Buteau JP, Moon D, Fahey MT
… +35 more, Roberts MJ, Ayati N, Papa N, Murphy DG, Kasivisvanathan V, Dhillon HM, Du YT, Dundee P, Foudoulis J, Hennes D, Hutton AC, Idiare J, Jack G, Kamath S, Lee SN, Lee SF, Lee ST, Leslie S, Levy SM, Link E, Mitchell C, Morigi JJ, Nguyen A, Olphert J, Patel MI, Pattison DA, Pearce A, Perera M, Thanigasalam R, Thomson A, Yaxley J, Thompson J, Hofman MS, Emmett L, PRIMARY2 Trial Investigators
BACKGROUND: MRI is recommended for men with clinical suspicion of significant prostate cancer. Those with high clinical risk but non-suspicious or equivocal MRI often undergo prostate biopsy, but have a low likelihood of...BACKGROUND: MRI is recommended for men with clinical suspicion of significant prostate cancer. Those with high clinical risk but non-suspicious or equivocal MRI often undergo prostate biopsy, but have a low likelihood of clinically significant prostate cancer, and a high incidence of clinically insignificant prostate cancer. We aimed to investigate whether gallium-68 ([Ga]Ga)-prostate-specific membrane antigen (PSMA)-11 PET-CT could reduce the number of people requiring prostate biopsy and limit biopsy to targeted cores, without compromising clinically significant prostate cancer diagnosis. METHODS: In this multicentre, non-inferiority, phase 3, randomised controlled trial, done at at seven Australian hospitals, we recruited biopsy-naive participants with clinical suspicion of significant prostate cancer, equivocal (Prostate Imaging-Reporting and Data System [PI-RADS] 3) or non-suspicious (PI-RADS 2) MRI but high clinical risk (eg, prostate-specific antigen [PSA] density of >0·1 ng/mL/mL, strong family history of prostate cancer, abnormal digital rectal examination, BRCA mutation, PSA >10 ng/mL, PSA doubling time <36 months, or PSA velocity >0·75 ng/mL per year), PSA of 20 ng/mL or less, and clinical T2 disease or less. Participants were randomly assigned (1:1) using a centralised web-based system to undergo [Ga]Ga-PSMA-11 PET-CT (experimental group) or systematic transperineal prostate biopsy (control group), using block sizes of two or four and stratification by study site. There was no masking for participants or investigators. Participants with positive [Ga]Ga-PSMA-11 PET-CT (PRIMARY score 3-5) underwent PSMA-PET-targeted transperineal prostate biopsies, whereas those with a negative result (PRIMARY score 1-2) avoided biopsy. The co-primary outcomes were the proportion of participants with clinically significant prostate cancer, defined as a Gleason score of 3 + 4 (≥10% pattern 4) or higher, and the proportion of participants in the [Ga]Ga-PSMA-11 PET-CT group who avoided biopsy within 6 months of random assignment. A two-sided 95% Wald CI based on a binomial model was used to estimate the risk difference in the proportion of participants with clinically significant prostate cancer (non-inferiority margin 10%) and to estimate the proportion of participants in the experimental group who had avoided biopsy 6 months after random assignment (20% threshold), analysed based on intention to treat. This trial is registered with ClinicalTrials.gov, NCT05154162, and participant follow-up is ongoing. FINDINGS: Between March 2, 2022, and Aug 24, 2025, 660 eligible male participants were enrolled and had a median age of 61 years (IQR 56-66), a median PSA of 5·2 ng/mL (4·0-7·0), and a median PSA density of 0·13 ng/mL/mL (0·09-0·17). There were PI-RADS 2 in 335 (51%) participants and PI-RADS 3 in 325 (49%) participants. Ethnicity data were not collected. 329 (50%) were assigned to the control group with systematic transperineal prostate biopsy, and 331 (50%) were assigned to the experimental group with [Ga]Ga-PSMA-11 PET-CT. The proportion of participants with clinically significant prostate cancer in the experimental group (39 [12%] of 331) was non-inferior to the control (51 [16%] of 329; difference -3·7% [95% CI -8·9 to 1·5%]; p=0·0093). Use of [Ga]Ga-PSMA-11 PET-CT avoided biopsy in 163 (49%) of 331 participants (95% CI 44 to 55%; p <0·0001). After prostate biopsy, participants reported similar proportions of pain (33 [21%] in the experimental group vs 62 [21%] in the control group), haematuria (60 [38%] vs 126 [43%]), and haematospermia (77 [48%] vs 133 [45%]). INTERPRETATION: [Ga]Ga-PSMA-11 PET-CT could have the potential to improve the diagnostic pathway of patients with a high clinical risk but non-suspicious or equivocal prostate MRI. Further research, including health-economic analyses and validation with other PSMA radiopharmaceuticals, are needed to confirm the clinical implementation and generalisability of this approach. FUNDING: Prostate Cancer Foundation, National Health and Medical Research Council, St Vincent's Curran Foundation, and Peter MacCallum Cancer Foundation.
BACKGROUND: Tyrosine kinase inhibitors (TKIs) have transformed chronic-phase chronic myeloid leukemia (CML) into a chronic condition with excellent long-term survival. As outcomes improve, attention has shifted toward tr...BACKGROUND: Tyrosine kinase inhibitors (TKIs) have transformed chronic-phase chronic myeloid leukemia (CML) into a chronic condition with excellent long-term survival. As outcomes improve, attention has shifted toward treatment-related metabolic effects and survivorship issues. Body weight and body mass index (BMI) are important indicators of metabolic health; however, the long-term effects of TKIs on these parameters remain incompletely characterized, particularly in real-world settings. This study evaluated longitudinal changes in body weight and BMI in adults with chronic-phase CML treated with TKIs. METHODS: We conducted a retrospective longitudinal observational study at a tertiary care center between January 2016 and December 2023. Adult patients with chronic-phase CML who initiated TKI therapy and had baseline and follow-up weight measurements were included. Patients with major preexisting metabolic conditions or factors likely to confound weight were excluded. Body weight and BMI were assessed at predefined time points up to 7 years. Paired analyses evaluated within-patient changes over time, and stratified analyses were performed according to initial TKI and cumulative exposure patterns. RESULTS: A total of 175 patients were included in the analytic cohort (82.9% male; mean age 39.2 ± 11.7 years). Mean baseline weight was 68.2 ± 14.4 kg, and baseline BMI was 24.6 ± 3.9 kg/m². Weight increased significantly from baseline at 6 months (+4.27 kg), 12 months (+6.00 kg), 18 months (+6.63 kg), and 24 months (+6.41 kg) (all p<0.001). At the last follow-up, the mean weight gain was 6.12 kg (p < 0.001), with 56.9% of patients achieving≥5% weight gain. The temporal pattern showed rapid weight gain during the first 6-12 months, followed by stabilization through 2-3 years with persistent elevation thereafter. Weight and BMI increases were observed across all first-line TKIs and cumulative exposure groups, without statistically significant differences between agents. CONCLUSION: In this real-world cohort of adults with chronic-phase CML, TKI therapy was associated with early and sustained increases in body weight and BMI, largely occurring within the first year of treatment. These changes likely reflect a combination of treatment-related metabolic effects and reversal of cancer-associated catabolism. Given the long life expectancy of patients with CML, routine metabolic surveillance and early lifestyle interventions should be incorporated into long-term management.
OBJECTIVES: In the last decades, artificial intelligence has made tremendous steps in supporting decision-making in healthcare. Bayesian networks (BNs) have emerged as powerful tools for probabilistic modelling and offer...OBJECTIVES: In the last decades, artificial intelligence has made tremendous steps in supporting decision-making in healthcare. Bayesian networks (BNs) have emerged as powerful tools for probabilistic modelling and offer important advantages compared with regression-based models. This systematic review identifies the available literature on BNs for prognostication in oncology, evaluates their performance and discusses how BNs can overcome limitations of traditional prediction models. DESIGN SETTING PARTICIPANTS: The systematic review was performed according to the Cochrane guidance and reported according to the guidelines for the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). The protocol was registered in PROSPERO. Studies identified in MEDLINE and EMBASE were included. MAIN OUTCOME MEASURES: Eligible studies investigated BNs as tools within oncology (solid or haematological malignancies). RESULTS: A total of 52 studies were included, with a median construction cohort size of 438 patients. More than half of studies harboured unclear or high concerns about bias. Most studies used score-based structure learning approaches to construct the BNs. External validation was applied in a minority of studies and showed excellent performance metrics when hybrid techniques (integration of machine-learning and expert knowledge) were applied. Studies comparing BN validation with Cox regression validation showed better performance for BNs in most studies. CONCLUSIONS: When constructed with hybrid techniques, BNs offer great potential to support decision-making in clinical oncology. Advantages include their ability to estimate treatment effects with non-randomised data, to model causal relationships, to apply counterfactual reasoning and to work with missing variables. To be implemented into clinical practice, hybrid construction techniques, high-quality external validation, prospective evaluation with a health technology assessment and adequate postmarketing surveillance and maintenance are essential. PROSPERO REGISTRATION NUMBER: CRD420251140130.
Nakashima I, Saito S, Zhao J
… +6 more, Tanaka M, Akahoshi E, Hasegawa A, Sugano-Ishihara M, Yagyu S, Nakazawa Y
Mol Ther Oncol
· 2026 Jun · PMID 42256207
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Despite advances in multimodal therapies, outcomes for pediatric patients with relapsed or refractory cancers remain poor. Chimeric antigen receptor (CAR) T cell therapy has demonstrated limited efficacy in solid tumors...Despite advances in multimodal therapies, outcomes for pediatric patients with relapsed or refractory cancers remain poor. Chimeric antigen receptor (CAR) T cell therapy has demonstrated limited efficacy in solid tumors due to the immunosuppressive tumor microenvironment (TME), which promotes T cell exhaustion and restricts CAR T cell expansion. This study evaluated a combinatorial approach to enhance CAR T function by reprogramming the TME to overexpress target antigens (TAs) and co-stimulatory molecules (CSMs) through a lipid nanoparticle-based CAR-T vaccination (CART-Vac). As proof of concept, rhabdomyosarcoma cells (Rh30) engineered to overexpress TAs and CSMs (Rh30-TACS) were examined. EPHB4-directed CAR T cells demonstrated enhanced cytotoxicity, proliferation, and cytokine secretion , and superior tumor control with increased T cell infiltration in Rh30-TACS tumors compared with Rh30 tumors. To induce TA and CSM expression in the TME, CART-Vac was designed to deliver mRNAs encoding truncated EPHB4, CD80, and CD137L. CART-Vac effectively mediated transient expression, significantly enhancing CAR T expansion and antitumor activity in both models. These findings suggest that CART-Vac can modulate the TME, offering a promising strategy to improve the therapeutic efficacy of CAR T cells in solid tumors.
Li Y, Nakkala JR, Akter L
… +4 more, Kang X, Song Y, VanLuinen E, Chen X
Mol Ther Oncol
· 2026 Jun · PMID 42256206
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Personalized neoantigen mRNA vaccines showed good efficacy in treating metastatic melanoma, pancreatic cancer, and breast cancer in early phase clinical trials. Strategies are needed to further enhance neoantigen mRNA va...Personalized neoantigen mRNA vaccines showed good efficacy in treating metastatic melanoma, pancreatic cancer, and breast cancer in early phase clinical trials. Strategies are needed to further enhance neoantigen mRNA vaccine-induced anti-tumor immunity. This study explored conventional adjuvant co-administration to enhance mRNA vaccine-induced anti-tumor immunity. We found a clinically used CpG 1018 adjuvant was highly effective to enhance ovalbumin (OVA) and neoantigen mRNA-induced T cell responses and anti-tumor immunity in B16F10-OVA melanoma models. Mechanistic studies found CpG 1018 mainly enhanced dendritic cell maturation and local cytokine/chemokine release but not mRNA translation. mRNA vaccine in the presence of CpG 1018 induced significantly higher levels of Granzyme B, IFNγ, and TNFα-secreting CD8+ T cells as compared to mRNA vaccine alone. We further found that potent anti-tumor immunity was associated with increased tumor-infiltration of CD8+ T cells and positively correlated with tumor-infiltrating CD8+ to CD4+ T cell ratios. Cell depletion studies found CD8+ T cells rather than CD4+ T cells or NK cells played crucial roles in CpG 1018-augmented mRNA vaccine efficacy. CpG 1018-adjuvanted mRNA vaccine induced transient body weight loss (<6%) with an overall good safety. Our data warrant further investigation of CpG 1018-adjuvanted neoantigen mRNA vaccine for potentially better tumor therapy.
Yang Y, Ronsley R, Kilburn L
… +3 more, Kim A, Wechsler-Reya RJ, Yang ZJ
Mol Ther Oncol
· 2026 Jun · PMID 42256204
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Medulloblastoma (MB), the most common malignant pediatric brain tumor, is treated with intensive multimodal regimens that cause substantial long-term toxicity and fail to prevent recurrence in up to 30% of patients. We i...Medulloblastoma (MB), the most common malignant pediatric brain tumor, is treated with intensive multimodal regimens that cause substantial long-term toxicity and fail to prevent recurrence in up to 30% of patients. We investigated triiodothyronine (T3), an FDA-approved thyroid hormone, as a differentiation-based therapeutic strategy for MB. Using a Sonic Hedgehog (SHH)-driven mouse model, two patient-derived xenografts (SHH and group 3), and drug-resistant TP53-mutant MB cells, we found that T3 and cytotoxic chemotherapy suppress tumor growth through complementary biological mechanisms: T3 promotes terminal differentiation of tumor cells, whereas cyclophosphamide (CTX) and irinotecan (CPT-11) induce caspase-3-dependent apoptosis. , T3 enhanced the tumor inhibitory effects of CTX and CPT-11, suppressed proliferation in chemotherapy-resistant cells, and promoted differentiation across MB subgroups. , sequential administration of T3 following chemotherapy suppressed post-treatment tumor regrowth and prolonged survival without increasing systemic toxicity. T3-induced transient tachycardia was effectively controlled with propranolol without compromising antitumor activity. Together, these findings support the potential of T3 as a clinically accessible differentiation-based therapy that enhances chemotherapy responses and suppresses post-treatment tumor regrowth in medulloblastoma.
Mei X, Li X, Wu Y
… +5 more, Fu D, Zhang F, Yan T, Gu W, Gao B
Mol Ther Oncol
· 2026 Jun · PMID 42256202
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PD-1 is a crucial molecule indispensable for maintaining immune homeostasis. Disrupting the interaction between PD-1 and its ligands can significantly enhance the immune system's ability to combat tumors. By integrating...PD-1 is a crucial molecule indispensable for maintaining immune homeostasis. Disrupting the interaction between PD-1 and its ligands can significantly enhance the immune system's ability to combat tumors. By integrating the PD-1 ligand-binding domain with the CD28 signal fragments (switch molecule) on T cells, we can utilize co-stimulatory signals to boost the function of T cells while removing the inhibition of immune checkpoint molecules. However, the extensive application of anti-PD-1 monoclonal antibodies in clinical settings may neutralize the PD-1 switch molecule, thereby restricting its therapeutic potential. In this study, we used sequential mutation and sorting techniques to rapidly evolve a PD-1 molecule that exhibits high affinity for PD-L1 while avoiding the recognition by five of the six clinically approved anti-PD-1 drugs. Experimental results verify that the Fc fusion protein and switch receptor based on such PD-1 mutant enhance the efficacy of therapeutic T cells.
Mol Ther Oncol
· 2026 Jun · PMID 42256201
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Expression of the αvβ6 integrin is upregulated on multiple solid epithelial tumors while this integrin is largely absent on the healthy human epithelium. In the present study, we sought to compare the biodistributions o...Expression of the αvβ6 integrin is upregulated on multiple solid epithelial tumors while this integrin is largely absent on the healthy human epithelium. In the present study, we sought to compare the biodistributions of three αvβ6-selective agents that could be used for the positron emission tomography (PET)-based detection of malignancies expressing this integrin. A streptavidin-coupled αvβ6-binding peptide (streptavidin-A20), an anti-αvβ6 monoclonal antibody (620W.7) and an αvβ6-targeted protein, derived from a modified adenovirus 5 receptor-binding domain (Ad5.KO1.A20), were radiolabeled with [Zr] and intravenously injected into mice bearing bilateral αvβ6-positive and -negative melanoma xenografts. Micro-PET imaging was performed at 0.33, 24, 48, 72, and (620W.7 group only) 144 h post-injection. Streptavidin-A20-based radiotracers preferentially accumulated in αvβ6-positive tumors, achieving >3.4:1 A375-β6:A375 activity ratios between 24 and 72 h post-injection, with off-target uptake restricted to the kidneys. 620W.7 exhibited roughly 2-fold greater accumulation in A375-β6 than A375 tumors, with lower levels of renal retention and greater activity detected in the liver and spleen. Despite having demonstrated selective binding to αvβ6-expressing cells , the Ad5.KO1.A20 protein failed to selectively traffic to tumors expressing this integrin . Nevertheless, streptavidin-A20 and 620W.7 demonstrated promise as αvβ6-selective agents for applications.
Zhang Y, Xiong N, Song Y
… +3 more, Lu X, Ni K, Tang Z
Mol Ther Oncol
· 2026 Jun · PMID 42232064
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R-loops, three-stranded nucleic acid structures comprising an RNA-DNA hybrid and a displaced single-stranded DNA strand, play context-dependent roles in cancer-serving essential physiological functions while also driving...R-loops, three-stranded nucleic acid structures comprising an RNA-DNA hybrid and a displaced single-stranded DNA strand, play context-dependent roles in cancer-serving essential physiological functions while also driving tumorigenesis when dysregulated. Their pathological effects are mediated through replication stress, genomic instability, transcriptional disruption, and defective RNA processing. This review highlights the emerging potential of targeting R-loops as a therapeutic strategy in oncology. We survey advanced methodologies for R-loop mapping, addressing technical limitations of current approaches, and advocate for multi-omics integration to elucidate R-loop dynamics and functional networks in cancers such as lung, bladder, and prostate malignancies. Critically, we explore two promising therapeutic avenues: (1) direct inhibition of R-loop resolvers to trigger excessive R-loop accumulation and replication catastrophe, and (2) synthetic lethality strategies that capitalize on cancer-specific R-loop handling defects. Clinical evidence supporting these approaches is discussed, along with challenges including tumor heterogeneity, detection limitations, and adaptive resistance. We argue that a multi-omics-driven understanding of R-loop biology will accelerate the translation of R-loop-directed therapies into precision oncology.