, based on routinely available clinical parameters, effectively identifies high-risk patients at initial diagnosis and may guide individualized treatment strategies. Full article

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

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21 pages, 1401 KB

Open AccessArticle

Conversion Surgery for Advanced Gastric Cancer According to First-Line Treatment Strategy: A Single-Center Experience with a Focused Review of the Literature

by Jun Kinoshita, Kenta Doden, Kengo Hayashi, Ryota Matsui, Hiroto Saito, Megumi Watanabe, Toshikatsu Tsuji, Daisuke Yamamoto and Noriyuki Inaki

Cancers 2026, 18(15), 2483; https://doi.org/10.3390/cancers18152483 - 2 Aug 2026

Abstract

Background/Objectives: First-line therapy for advanced gastric cancer (AGC) has evolved from cytotoxic chemotherapy to HER2-targeted and immune checkpoint inhibitor (ICI)-based regimens, yet conversion surgery (CS) outcomes across these strategies remain poorly characterized. We describe CS outcomes and prognostic factors by first-line strategy at [...] Read more.

Background/Objectives: First-line therapy for advanced gastric cancer (AGC) has evolved from cytotoxic chemotherapy to HER2-targeted and immune checkpoint inhibitor (ICI)-based regimens, yet conversion surgery (CS) outcomes across these strategies remain poorly characterized. We describe CS outcomes and prognostic factors by first-line strategy at a single center. Methods: We retrospectively reviewed 187 patients with AGC who began first-line therapy from 2011, grouped as cytotoxic (CTX, n = 127), HER2-targeted (trastuzumab, n = 21), or ICI (n = 39). CS was defined as resection after response, including an extended oligometastatic definition (n = 74). Overall survival (OS) was measured from chemotherapy initiation, and prognostic factors were assessed by Cox regression. Results: Median OS was 14.8, 18.9, and 20.9 months for CTX, trastuzumab, and ICI, respectively (p = 0.048). CS rates were comparable (41%, 33%, and 38%; p = 0.794). Pathological response was more pronounced after trastuzumab/ICI (grade 3 and ypStage 0/1; both p < 0.001). Among CS cases, R0 resection (hazard ratio [HR] 0.31) and trastuzumab/ICI therapy (HR 0.37) were independent favorable factors, whereas high inflammatory–nutritional indices (NLR, CAR) were independent poor prognostic factors. OS was comparable between oligometastatic and conventional CS (p = 0.324). Conclusions: In this hypothesis-generating study, response depth tracked tumor biology, whereas survival was determined by R0 resection, targeted/ICI therapy, and host inflammatory–nutritional status—two largely dissociable axes informing biology- and host-based selection of CS candidates for prospective testing. Full article

(This article belongs to the Special Issue Current Status and Prospects of Multimodal Treatment for Upper Gastrointestinal Cancer)

29 pages, 65496 KB

Open AccessArticle

Multi-Omics Identification of Vasculogenic Mimicry-Associated Molecular Subtypes in Hepatocellular Carcinoma for Prognostic Stratification and Therapeutic Response Prediction

by Yuting Tao, Shuzhen Liao, Tao Liu, Ruyi Lai, Chao Feng and Qiuyan Wang

Cancers 2026, 18(15), 2482; https://doi.org/10.3390/cancers18152482 - 2 Aug 2026

Abstract

Objective: Vasculogenic mimicry (VM), characterized by the de novo formation of microvascular-like channels derived from aggressive tumor cells without involving traditional endothelial cells, is a pivotal pathological hallmark driving extreme invasiveness and dismal prognosis in hepatocellular carcinoma (HCC). This study aimed to establish [...] Read more.

Objective: Vasculogenic mimicry (VM), characterized by the de novo formation of microvascular-like channels derived from aggressive tumor cells without involving traditional endothelial cells, is a pivotal pathological hallmark driving extreme invasiveness and dismal prognosis in hepatocellular carcinoma (HCC). This study aimed to establish a VM-based molecular subtyping system and systematically characterize its associated biological features, thereby providing a potential framework for individualized prognostic assessment and treatment decision-making in HCC. Methods: We integrated curated VM-associated gene sets with single-cell RNA sequencing data to identify malignant epithelial cell-enriched VM-associated candidate genes. Subsequently, univariate Cox regression, LASSO-Cox regression, and multivariate Cox regression were sequentially performed to identify six prognostic VM-related genes: HSPA9, TGFA, MAD2L1, PROM1, AGXT, and GCGR. HCC patients were stratified into VM, Mixed-VM, and Non-VM subtypes according to VM scores. Kaplan–Meier survival analysis, time-dependent ROC analysis, and Cox regression were used to assess prognostic performance. The biological features of the classification system were evaluated using bulk transcriptomic cohorts, spatial transcriptomics, Cytometry by Time-of-Flight (CyTOF), metabolomics, lipidomics, somatic mutation and copy number alteration analyses, and treatment-related HCC cohorts. Results: The VM score-based classification stratified HCC patients into three molecular subtypes with distinct prognostic and biological characteristics. Patients classified as the VM subtype had significantly poorer overall survival than those classified as Mixed-VM or Non-VM subtypes, and this prognostic pattern was validated across independent cohorts. Multi-omics analyses showed that the VM subtype was associated with YAP-TAZ-TEAD-related transcriptional programs, stemness/proliferation-related features, immunoregulatory and exhaustion-like tumor microenvironmental characteristics, and distinct metabolic and lipidomic alterations involving modified nucleosides, keto acid-related metabolites, cholesteryl esters, and sphingolipid-related species. Spatial transcriptomics revealed focal enrichment of VM-score-high regions and their association with YAP-TAZ-TEAD and immune checkpoint-related signatures. In orthotopic HCC mouse models, YAP1 overexpression increased PAS⁺/CD34⁻ VM-like structures, whereas verteporfin treatment reduced these structures. In two treatment-related cohorts, the Non-VM subtype showed higher response rates to sorafenib and transarterial chemoembolization (TACE) than the VM subtype. Connectivity Map (CMap)-based computational drug prioritization and molecular docking analysis prioritized ivermectin as a candidate compound; however, its antitumor activity requires further experimental validation. Conclusions: This study establishes a VM score-based molecular classification framework for HCC and identifies VM-subtype-associated prognostic, spatial, immune, metabolic, genomic, and therapeutic features. These findings provide a candidate framework for molecular risk stratification and subtype-guided therapeutic exploration in HCC. Full article

(This article belongs to the Section Cancer Therapy)

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14 pages, 2228 KB

Open AccessArticle

Interpreting Circulating Bile Acid Profiles in Pancreatic Cancer: The Role of Cholestasis and Its Management

by Elisa Danese, Alessandro Esposito, Matteo De Pastena, Fabio Del Ben, Gabriella Lionetto, Alessia Scirpoli, Mariateresa Rizza, Roberto Salvia and Giuseppe Lippi

Cancers 2026, 18(15), 2481; https://doi.org/10.3390/cancers18152481 - 2 Aug 2026

Abstract

Background: Circulating bile acid (BA) profiles are increasingly explored in pancreatic cancer, although their interpretation is often complicated by biliary obstruction and its clinical management. In this study, we characterized plasma BA profiles in pancreatic ductal adenocarcinoma (PDAC) and assessed the relative contributions [...] Read more.

Background: Circulating bile acid (BA) profiles are increasingly explored in pancreatic cancer, although their interpretation is often complicated by biliary obstruction and its clinical management. In this study, we characterized plasma BA profiles in pancreatic ductal adenocarcinoma (PDAC) and assessed the relative contributions of tumor localization, histological subtype, cholestasis, and cholestasis-related interventions. Methods: Plasma BAs were quantified by LC-MS/MS in patients with PDAC of the pancreatic head (hPDAC, n = 132), PDAC of the body-tail (tPDAC, n = 42), and non-PDAC tumors of the pancreatic head (hnonPDAC, n = 34). BA concentrations and derived ratios were log-transformed and standardized, and their associations with bilirubin were examined using multivariable linear models, LOESS, and multivariate longitudinal analyses. Results: UDCA therapy was associated with markedly increased circulating UDCA, higher total BA concentrations, and enrichment of secondary BA species. Direct bilirubin explained more variability in BA composition than binary jaundice classification and showed a non-linear association with BA remodeling, with a distinct metabolic profile emerging only at high bilirubin levels. Longitudinally, BA profiles changed substantially over time in hPDAC, largely in parallel with bilirubin, whereas they remained comparatively stable in tPDAC. After adjustment for bilirubin, tumor-related differences were modest and context-dependent. Conclusions: Overall, circulating BA profiles in pancreatic cancer appear to be driven predominantly by cholestasis and its management rather than by tumor-related features alone. Full article

(This article belongs to the Section Cancer Causes, Screening and Diagnosis)

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23 pages, 4414 KB

Open AccessArticle

DNA Methyltransferase Inhibitors, Decitabine and Guadecitabine Overcome Immune-Checkpoint Blockade Resistance and Achieve Tumor Regression in the E0771 and 4T1 Murine Models of Triple-Negative Breast Cancer

by S. Jennifer Wang, Carolyn Haynes, Laura Graham, Akhila Kunuthuru, Gina Tuzzolo, Anaya Surve, Madison Isbell, Jian He, Rebecca K. Martin and Harry Bear

Cancers 2026, 18(15), 2480; https://doi.org/10.3390/cancers18152480 - 2 Aug 2026

Abstract

Background: Immune-checkpoint blockade (ICB) is a recent addition to the treatment options for breast cancer, especially the triple-negative (TNBC) subset. Inhibiting immunosuppressive factors in the tumor microenvironment (TME) and preventing or reversing T cell exhaustion may increase the likelihood of a response to [...] Read more.

Background: Immune-checkpoint blockade (ICB) is a recent addition to the treatment options for breast cancer, especially the triple-negative (TNBC) subset. Inhibiting immunosuppressive factors in the tumor microenvironment (TME) and preventing or reversing T cell exhaustion may increase the likelihood of a response to ICB. We have shown that decitabine and guadecitabine, DNA methyltransferase inhibitors (DNMTi), prevent the systemic and TME accumulation of myeloid-derived suppressor cells (MDSCs), which are immunosuppressive. Results: Here, we show that adding DNMTi to the neoadjuvant + adjuvant ICB-based treatment of ICB-resistant 4T1 and E0771 murine tumors in Balb/C and C57Bl/6 mice, respectively, effectively reduced the tumor burden, with 52% of 4T1 tumors completely regressing across several studies. DNMTi-based therapy overcame ICB resistance (ICBR) in a selected subline of E0771, and treated tumors showed a reduction in MDSCs. We also show that, in E0771, DNMTi can overcome ICBR to multiple checkpoint inhibitors, and in 4T1, it can modulate anti-tumor immunity by enhancing central memory T cell (Tcm) formation and reducing T cell exhaustion. Conclusion: These pre-clinical findings support the further investigation of incorporating DNMTi as a new immunotherapy modality for TNBC. Full article

(This article belongs to the Special Issue Cancer Genetics and Epigenetics: Their Roles and Clinical Implications (2nd Edition))

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10 pages, 1026 KB

Open AccessArticle

Postoperative Diffusion-Weighted Imaging Hyperintensity Following Combined Photodynamic Diagnosis and Therapy Using 5-Aminolevulinic Acid and Talaporfin Sodium in Malignant Brain Tumors

by Takumi Inaba, Narushi Sugii, Hidehiro Kohzuki, Shunichiro Miki, Takao Tsurubuchi, Masahide Matsuda and Eiichi Ishikawa

Cancers 2026, 18(15), 2479; https://doi.org/10.3390/cancers18152479 - 2 Aug 2026

Abstract

Background/Objective: Intraoperative local photodynamic therapy (PDT) using talaporfin sodium (TS) and photodynamic diagnosis (PDD) with 5-aminolevulinic acid (5-ALA) are valuable adjuncts in the treatment of malignant brain tumors. Although their concomitant use was previously contraindicated due to photosensitivity concerns, a 2022 regulatory [...] Read more.

Background/Objective: Intraoperative local photodynamic therapy (PDT) using talaporfin sodium (TS) and photodynamic diagnosis (PDD) with 5-aminolevulinic acid (5-ALA) are valuable adjuncts in the treatment of malignant brain tumors. Although their concomitant use was previously contraindicated due to photosensitivity concerns, a 2022 regulatory revision permitted their combined application. Transient postoperative hyperintensity on diffusion-weighted imaging (DWI) at the irradiation site serves as a biomarker for PDT effects, but the radiological and clinical impact of combining 5-ALA and TS remains unclarified. To compare and evaluate postoperative DWI findings and clinical outcomes in patients undergoing TS-PDT with or without concomitant 5-ALA-guided PDD. Methods: This retrospective study analyzed 34 patients with recurrent primary malignant brain tumors who underwent TS-PDT between January 2019 and November 2025. Patients were divided into a TS alone group (n = 19) and a TS + 5-ALA group (n = 15). Postoperative DWI hyperintensity thickness and minimum apparent diffusion coefficient (ADC) values at the laser irradiation site were measured. Adverse events including photosensitivity were also compared. Results: No significant differences were observed between the TS alone and TS + 5-ALA groups in DWI hyperintensity thickness (3.71 mm vs. 3.90 mm; p = 0.703 or median ADC values (601.0 × 10⁻⁶ mm²/s vs. 527.0 × 10⁻⁶ mm²/s; p = 0.205). Furthermore, there were no significant differences in the incidence of photosensitivity and liver enzyme elevation. Conclusion: Concomitant use of 5-ALA-PDD and TS-PDT can be used without worsening DWI findings at the PD laser irradiation site. Full article

(This article belongs to the Special Issue Multidisciplinary Strategies in Challenging Neuro-Oncological Surgery)

26 pages, 8532 KB

Open AccessSystematic Review

Predictive Accuracy of Chemotherapy Toxicity Tools in Older Adults with Cancer: A Systematic Review and Diagnostic Test Accuracy Meta-Analysis

by Edwin Aguirre-Milachay, Mario J. Valladares-Garrido, Nallely V. Chapoñan-Agip, Nelson Luis Cahuapaza-Gutierrez, Betzy C. Torres-Zegarra, Milagros Diaz-Torres, Darwin A. León-Figueroa and Fernando M. Runzer-Colmenares

Cancers 2026, 18(15), 2478; https://doi.org/10.3390/cancers18152478 - 2 Aug 2026

Abstract

Background: Older adults with cancer are at increased risk of severe treatment-related toxicity. CARG, CRASH, and CARG-BC were developed as toxicity-risk prediction models, whereas G8 was developed as a geriatric screening instrument but has also been evaluated as a predictor of treatment-related toxicity. [...] Read more.

Background: Older adults with cancer are at increased risk of severe treatment-related toxicity. CARG, CRASH, and CARG-BC were developed as toxicity-risk prediction models, whereas G8 was developed as a geriatric screening instrument but has also been evaluated as a predictor of treatment-related toxicity. This study aimed to assess, separately for each instrument, the accuracy with which these tools identify older adults who develop severe chemotherapy-related toxicity. Methods: A systematic review and meta-analysis were conducted in accordance with PRISMA 2020 guidelines. Seven databases were searched through May 2026 for observational studies evaluating the predictive accuracy of the CARG, CRASH, CARG-BC and G8 tools in patients aged ≥65 years initiating chemotherapy. Pooled sensitivity and specificity with 95% confidence intervals (CIs) were calculated, and ROC curves were constructed. Risk of bias was assessed using QUADAS-2 and certainty of evidence was evaluated using GRADE. Results: Twenty-one studies were included, with an overall toxicity prevalence of 52.6%. CARG demonstrated a pooled sensitivity of 79.7% and specificity of 38.3% (AUC = 0.632). CRASH showed sensitivity of 86.9% and specificity of 68.2% (AUC = 0.866), but estimates were based on only four studies. CRASH hematological toxicity showed sensitivity of 75.9% and specificity of 53.1% (AUC = 0.694), with substantial heterogeneity. G8 yielded sensitivity of 69.5% and specificity of 41.5% (AUC = 0.666). CARG-BC showed sensitivity of 83.3% and specificity of 54.4% (AUC = 0.763), based on two breast cancer studies. Certainty of evidence ranged from low to very low. Conclusions: The instruments have distinct purposes and were not pooled against one another. CARG and G8 may be useful for initial risk screening, whereas CRASH showed a more balanced profile but remains supported by limited evidence. None should be used as a stand-alone basis to withhold or modify treatment. Full article

(This article belongs to the Section Systematic Review or Meta-Analysis in Cancer Research)

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12 pages, 684 KB

Open AccessArticle

PTEN Protein Loss in Diagnostic Prostate Biopsies Is Associated with Gleason Score Upgrading in Radical Prostatectomy

by Nives Kolesarić, Ivan Pezelj, Igor Tomašković, Goran Štimac, Monika Ulamec and Božo Krušlin

Cancers 2026, 18(15), 2477; https://doi.org/10.3390/cancers18152477 - 2 Aug 2026

Abstract

Background/Objectives: Prostate needle biopsy often underestimates tumor aggressiveness due to limited tissue sampling, leading to Gleason score upgrading after radical prostatectomy (RP). Phosphatase and Tensin Homolog (PTEN) loss is an established tissue-based marker of adverse prostate cancer biology. This study evaluated whether reduced [...] Read more.

Background/Objectives: Prostate needle biopsy often underestimates tumor aggressiveness due to limited tissue sampling, leading to Gleason score upgrading after radical prostatectomy (RP). Phosphatase and Tensin Homolog (PTEN) loss is an established tissue-based marker of adverse prostate cancer biology. This study evaluated whether reduced or absent PTEN immunoreactivity in diagnostic biopsies is associated with subsequent Gleason score and International Society of Urological Pathology (ISUP) Grade Group upgrading in RP specimens. Methods: This retrospective study included 85 prostate cancer patients who underwent multiparametric magnetic resonance imaging (mpMRI)-guided biopsy and subsequent RP. PTEN expression on biopsy samples was assessed via immunohistochemistry. Patients were stratified into PTEN-preserved (PTEN+, n = 75) and PTEN-deficient (PTEN−, n = 10) groups. Results: Upgrading occurred in 70% (7/10) of PTEN-deficient cases compared with 20% (15/75) of PTEN-preserved cases. This difference was statistically significant (two-sided Fisher’s exact p = 0.0024), with PTEN-deficient patients showing a 3.50-fold higher relative risk of upgrading (RR = 3.50, 95% CI: 1.91–6.43). Preoperative PSA levels (p = 0.91) and Prostate Imaging Reporting and Data System (PI-RADS) scores (p = 0.73) did not differ significantly between the groups. Conclusions: Reduced PTEN protein expression, as assessed by immunohistochemistry in prostate needle biopsies, was significantly associated with Gleason score/ISUP Grade Group upgrading at radical prostatectomy. PTEN immunohistochemistry warrants further evaluation as a potentially complementary tissue-based marker of biopsy undergrading. However, the observed unadjusted association does not establish PTEN immunoreactivity as an independent predictor of upgrading. Full article

(This article belongs to the Special Issue Prostate Cancer Pathology and Grade)

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30 pages, 638 KB

Open AccessSystematic Review

Functional Outcomes and Anti-Reflux Performance of Reconstruction Methods Following Proximal Gastrectomy: A Systematic Review

by Kazuaki Tanabe, Ruxin Lei, Yoshihiro Saeki, Emi Chikuie and Hideki Ohdan

Cancers 2026, 18(15), 2476; https://doi.org/10.3390/cancers18152476 - 1 Aug 2026

Abstract

Proximal gastrectomy preserves gastric function; however, reconstruction choice influences reflux control and quality of life (QOL), and the comparative efficacy of available techniques remains unclear. A PRISMA-guided search of PubMed and Web of Science Core Collection (January 2000–April 2025) identified studies reporting reflux [...] Read more.

Proximal gastrectomy preserves gastric function; however, reconstruction choice influences reflux control and quality of life (QOL), and the comparative efficacy of available techniques remains unclear. A PRISMA-guided search of PubMed and Web of Science Core Collection (January 2000–April 2025) identified studies reporting reflux or QOL outcomes after proximal gastrectomy. Eligible studies included adult gastric cancer cohorts with original clinical data. Two reviewers independently screened articles, extracted predefined variables, and performed a narrative synthesis. The protocol was archived on the OSF. Thirty-two studies (2958 patients) met inclusion criteria. Simple esophagogastrostomy (EG) consistently demonstrated the poorest reflux control and widest range of stricture rates. Double-tract reconstruction (DTR) showed a generally favorable balance among reflux control, low leakage rates, and acceptable stricture rates, suggesting that it may represent a practical and broadly applicable reconstruction option. Jejunal interposition and pouch variants were reported in small, heterogeneous series, limiting their generalizability. Among valve-forming methods, the double-flap technique was associated with very low rates of endoscopic reflux in two Los Angeles–graded cohorts, though a 4–6% stricture rate remained a concern. Evidence for the side overlap with fundoplication by Yamashita, both original and modified, was sparse and inconsistent. Global QOL, assessed using PGSAS-45/37 and EORTC instruments, did not differ consistently between reconstruction types, although specific domains—such as appetite loss, nausea, and weight maintenance—varied sporadically. Available evidence suggests that DTR may be considered a practical and broadly applicable reconstruction option following proximal gastrectomy, whereas the double-flap technique appears to provide strong reflux control but may be associated with a risk of anastomotic stricture. Simple EG may was associated with higher reflux rates across studies and may be less favorable for reflux control. Larger multicenter studies using standardized, nutrition-sensitive QOL measures and physiological reflux testing are needed to optimize reconstruction choice. However, substantial heterogeneity and the limited quality of the available evidence preclude definitive conclusions regarding the superiority of any single reconstruction method. Full article

(This article belongs to the Special Issue Clinical Outcomes in Upper GI Cancers)

22 pages, 1983 KB

Open AccessArticle

Benchmarking Open-Source Pathology Foundation Models for Breast Cancer Biomarker Prediction from H&E Whole-Slide Images

by Samir Atiya, Jiayou Liang, Kwaku Ofori-Atta, Michelle Peng, Huili Wang, Yifei Zhou, Ankush Patel, Mary Edgertion, Junhan Zhao and Utku Pamuksuz

Cancers 2026, 18(15), 2475; https://doi.org/10.3390/cancers18152475 - 1 Aug 2026

Abstract

Background/Objectives: Breast cancer biomarker detection through immunohistochemistry (IHC) is essential for treatment planning but faces challenges including turnaround time, variability, and laboratory resource constraints. Large open-source vision-language foundation models offer a potential avenue for inferring biomarker status directly from hematoxylin-and-eosin (H&E)-stained whole-slide images [...] Read more.

Background/Objectives: Breast cancer biomarker detection through immunohistochemistry (IHC) is essential for treatment planning but faces challenges including turnaround time, variability, and laboratory resource constraints. Large open-source vision-language foundation models offer a potential avenue for inferring biomarker status directly from hematoxylin-and-eosin (H&E)-stained whole-slide images (WSIs). Methods: We evaluated two open-source pathology foundation models—TITAN (Transformer-based Pathology Image and Text Alignment Network, approximately 48.5 M parameters) and CHIEF (Clinical Histopathology Imaging Evaluation Foundation Model, approximately 1.2 M parameters)—for predicting estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status from H&E-stained breast cancer WSIs. WSI data were obtained from The Cancer Genome Atlas Breast Invasive Carcinoma collection (TCGA-BRCA) via the NCI Imaging Data Commons, with biomarker labels from the NCI Genomic Data Commons. In total, 937 cases (995 WSIs; 78.3% ER-positive) were evaluated for ER, 934 cases (992 WSIs; 68.4% PR-positive) for PR, and 646 cases (691 WSIs; 21.1% HER2-positive) for HER2. All evaluation was performed under a strict patient-level 50/25/25 split with 10 independent random partitions; metrics are reported as the mean across partitions with percentile-based 95% confidence intervals. Performance was assessed using area under the receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC), sensitivity, specificity, and positive predictive value (PPV). Results: TITAN and CHIEF achieved comparable performance for ER (TITAN AUROC: 0.885 [95% CI: 0.848, 0.921], AUPRC: 0.954 [0.940, 0.964]; CHIEF AUROC: 0.877 [0.831, 0.914], AUPRC: 0.955 [0.938, 0.969]) and PR (TITAN AUROC: 0.799, AUPRC: 0.868; CHIEF AUROC: 0.791, AUPRC: 0.864). At the default 0.5 operating point, ER PPV was 0.90 and PR PPV was 0.79–0.81. For HER2, both models achieved AUROC values of 0.71–0.74 and AUPRC values of 0.41–0.45—well above the prevalence-based random baseline (approximately 0.211)—but default-threshold sensitivity was very low (approximately 0.07–0.08), reflecting class imbalance and the use of an uncalibrated default threshold rather than a categorical absence of morphologic signal. Conclusions: Under retrospective evaluation, both models demonstrate strong discriminative performance for ER and moderate performance for PR; HER2 prediction at the default operating point is limited and motivates threshold-calibration and multimodal extensions before any clinical use. AUPRC summarizes precision−recall behavior across thresholds and is distinct from threshold-specific precision (PPV); the two should be reported together for clinical-utility assessment in pathology AI. The findings are hypothesis-generating and motivate prospective external validation across independent institutional cohorts before any clinical deployment is considered. Full article

(This article belongs to the Topic Artificial Intelligence in Computational Pathology for Cancer Diagnosis)

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27 pages, 1160 KB

Open AccessReview

Thyroid Cancer: From Potential Drivers to Real Modulators

by Shafiya Imtiaz Rafiqi and Juan Carlos Jaume

Cancers 2026, 18(15), 2474; https://doi.org/10.3390/cancers18152474 - 1 Aug 2026

Abstract

The advent of cancer immunotherapy opened a transformative era in oncology, shifting the focus from targeting mutated genes through precision oncology to harnessing the body’s immune system via agnostic therapies. This paradigm has demonstrated that a deeper understanding of the tumor immune microenvironment [...] Read more.

The advent of cancer immunotherapy opened a transformative era in oncology, shifting the focus from targeting mutated genes through precision oncology to harnessing the body’s immune system via agnostic therapies. This paradigm has demonstrated that a deeper understanding of the tumor immune microenvironment (TIME) can transcend the challenges posed by cancer’s genetic diversity and evolutionary dynamics. In the case of thyroid cancer, progress in immunotherapy has been comparatively slow. Much of the current research still centers on the genetic landscape of thyroid tumors rather than on comprehensive exploration of their TIME. The TIME, composed of immune cells such as macrophages, lymphocytes, natural killer cells, and mast cells, along with a network of signaling molecules, evolves alongside tumor growth and metastasis. It both influences and is influenced by genetic alterations, metabolic conditions, and therapeutic interventions. This dynamic crosstalk defines the clinical and biological heterogeneity of thyroid cancers; from the aggressive anaplastic thyroid carcinoma (ATC) to the more indolent papillary thyroid carcinoma (PTC). Mapping the spatial and temporal changes within the TIME offers the opportunity to design therapies that counter immune evasion and enhance treatment response. As understanding of the tumor microenvironment deepens, thyroid cancer therapy is undergoing a major shift; from strategies aimed merely at genetic mutations to integrated, combinational approaches incorporating personalized immunotherapy. Building on recent findings, which detail immune cell composition and therapeutic implications in thyroid malignancies, this review expands on the molecular and cellular mechanisms shaping the microenvironment. We highlight how oncogenic signaling, stromal remodeling, and metabolic reprogramming coordinate to influence tumor immunity, and we explore emerging strategies that aim to reengineer the tumor microenvironment for improved therapeutic outcomes. Full article

(This article belongs to the Special Issue Tumor Microenvironment of Thyroid Carcinoma)

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