Mol Ther Oncol
· 2026 Jun · PMID 42170678
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Carcinoma of the gallbladder (CAGB) carries a poor prognosis. While alterations in the bile microbiome and lipidome have been linked to CAGB development, the contribution of the fungal microbiome remains unexplored. We i...Carcinoma of the gallbladder (CAGB) carries a poor prognosis. While alterations in the bile microbiome and lipidome have been linked to CAGB development, the contribution of the fungal microbiome remains unexplored. We investigated fungal microbiome alterations and identified key fungal peptides capable of segregating CAGB patients. Bile samples from gallstone (GS) patients ( = 10), CAGB patients ( = 16), and healthy controls ( = 16) underwent fungal peptide-based diversity analysis and metabolomic profiling. Findings were cross-validated in plasma, correlated with clinical parameters and analyzed using machine learning. Six phyla and 24 fungal species were differentially regulated ( < 0.05). Alpha/beta diversity was higher in CAGB compared to GS and controls ( < 0.05). Ninety-three fungal peptides were upregulated and 63 downregulated in CAGB ( < 0.05, fold change [FC] > 1.5). CAGB patients showed significant enrichment of (log2FC > 12.21), (FC > 11.25), Saccharomyces (FC > 10.89), (FC > 10.68), and (FC > 10.38). Fungal-metabolite correlations (r > 0.5, < 0.05) linked these taxa to lysine biosynthesis, taurine and hypotaurine metabolism, fatty acid metabolism in bile, and cysteine/methionine, ascorbate, and purine metabolism in plasma. Fungal peptide panel achieved 96% diagnostic efficiency for mortality prediction with>90% accuracy, sensitivity, and specificity. Bile fungal diversity correlates with CAGB development and identifies fungal peptide panel capable of segregation of CAGB patients.
McClellan BL, Peña Agudelo JA, Mujeeb AA
… +22 more, Dabaja AA, Zhu Z, Raghuram S, Varela ML, Tronrud C, Banerjee K, Wei A, Calatroni C, Zhang LH, Romero LC, Oh P, Alghamri MS, Robbins A, Perricone M, Wang Y, Shay B, Sajjakulnukit P, Lyssiotis CA, Welch JD, Schwendeman A, Lowenstein PR, Castro MG
Mol Ther Oncol
· 2026 Jun · PMID 42170677
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Gliomas account for ∼80% of primary malignant brain tumors. Many CNS WHO grade 2-3 and some grade 4 gliomas harbor mutant isocitrate dehydrogenase 1 (mIDH1), which causes a gain-of-function mutation (IDH1 R132H) leading...Gliomas account for ∼80% of primary malignant brain tumors. Many CNS WHO grade 2-3 and some grade 4 gliomas harbor mutant isocitrate dehydrogenase 1 (mIDH1), which causes a gain-of-function mutation (IDH1 R132H) leading to the production of 2-hydroxyglutarate (2HG). Mutant IDH1-induced 2HG, through epigenetic reprogramming elicits an immune-permissive tumor microenvironment (TME). An immunosuppressive mechanism in the glioma TME involves adenosine production via the ectoenzyme CD73. This study investigates mIDH1's influence on CD73 expression and adenosine levels. We demonstrate that mIDH1 glioma cells exhibit reduced CD73 expression, driven by DNA hypermethylation, leading to reduced adenosine levels. Since wtIDH1 gliomas have high CD73 expression, we evaluated CD73 blockade as an immunotherapy target. We show that CD73 inhibition used as monotherapy did not improve survival in wtIDH1 glioma-bearing mice. However, when combined with immune-stimulatory Ad-TK (adenoviral vectors encoding herpes simplex virus thymidine kinase) and Ad-Flt3L (adenoviral vectors encoding FMS-like tyrosine kinase 3 ligand) gene therapy, CD73 blockade significantly enhanced therapeutic efficacy and increased anti-glioma effector T cell activity. These findings reveal that CD73 inhibition used in combination with immune-stimulatory Ad-TK/Ad-Flt3L gene therapy may be an effective treatment for wtIDH1 gliomas, which could be readily translated to the clinical arena.
Rossi J, Martinello C, Sorrentino R
… +5 more, Guyonnet-Duperat V, Amintas S, Abrey Recalde MJ, Verhoeyen E, Dabernat S
Mol Ther Oncol
· 2026 Jun · PMID 42170676
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Lentiviral vectors (LVs) are emerging as versatile tools for the efficient and stable delivery of therapeutic genes. Although VSV-G-pseudotyped LVs remain the standard for genetic engineering, their broad tropism and se...Lentiviral vectors (LVs) are emerging as versatile tools for the efficient and stable delivery of therapeutic genes. Although VSV-G-pseudotyped LVs remain the standard for genetic engineering, their broad tropism and serum sensitivity limit their applicability for cancer therapy, where precise targeting is essential for efficacy and safety. This review synthesizes two decades of advances in LV pseudotyping, comparing natural viral envelopes, engineered targeting strategies, and multicomponent glycoprotein systems that reshape vector tropism. We discussed donor-derived envelopes such as measles virus, baboon endogenous retrovirus, Nipah virus, and Sindbis virus, highlighting their value for transducing hematopoietic, immune, and tumor cells. We also examined next-generation retargeting innovations, including engineered receptor-binding domains, display of cytokines or antibody fragments, and VSV-G mutants that ablate natural receptor interactions, to enhance specificity for T cells, B cells, hematopoietic stem cells, and tumor-associated antigens. Finally, we review the recent emergence of engineered virus-like particles (VLPs) as precision tools for delivery of CRISPR-Cas9, base-editing, and prime-editing complexes. Collectively, these advances position receptor-targeted lentiviral and VLP systems as promising platforms for the next generation of precision oncology, enabling selective CAR T/NK cell generation, targeted tumor modification, and cell-restricted gene editing.
BACKGROUND: Adjuvant chemotherapy following surgical resection is the standard treatment for patients with pathological stage III (pStageIII) gastric cancer (GC) in Japan. Capecitabine plus oxaliplatin (CapeOX) and docet...BACKGROUND: Adjuvant chemotherapy following surgical resection is the standard treatment for patients with pathological stage III (pStageIII) gastric cancer (GC) in Japan. Capecitabine plus oxaliplatin (CapeOX) and docetaxel plus S-1 (DS) are recommended adjuvant regimens for this disease; however, no studies have compared the treatment outcomes of the two regimens. Therefore, this study aimed to evaluate the safety and efficacy of CapeOX versus DS as adjuvant chemotherapy in patients with pStage III GC. METHODS: We retrospectively reviewed the clinical information and treatment outcomes (including relapse-free survival [RFS] and adverse events) of patients with pStageIII GC who received either CapeOX or DS as adjuvant chemotherapy at our institution from February 2016 to May 2022 Results: A total of 73 patients (CapeOX, 31; DS 42) were included in this study. There was no significant difference in RFS between the two groups (3-year RFS: 37% in the CapeOX group vs. 44% in the DS group; HR=1.30 [95% CI: 0.71-2.37], p=0.400). In the multivariable analysis for RFS, treatment regimen was not identified as a prognostic factor for RFS (HR=1.02, [95% CI: 0.49-2.09], p=0.957). Compared with DS, CapeOX was associated with lower incidences of any-grade oral mucositis (10% vs. 50%, p<0.001) and any grade alopecia (6% vs. 74%, p<0.001), and a higher incidence of any-grade peripheral sensory neuropathy (81% vs. 24%, p<0.001). CONCLUSIONS: This analysis suggests that CapeOX and DS offer comparable efficacy as adjuvant chemotherapy for pStageIII GC in terms of RFS, while exhibiting distinct adverse event profiles.
Weindler S, Hundsberger T, Addeo A
… +25 more, Froesch P, Früh M, Gautschi O, Hasler-Strub U, Janthur WD, Mangana J, Mangas C, Mark MT, Maul JT, Maul LV, Mauti LA, Metaxas Y, Nothhelfer T, Özdemir BC, Le Rhun E, Rothschild SI, Schmid S, Seystahl K, Schucht P, Vetter M, Weller M, Witzel I, Zaman K, Putora PM, Glatzer M
BACKGROUND/OBJECTIVES: Guidelines suggest intrathecal (IT) pharmacotherapy for patients with leptomeningeal disease (LMD). However, evidence on the benefit of IT treatment is limited and IT therapy is an invasive procedu...BACKGROUND/OBJECTIVES: Guidelines suggest intrathecal (IT) pharmacotherapy for patients with leptomeningeal disease (LMD). However, evidence on the benefit of IT treatment is limited and IT therapy is an invasive procedure in patients with limited life expectancy. Available drugs for IT therapy do not play a role in systemic treatment of the most common cancers related to LMD and it is unclear to which extent and how the recommendation for IT therapy is implemented in daily clinical practice. METHODS: A panel of 24 dedicated Swiss experts in the field of breast cancer, lung cancer, melanoma and neuro-oncology recommended by the disease group leaders of the Swiss Cancer Institute (formerly SAKK) provided their decision criteria for the use of IT treatment in LMD. Treatment strategies were converted into decision trees and evaluated for consensus and discrepancies based on the objective consensus methodology. RESULTS: We identified 11 criteria relevant for decision making in IT therapy for LMD. The criteria most often used in the decision making process were confirmed leptomeningeal disease (positive cerebrospinal fluid (CSF)), performance status, availability of systemic drugs with CNS efficacy and extra-cranial disease control. Only half of all participating experts recommend IT therapy in their daily practice. Swiss experts from the field of neuro-oncology most often recommended IT treatment whereas lung cancer experts were most reluctant. CONCLUSION: Implementation of IT pharmacotherapy in daily clinical practice varies widely both between individual experts and between experts` specialization in different cancers. Only half of the participating experts would recommend intrathecal therapy to their patients. In everyday clinical practice, treatment recommendations are highly individualized and optimal care for LMD can only be achieved involving a truly multidisciplinary team of specialists.
Massumi M, Li G, Owji H
… +3 more, Yang G, Girda E, Hatefi A
Mol Ther Oncol
· 2026 Jun · PMID 42164422
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Cancer stem-like cells (CSCs) drive ovarian cancer metastasis, therapeutic resistance, and relapse. This study aimed to develop a combination therapeutic strategy capable of eliminating both rapidly proliferating ovarian...Cancer stem-like cells (CSCs) drive ovarian cancer metastasis, therapeutic resistance, and relapse. This study aimed to develop a combination therapeutic strategy capable of eliminating both rapidly proliferating ovarian cancer cells and drug-resistant CSCs, thereby eradicating metastatic disease and preventing relapse. We engineered an adipose-derived mesenchymal stem cell clone (ASC-shCE2:yCD) that homes to tumors and locally converts the prodrugs irinotecan and 5-fluorocytosine (5-FC) into the cytotoxic agents SN38 and 5-fluorouracil (5-FU). This approach was combined with natural killer (NK) cell immunotherapy to eradicate CSCs that survived chemotherapy. Using patient-derived, drug-resistant metastatic ovarian cancer models, we show that exposure to SN38 or 5-FU upregulates NKG2D stress ligands (MICA/B) on CSCs, enhancing their susceptibility to NK-mediated cytotoxicity. Real-time imaging demonstrated rapid homing of engineered adipose-derived stem cells (ASCs) to tumor sites within 3 days. In triple-immunodeficient CIEA NOG mice, ASC-directed enzyme/prodrug therapy followed by NK cell immunotherapy eliminated metastatic ovarian tumors and prevented relapse during the monitoring period. Histopathological and hematological analyses revealed no clinically significant toxicity. Collectively, these findings establish a stem cell-directed chemoimmunotherapy that primes drug-resistant ovarian cancer cells for immune elimination, offering a rationale and effective strategy to safely eradicate metastatic disease and prevent recurrence.
Curr Treat Options Oncol
· 2026 May · PMID 42159630
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OPINION STATEMENT: Hemithorax irradiation (HT‑RT) is a cornerstone multimodal treatment for high‑risk chest wall bone and soft tissue sarcomas, particularly Ewing sarcoma in children and young adults. Current non‑randomi...OPINION STATEMENT: Hemithorax irradiation (HT‑RT) is a cornerstone multimodal treatment for high‑risk chest wall bone and soft tissue sarcomas, particularly Ewing sarcoma in children and young adults. Current non‑randomized evidence consistently shows HT‑RT reduces systemic relapse-especially lung metastases-without compromising local control or causing unmanageable acute toxicities, and modern techniques (IMRT, VMAT, proton therapy) further improve its therapeutic ratio by lowering late toxicity. Major gaps remain: no prospective randomized controlled trials (RCTs) confirm independent efficacy, the biological mechanisms are unclear, and long‑term pulmonary function and survivorship data in children are insufficient. Future research must prioritize prospective RCTs, pediatric‑specific dose constraints, advanced technique validation, and mechanistic studies to refine patient selection and optimize outcomes for this high‑risk population. CLINICAL TRIAL NUMBER: Not applicable.
Despite revolutionary advances in genomic technologies, a persistent disconnect exists between research discoveries and clinical implementation. This translational gap stems from misaligned incentive and funding structur...Despite revolutionary advances in genomic technologies, a persistent disconnect exists between research discoveries and clinical implementation. This translational gap stems from misaligned incentive and funding structures: researchers prioritise publications over clinical uptake, with funding ending at proof-of-concept; clinicians face time constraints and integration challenges; regulators struggle with rapidly evolving technologies and genomics-specific complexities including variant classification and data governance. We propose that dedicated translational medicine centres are essential to bridge this divide. These centres require multidisciplinary teams spanning clinician-scientists, regulatory affairs specialists, health economists, biostatisticians and bioinformaticians, providing end-to-end support from feasibility assessment through to regulatory approval. Success requires government investment, explicit health equity assessments and measuring achievement through clinical uptake rather than traditional academic metrics.
BACKGROUND: The association between BRAF V600E mutation and clinicopathological features of papillary thyroid carcinoma (PTC) remains controversial. This study aimed to explore its prognostic value via meta-analysis. MET...BACKGROUND: The association between BRAF V600E mutation and clinicopathological features of papillary thyroid carcinoma (PTC) remains controversial. This study aimed to explore its prognostic value via meta-analysis. METHODS: Databases including PubMed, Cochrane Library, Embase, and Web of Science were systematically searched for studies published before June 1, 2025. Pooled odds ratio (OR) with 95% confidence interval (CI) was used as the effect size, analyzed by R 4.4.2. RESULTS: A total of 26 studies (2010-2024) involving 13,999 patients were included. BRAF V600E mutation was significantly positively associated with capsular invasion (OR=1.80, 95% CI:1.16-2.78) and extrathyroidal extension (OR=1.62, 95% CI:1.36-1.94), and negatively associated with concomitant Hashimoto's thyroiditis (OR=0.55, 95% CI:0.32-0.94). A marginal association trend was observed with gender, with male patients showing a higher likelihood of harboring the BRAF V600E mutation (OR=1.26, 95% CI:1.10-1.44, P=0.0525), while no significant associations were found with age, tumor size, multifocality, central or lateral lymph node metastasis. CONCLUSIONS: BRAF V600E mutation correlates with specific clinicopathological features of PTC and serves as a potential prognostic predictor.
BACKGROUND: Around 57 000 people are diagnosed with breast cancer annually in the UK. Radiotherapy can improve local control and survival, but it can also cause long-term side-effects. UK hypofractionation trials have de...BACKGROUND: Around 57 000 people are diagnosed with breast cancer annually in the UK. Radiotherapy can improve local control and survival, but it can also cause long-term side-effects. UK hypofractionation trials have defined dose constraints for heart and lung, reducing heart exposure and treatment burden in a research setting. However, real-world data on heart and lung doses remain scarce. In 2022, the National Health Service (NHS) in England procured a cloud-based radiation dosimetry repository (ProKnow). Using this resource, we aimed to characterise heart and lung doses in routine breast radiotherapy, quantify variation between centres, inform national guidance, and support quality improvement. METHODS: On Dec 11, 2024, NHS England invited all 49 NHS radiotherapy centres in England to upload anonymised radiotherapy plans to ProKnow. Plan upload was stratified by laterality; breast, chest wall, or partial-breast only (26 Gy in five fractions); breast or chest wall and axilla (40 Gy in 15 fractions); and breast or chest wall and axilla and internal mammary chain (40 Gy in 15 fractions). Use of field-based versus volumetric-modulated arc therapy was recorded. Dose-volume heart and lung metrics were analysed against national scorecards derived from UK trials. FINDINGS: Between Dec 11, 2024, and April 24, 2025, 48 of 49 centres participated, contributing 30 582 plans. 27 368 were harvested for analysis, of which 26 236 (95·9%) were analysable. For breast, chest wall, or partial-breast-only treatments, 10 012 (99·8%) of 10 031 left-sided cases and 6961 (99·9%) of 6962 right-sided cases achieved mean heart doses (MHD) below 2 Gy (median MHD 0·57 Gy [IQR 0·43-0·74; left] and 0·25 Gy [0·18-0·36; right]). For nodal plans including internal mammary chain, median MHDs were 3·3 Gy (IQR 2·3-4·5; left) and 2·3 Gy (1·1-3·7; right). 2405 (98·3%) of 2446 plans met the 6 Gy constraint. 8697 (92·1%) of 9448 left-sided breast, chest wall, or partial-breast plans met the optimal lung dose constraint (volume of ipsilateral lung receiving >7·8 Gy being ≤15%) and 1155 (96·0%) of 1203 left-sided nodal-internal mammary chain plans met the mandatory lung dose constraint (volume of lung receiving >17 Gy being ≤35%). Volumetric-modulated arc therapy was used in 65 (0·3%) of 21 119 breast-only plans, 276 (10·5%) of 2638 nodal-non-internal mammary chain plans, and 1738 (70·1%) of 2479 internal mammary chain plans. Volumetric-modulated arc therapy delivered superior target volume coverage but higher MHDs compared to field-based techniques. INTERPRETATION: This breast radiotherapy dosimetry audit shows the feasibility of high-quality large-scale, real-world dosimetric collection and evaluation across the NHS in England. Heart and lung doses predominantly met constraints and were comparable to international benchmarks. However, dosimetric variation existed between centres, particularly in volumetric-modulated arc therapy planning, identifying opportunities for quality improvement. FUNDING: NHS England.
Curr Treat Options Oncol
· 2026 May · PMID 42149317
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Solitary fibrous tumor (SFT) is an exceedingly rare mesenchymal neoplasm classified as a soft tissue sarcoma (STS). While historically considered indolent, up to 50% of cases can recur or metastasize after long-term foll...Solitary fibrous tumor (SFT) is an exceedingly rare mesenchymal neoplasm classified as a soft tissue sarcoma (STS). While historically considered indolent, up to 50% of cases can recur or metastasize after long-term follow-up. Complete surgical resection constitutes the cornerstone of treatment for localized disease, while the management of locally advanced or metastatic SFT poses a significant clinical challenge underscoring the need for effective systemic therapies. Antiangiogenic agents have shown promising outcomes, particularly in non-dedifferentiated SFT, and are increasingly favored by some as first-line options. Regarding chemotherapy, traditional anthracycline-based STS regimens have demonstrated limited efficacy, shifting the current focus towards combinations with alkylating agents, such as dacarbazine, and other agents such as microtubule inhibitors, like trabectedin. This review summarizes current systemic therapeutic strategies for SFT, highlighting the central role of antiangiogenic therapy as the standard backbone for managing advanced disease. It also discusses current data on chemotherapy, as well as molecularly targeted and immunomodulatory approaches, which are emerging options that require further validation. In addition, we discuss evolving concepts in systemic treatment sequencing, predictive biomarkers, advanced therapeutic combinations under clinical evaluation, and potential future therapeutic agents and targets.
BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is a non-invasive therapy for inoperable primary renal cell carcinoma. However, long-term prospective clinical trial data are scarce. We aimed to use pooled data...BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is a non-invasive therapy for inoperable primary renal cell carcinoma. However, long-term prospective clinical trial data are scarce. We aimed to use pooled data from two clinical trials (FASTRACK and FASTRACK II) to evaluate activity and safety of SABR in the long term. METHODS: In this pooled analysis, we used data from FASTRACK, a single-institutional, phase 1, prospective clinical trial conducted at the Peter MacCallum Cancer Centre (Melbourne, VIC, Australia), and FASTRACK II, an international, non-randomised, phase 2 clinical trial conducted in seven academic hospitals in Australia and one in the Netherlands. The treatment protocol, inclusion and exclusion criteria, and dose constraints were the same in both trials. Patients had primary renal cell carcinoma and were deemed medically inoperable or high-risk for surgery, were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 2 or less, tumours of 10 cm or less in maximal dimension, and N0-N1 disease. Tumours 4 cm or smaller in FASTRACK II and smaller than 5 cm in FASTRACK received a single fraction of 26 Gy and larger tumours received 42 Gy in three fractions 48 h apart. Local control (freedom from local progression) was the primary endpoint, assessed using Response Evaluation Criteria in Solid Tumours (version 1.1) criteria. The analyses were conducted only in patients who commenced protocol treatment. Safety was evaluated with the Common Terminology Criteria for Adverse Events in participants who started protocol treatment. A patient representative was involved in the study design and conduct of FASTRACK II. Both trials were registered with ClinicalTrials.gov (FASTRACK: NCT01676428; FASTRACK II: NCT02613819) and are both completed. FINDINGS: 108 patients were enrolled between June 28, 2012, and Oct 17, 2014 (FASTRACK), and between July 28, 2016, and Feb 27, 2020 (FASTRACK II). Five patients did not receive treatment (one opted for surgery, three did not meet dose constraints and were withdrawn, and one died before treatment). Median age was 76·9 years (IQR 70·0-81·9). 74 (72%) of 103 patients analysed were male and 29 (28%) were female. Race and ethnicity data were not collected. The median follow-up was 5·0 years (IQR 2·3-6·0). Local control at 1 year was 100%, at 3 years was 98% (89-100), and at 5 years was 98% (89-100), with local progression occurring in only one patient who had both local and distant progression at 28 months. Eight (8%) patients had grade 3 adverse events: abdominal or flank pain (four [4%] patients), nausea or vomiting (two [2%]), colonic obstruction (two [2%]), fatigue (one [1%]), and colitis or diarrhoea (one [1%]). All grade 3 or worse adverse events occurred within 2 years of SABR delivery. No grade 4 adverse events or treatment-related deaths were reported. INTERPRETATION: This pooled analysis from two clinical trials of SABR in patients with larger primary kidney tumours unsuitable for surgery supports evidence of long-term local control and low rate of severe adverse events. These results support further investigation through a randomised trial comparing SABR with surgery in select operable patients. FUNDING: None.
BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is an emerging, non-invasive alternative for primary renal cell carcinoma. We aimed to provide the final long-term trial outcomes of TransTasman Radiation Oncolo...BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is an emerging, non-invasive alternative for primary renal cell carcinoma. We aimed to provide the final long-term trial outcomes of TransTasman Radiation Oncology Group (TROG) 15.03 FASTRACK II, the first phase 2 trial investigating SABR for primary renal cell carcinoma to our knowledge. METHODS: FASTRACK II was a non-randomised, phase 2 study conducted in eight hospitals in Australia and the Netherlands by TROG and the Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group. Here, we report the final pre-planned follow-up results. Adult patients (aged ≥18 years) with histologically confirmed primary renal cell carcinoma, who were medically inoperable, high risk, or declined surgery, had an Eastern Cooperative Oncology Group performance status of 2 or less, had tumours 10 cm or less in size, and had N0-N1 disease were included. Patients underwent either a single fraction SABR of 26 Gy for tumours 4 cm or less in maximum diameter, or 42 Gy in three fractions delivered 48 h apart for tumours more than 4 cm in maximum diameter. The primary outcome was freedom from local progression to assess local control after SABR evaluated with the Response Evaluation Criteria in Solid Tumours. The primary endpoint and safety were evaluated in the intention-to-treat population. A patient representative was involved in the study design and conduct. The trial was registered with ClinicalTrials.gov (NCT02613819) and is closed to enrolment. FINDINGS: Between July 28, 2016, and Feb 27, 2020, 71 patients were enrolled and one withdrew consent before treatment. Median follow-up was 62 months (IQR 60-72), median age was 77 years (70-82). 49 (70%) of 70 patients were male and 21 (30%) were female. Race and ethnicity data were not collected. The median tumour size was 46 mm (37-55), with 24 (34%) patients with T1a disease, 39 (56%) with T1b disease, six (9%) with T2a disease, and one (1%) with T3a disease. One patient (1%) had nodal involvement (N1). SABR resulted in 100% local control at 36 months, 60 months, and 84 months. Seven (10%) patients had at least one grade 3 adverse event within 9 months of SABR that was designated possibly, probably, or definitely related to treatment: nausea and vomiting (three [4%] events); abdominal, flank, or tumour pain (four [6%]); colonic obstruction (two [3%]); and diarrhoea (one [1%]). No new long-term safety signals, grade 4 events, or treatment-related deaths were noted. INTERPRETATION: Long-term follow-up supports the safety and local control of SABR for non-surgical patients with renal cell carcinoma, with no observed local recurrences or cancer-related deaths in this cohort, which had predominantly T1b disease or higher. FUNDING: The Cancer Australia Priority-driven Collaborative Cancer Research Scheme and Varian.
Le F, Jiang Y, Chen Y
… +3 more, Huang X, Ouyang Q, Lü S
Clin Med Insights Oncol
· 2026 · PMID 42136970
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Head and neck squamous cell carcinoma (HNSCC) ranks as the seventh most common cancer globally, with etiological subtypes-carcinogen-driven (human papillomavirus [HPV-negative]) and HPV-driven-shaping tumor immunogenicit...Head and neck squamous cell carcinoma (HNSCC) ranks as the seventh most common cancer globally, with etiological subtypes-carcinogen-driven (human papillomavirus [HPV-negative]) and HPV-driven-shaping tumor immunogenicity and treatment responses. This review highlights immunotherapy's evolution, focusing on PD-1/PD-L1 blockade. HPV-positive tumors feature a "hot" microenvironment with dense tumor-infiltrating lymphocytes (TILs) and PD-L1 upregulation, yielding better immune checkpoint inhibitor (ICI) outcomes. In contrast, HPV-negative cases exhibit a "cold," immunosuppressive profile with inferior ICI responses. Landmark trials like KEYNOTE-048 and CheckMate 141 established pembrolizumab and nivolumab as standards for recurrent/metastatic HNSCC, improving median OS (overall survival) by 2 to 4 months over the EXTREME regimen (cetuximab plus platinum-based chemotherapy), especially in patients with PD-L1 Combined Positive Score (CPS) ⩾ 1. Combination strategies enhance efficacy through multiple mechanisms: chemotherapy induces immunogenic cell death, radiotherapy elicits abscopal effects, and cetuximab provides additional antitumor activity. In locally advanced disease, the KEYNOTE-689 trial demonstrated superior event-free survival with perioperative pembrolizumab versus placebo (59.7 vs 29.6 months), supporting treatment de-escalation strategies. Management of immune-related adverse events follows established NCCN/SITC guidelines. Emerging therapies, including anti-LAG-3/TIM-3 and oncolytic viruses, target resistance. Future efforts emphasize multiomic biomarkers and equitable access to optimize outcomes in this heterogeneous malignancy.
BACKGROUND: FAST-Forward aimed to identify a 1-week adjuvant radiotherapy schedule for early-stage breast cancer that was as safe and efficacious as the standard 3-week schedule of 40 Gy in 15 fractions over 3 weeks. Pri...BACKGROUND: FAST-Forward aimed to identify a 1-week adjuvant radiotherapy schedule for early-stage breast cancer that was as safe and efficacious as the standard 3-week schedule of 40 Gy in 15 fractions over 3 weeks. Primary analysis showed non-inferiority of 5-year ipsilateral breast recurrence for 26 Gy and 27 Gy in five fractions over 1 week, with 26 Gy also having similar results to 40 Gy for normal tissue effects. Here, we report 10-year outcomes of the FAST-Forward trial and 5-year efficacy outcomes of a substudy assessing the approach in patients requiring axillary treatment. METHODS: FAST-Forward is a multicentre, open-label, non-inferiority, phase 3, randomised controlled trial done at 97 hospitals (47 radiotherapy centres and 50 referring hospitals) in the UK. Patients aged 18 years or older with invasive carcinoma of the breast (pT1-3, pN0-1, M0) after breast conservation surgery or mastectomy were eligible. We randomly allocated patients (in a 1:1:1 ratio with random permuted blocks, stratified by radiotherapy centre) to either 40 Gy in 15 fractions (over 3 weeks), 27 Gy in five fractions (over 1 week), or 26 Gy in five fractions (over 1 week) to the whole breast or chest wall. Allocation was not masked because of the nature of the intervention. The primary endpoint was non-inferiority of ipsilateral breast recurrence at 5 years. Here, we report the planned 10-year analysis assessed in the intention-to-treat population (all participants who were randomly assigned and consented for use of data). We also report a planned intention-to-treat analysis of a subsequent substudy assessing 5-year efficacy of the same schedules in patients meeting the study criteria but requiring axillary treatment. The clinical trial was registered with ISRCTN (ISRCTN19906132); the main trial is complete, follow-up of the substudy cohort is ongoing. FINDINGS: Between Nov 24, 2011, and June 19, 2014, 4110 participants were enrolled in the main FAST-Forward trial. 23 withdrew consent for data use and were excluded and 4087 participants were included in the intention-to-treat population for this 10-year analysis. Participants were randomly assigned to 40 Gy (n=1358), 27 Gy (n=1362), or 26 Gy (n=1367). Median follow-up was 10·1 years (IQR 10·0-10·2). Ipsilateral breast recurrence was reported for 116 participants (45 in the 40 Gy group, 41 in the 27 Gy group, and 30 in the 26 Gy group), with 10-year cumulative incidence of 3·6% (95% CI 2·7-4·9) for the 40 Gy group, 2·9% (2·1-4·0) for the 27 Gy group, and 2·1% (1·5-3·1) for the 26 Gy group. 10-year clinician-reported moderate or marked breast or chest wall effects occurred in 100 (13·1%) of 765 participants in the 40 Gy group, 157 (19·3%) of 814 in the 27 Gy group, and 111 (14·4%) of 770 in the 26 Gy group. Between April 11, 2016, and Oct 2, 2018, 469 participants enrolled in the nodal substudy, 466 of which were included in intention-to-treat analyses. Median follow-up was 7·0 years (IQR 6·2-7·1) and 32 locoregional recurrences were reported. INTERPRETATION: Long-term follow-up confirms that 26 Gy in five fractions over 1 week is safe and efficacious for adjuvant radiotherapy to the breast or chest wall, supporting its use as a standard of care. Efficacy data for this schedule in the axillary nodal radiotherapy setting are reassuring; however, sample size limits precision of estimation for this subgroup on its own. FUNDING: UK National Institute for Health and Care Research.
BACKGROUND: Radiotherapy volumes for patients with glioblastoma have remained unchanged for decades and result in large volumes of irradiated brain. We aimed to show the safety of a small-margin, MRI-guided adaptive radi...BACKGROUND: Radiotherapy volumes for patients with glioblastoma have remained unchanged for decades and result in large volumes of irradiated brain. We aimed to show the safety of a small-margin, MRI-guided adaptive radiotherapy approach for glioblastoma. METHODS: This single-arm, phase 2 trial was done at Sunnybrook Health Sciences Centre, Toronto, ON, Canada, and included patients with pathologically confirmed glioblastoma and planned for concurrent daily chemoradiotherapy up to 60 Gy in 30 daily fractions over 6 weeks (long course) or 40 Gy in 15 daily fractions over 3 weeks (short course). Eligible patients were adults (≥18 years) with an expected life expectancy greater than 12 weeks and an Eastern Cooperative Oncology performance status less than or equal to 2. A 5 mm clinical target volume (CTV) was applied, with the allowance of associated T2-weighted fluid-attenuated inversion recovery hyperintense regions in a personalised way at the discretion of the treating physician. All patients were treated with 1·5 T MRI-guided linear accelerator (MR-Linac) incorporating weekly gadolinium-enhanced online adaptive fractions. The primary outcome was the risk of marginal failure powered for non-inferiority with a margin of 10% compared with a historical control. All patients were included in the primary and safety analyses. This study is registered with ClinicalTrials.gov, NCT04726397. FINDINGS: Between April 28, 2021, and May 12, 2023, 109 patients were assessed for eligibility and 98 were enrolled and received treatment on the UNITED protocol with 59 [60%] patients receiving long-course radiotherapy and 39 [40%] receiving short-course radiotherapy. Median follow-up was 14·2 months (IQR 8·9-19·7). 53 (54%) of 98 patients were male and 45 (46%) were female. The observed risk of marginal failure was 4% (95% CI 0-8). The most common grade 3-4 adverse events were lymphopenia (eight [11%] of 72 patients without baseline lymphopenia) and thrombocytopenia (four [4%] of 98 patients). Serious adverse events occurred in one (1%) patient due to febrile neutropenia and there were no treatment-related deaths. INTERPRETATION: MRI-guided adaptation for glioblastoma enables margin de-escalation and resulted in a low rate of marginal failure. A randomised trial comparing this technique to a standard large-margin radiotherapy approach will establish whether toxicity and quality-of-life improvements can be realised. FUNDING: None.