Cancers

25 pages, 8889 KB

Open AccessSystematic Review

Skull-Base Plasmacytomas: A Systematic Review on Therapeutic Trends

by Francisco Call-Orellana, Kishore Balasubramanian, Hanyu Qiu, Alexander Houpt, Tushar Kanti Bhadra, Georgios Toumbas, Beste Gülsuna, Jeffrey Zuccato, Panayiotis Pelargos, Abdul Basit Khan and Hakeem J. Shakir

Cancers 2026, 18(15), 2495; https://doi.org/10.3390/cancers18152495 (registering DOI) - 4 Aug 2026

Abstract

Background: Skull base plasmacytomas are rare plasma cell neoplasms arising from the clivus, sphenoid bone, and petrous apex, presenting with cranial neuropathies and bearing a high risk of progression to multiple myeloma. Optimal management remains poorly defined due to their rarity. Objective: The [...] Read more.

Background: Skull base plasmacytomas are rare plasma cell neoplasms arising from the clivus, sphenoid bone, and petrous apex, presenting with cranial neuropathies and bearing a high risk of progression to multiple myeloma. Optimal management remains poorly defined due to their rarity. Objective: The objectives of this study are to comprehensively characterize the clinical presentation, management strategies, and outcomes of skull base plasmacytomas and identify evolving trends in the literature. Methods: A systematic search of PubMed, EMBASE, Web of Science, and Cochrane databases was conducted, yielding 92 studies (18 case series and 74 case reports) encompassing 118 patients. Data on the demographics, symptoms, imaging, histopathology, treatment, and outcomes were extracted and analyzed. Results: The median patient age was 56 years; visual disturbances (66.1%) and headache (54.2%) were the most common presenting symptoms. The middle and posterior cranial fossae were most frequently involved, and cranial nerve VI was most affected (65.7%). Surgical resection was performed in 63.6% of cases with a gross total resection in 36%. At a median follow-up of 12 months (calculated across the entire cohort of 118 patients, including the 29 who presented with a prior diagnosis of multiple myeloma), 81.4% were alive, with symptom resolution at 38.1% or improvement at 26.2%. Recurrence occurred in 19.4% of patients, and multiple myeloma developed in 25.8% of patients without a prior diagnosis. Multiple myeloma status was the only independent predictor of survival on multivariate analysis (OR = 10.14, 95% CI: 1.63–63.04, p = 0.013). Conclusions: Skull base plasmacytomas show consistent clinical patterns but variable management strategies. Surgery is increasingly utilized; yet, its survival benefit remains unclear. Prospective multicenter studies with standardized outcome reporting and molecular profiling are needed to optimize individualized care. Full article

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

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30 pages, 1327 KB

Open AccessReview

Rewiring of the Apoptotic Rheostat in HTLV-1 Infection and Adult T-Cell Leukemia/Lymphoma

by Arezoo Darbandi, Vittoria Raimondi, Francesco Ciccarese, Donna M. D’Agostino and Vincenzo Ciminale

Cancers 2026, 18(15), 2494; https://doi.org/10.3390/cancers18152494 (registering DOI) - 4 Aug 2026

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of an aggressive malignancy of mature T-cells termed adult T-cell leukemia/lymphoma (ATLL), as well as a spectrum of chronic inflammatory diseases. A defining feature of HTLV-1 infection is a profound dysregulation of [...] Read more.

Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of an aggressive malignancy of mature T-cells termed adult T-cell leukemia/lymphoma (ATLL), as well as a spectrum of chronic inflammatory diseases. A defining feature of HTLV-1 infection is a profound dysregulation of apoptotic pathways, which is a key determinant of long-term viral persistence and favors malignant transformation. This review describes the mechanisms through which HTLV-1 gene products, including Tax and HBZ, reprogram host-cell signaling controlling the “apoptotic rheostat”, an integrated network connecting redox metabolism, and response to apoptotic cues and immune pressure. We also highlight emerging therapeutic strategies to restore sensitivity to apoptosis, including BH3-mimetic drugs and rational combination approaches. Deciphering how HTLV-1 reconfigures the apoptotic network provides a conceptual and therapeutic framework for targeting death pathway vulnerabilities in ATLL and potentially other hematological neoplasms. Full article

(This article belongs to the Special Issue Retroviruses and Cancer Development: Molecular Mechanisms and Therapeutic Prospects)

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22 pages, 2652 KB

Open AccessArticle

Moderately Hypofractionated Online Adaptive Radiotherapy for Cervical Cancer: A Prospective Study of Feasibility, Acute Toxicity and Dosimetric Benefits

by Zheng Zeng, Yining Chen, Xiangyin Meng, Yuliang Sun, Junfang Yan, Ke Hu and Fuquan Zhang

Cancers 2026, 18(15), 2493; https://doi.org/10.3390/cancers18152493 (registering DOI) - 4 Aug 2026

Abstract

Background/Objectives: Moderately hypofractionated radiotherapy (MHRT) may shorten treatment duration for cervical cancer but raises concerns regarding toxicity due to substantial interfractional pelvic organ motion. This prospective study evaluated the feasibility, workflow efficiency, dosimetric benefits, and acute toxicities of daily online adaptive radiotherapy (oART)-guided [...] Read more.

Background/Objectives: Moderately hypofractionated radiotherapy (MHRT) may shorten treatment duration for cervical cancer but raises concerns regarding toxicity due to substantial interfractional pelvic organ motion. This prospective study evaluated the feasibility, workflow efficiency, dosimetric benefits, and acute toxicities of daily online adaptive radiotherapy (oART)-guided MHRT. Methods: Thirty patients with FIGO 2018 stage IB1–IIB or IIIC1 cervical squamous cell carcinoma receiving definitive chemoradiotherapy were prospectively included between September 2023 and April 2024 (NCT05994300). All patients underwent daily oART, receiving 43.35 Gy in 17 fractions to the pelvic target volume, with a simultaneous integrated boost to 54.40 Gy in 17 fractions for involved lymph nodes. The adaptive workflow consisted of iterative cone-beam computed tomography acquisition, artificial intelligence-assisted contouring, physician review, plan adaptation, and treatment verification. Workflow efficiency, plan selection, target coverage, organ-at-risk (OAR) sparing, treatment completion, early tumor response and acute toxicity were prospectively assessed. Results: A total of 510 adaptive fractions were delivered. The first-attempt adaptation success rate was 99.0%, and adapted plans were selected in 99.4% of fractions. The mean adaptive workflow and total treatment times were 17.3 and 23.3 min per fraction, respectively. Compared with scheduled plans, adapted plans significantly improved target coverage, with V_100% increasing by 7.26% for the planning target volume of the uterus and 8.79% for planning target volume of the cervix (both p < 0.001), while significantly reducing doses to the bladder, rectum, small bowel, bone marrow, and femoral heads. All patients achieved complete clinical response at 3 months. Acute toxicity was generally manageable; Grade ≥ 3 gastrointestinal, genitourinary, and hematologic toxicities occurred in 10%, 0%, and 40% of patients, respectively, including one Grade 4 neutropenia event, and no treatment interruptions. Conclusions: Daily oART-guided MHRT was feasible and efficient, providing improved target coverage and reduced OAR doses compared with scheduled plans. Acute toxicity was acceptable. These findings provide early prospective evidence supporting the feasibility of this treatment strategy and warrant further validation in larger prospective studies with longer follow-up. Full article

(This article belongs to the Special Issue Clinical Application of Proton Therapy and Advanced Radiotherapy in Gynecological Cancer)

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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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