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Evolutionary and immune microenvironment dynamics during neoadjuvant treatment of esophageal adenocarcinoma.
No full textLocally advanced esophageal adenocarcinoma remains difficult to treat and the ecological and evolutionary dynamics responsible for resistance and recurrence are incompletely understood. Here, we performed longitudinal multiomic analysis of patients with esophageal adenocarcinoma in the MEMORI trial. Multi-region multi-timepoint whole-exome and paired transcriptome sequencing was performed on 27 patients before, during and after neoadjuvant treatment. We found major transcriptomic changes during treatment with upregulation of immune, stromal and oncogenic pathways. Genetic data revealed that clonal sweeps through treatment were rare. Imaging mass cytometry and T cell receptor sequencing revealed remodeling of the tumor microenvironment during treatment. The presence of genetic immune escape, a less-cytotoxic T cell phenotype and a lack of clonal T cell expansions were linked to poor treatment response. In summary, there were widespread transcriptional and environmental changes through treatment, with limited clonal replacement, suggestive of phenotypic plasticity
Partial-breast radiotherapy after breast conservation surgery for women with early breast cancer (UK IMPORT LOW): 10-year outcomes from a multicentre, open-label, randomised, controlled, phase 3, non-inferiority trial.
No full textBACKGROUND: The IMPORT LOW trial evaluated partial-breast radiotherapy with intensity-modulated radiotherapy in women with early-stage breast cancer at below average risk of ipsilateral breast tumour recurrence (IBTR). 5-year results concluded non-inferiority of IBTR for reduced-dose and partial-breast radiotherapy, with similar or lower frequency of adverse effects compared with whole-breast radiotherapy. We report outcomes after 10 years. METHODS: IMPORT LOW was a randomised, open-label, multicentre, non-inferiority, phase 3 trial. Women were eligible if they were aged 50 years or older and had had breast conservation surgery for unifocal invasive ductal adenocarcinoma, pT1-2 (tumour size of ≤3 cm), N0-1 (none to three positive axillary nodes), grades 1-3, with microscopic margins of non-cancerous tissue of 2 mm or more. Patients were ineligible if they had a previous malignancy of any kind (except non-melanomatous skin cancer), had undergone mastectomy, or had received neoadjuvant or concurrent adjuvant chemotherapy. Patients were randomly assigned (1:1:1) by randomly permuted blocks to radiotherapy regimens of 40 Gy in 15 fractions to the whole breast (whole-breast group), 36 Gy in 15 fractions to the whole breast plus 40 Gy in 15 fractions to the partial breast (reduced-dose group), or 40 Gy in 15 fractions to the partial breast (partial-breast group). Participants were stratified by treatment centre, without masking. The primary endpoint was IBTR. 10-year outcomes were analysed in the intention-to-treat population. Clinician-reported late adverse effects were evaluated in all participants with available data analysed according to allocated treatment. The study is registered in the ISRCTN registry (ISRCTN12852634) and is now complete. FINDINGS: 2018 patients were recruited between May 3, 2007, and Oct 5, 2010, from 30 radiotherapy centres in the UK and randomly assigned to the whole-breast group (n=675), reduced-dose group (n=674), or partial-breast group (n=669). Two participants subsequently withdrew consent. Median age was 63 years (IQR 58-68). 854 (42%) of 2016 patients had grade 1 tumours, 959 (48%) had grade 2 tumours, and 200 (10%) had grade 3 tumours (three tumours were ungradable); 59 (3%) had node-positive disease. Median follow-up was 120 months (IQR 119-122) for the whole-breast group, 121 months (IQR 120-122) for the reduced-dose group, and 120 months (IQR 119-122) for the partial-breast group. By 10 years, IBTR events were reported for 45 of 2016 participants: 17 of 674 in the whole-breast group, 11 of 673 in the reduced-dose group, and 17 of 669 in the partial-breast group, with cumulative incidence of 2·8% (95% CI 1·8-4·5), 1·9% (1·1-3·5), and 3·0% (1·9-4·8), respectively. The estimated absolute difference in 10-year IBTR incidence was -1·02% (95% CI -1·98 to 0·99) for the reduced-dose group and 0·16% (-1·28 to 2·89) for the partial-breast group compared with the whole-breast group. Similar low levels of moderate or marked adverse effects were recorded for participants in all three groups in 10-year clinical assessments. Breast shrinkage had the highest incidence (30 [9%] of 321 in the whole-breast group, 28 [9%] of 322 in the reduced-dose group, and 22 [7%] of 333 in the partial-breast group). INTERPRETATION: Long-term follow-up provides further evidence that partial-breast and reduced-dose radiotherapy are as safe and effective as whole-breast radiotherapy in patients with low-risk early breast cancer. These results reaffirm the use of partial-breast radiotherapy delivered with intensity-modulated radiotherapy in this population as standard of care. FUNDING: Cancer Research UK
Apparent diffusion coefficient as a quantitative biomarker for prostate cancer treatment response on a 1.5 Tesla magnetic resonance-linear accelerator: Impact of image registration and acquisition type.
No full textBACKGROUND AND PURPOSE: Diffusion-weighted magnetic resonance imaging (DW-MRI) is a quantitative biomarker for cancer detection and treatment monitoring. On magnetic resonance-linear accelerator (MR-Linac) systems, diffusion-weighted echo planar imaging (DW-EPI) suffers from geometric distortion, reducing the repeatability of apparent diffusion coefficient (ADC) measurements. This study evaluated the effect of low-distortion split acquisition of fast spin-echo signal (SPLICE) sequences, and of image registration on the repeatability coefficient (RC) of ADC. MATERIALS AND METHODS: ADC bias, repeatability, signal-to-noise ratio (SNR) and geometric fidelity were measured in a diffusion phantom using three DW-EPI and two DW-SPLICE protocols. ADC short-term and long-term RCs were measured in healthy volunteers. In patients, the registration of DW-EPI to unweighted images (b0) was tested for its effect on RC in gross tumour volume (GTV) and non-tumour prostate (NT-P), and for its ability to detect significant ADC changes. RESULTS: Phantom experiments showed strong linear correlation with ground-truth ADC (R2 > 0.99). Among EPI protocols, DW-EPI-AP offered the best balance of high SNR and low RC, while Z-direction encoded DW-EPI was the most variable. Both DW-SPLICE variants exhibited reduced distortion compared with EPI but poorer repeatability. In volunteers, long-term RCs (8.0-33.7 %) varied more than short-term RCs (8.9-15.4 %). In patients, registration improved RCs (GTV: 28.0 → 25.1 %; NT-P: 19.6 → 12.6 %) and improved detection of significant ADC change in patients (GTV: 0/6 → 1/6; NT-P: 2/6 → 5/6). CONCLUSION: RC and accuracy of DW-EPI agrees with published literature and improves after registration. DW-SPLICE shows lower geometric distortion but would require further optimization and validation to improve repeatability
Dosimetric Comparison of CyberKnife and Conventional Linac Prostate Stereotactic Body Radiation Therapy Plans: Analysis of the PACE-B Study.
No full textPURPOSE: In the PACE-B study, a nonrandomized comparison of toxicity outcomes between stereotactic body radiation therapy (SBRT) platforms revealed fewer urinary side effects with CyberKnife (CK) compared with conventional linac (CL) SBRT. This analysis compares baseline characteristics and planning dosimetry between the CK-SBRT and CL-SBRT cohorts in PACE-B, aiming to provide insight into possible reasons for differing toxicity outcomes between the platforms. METHODS AND MATERIALS: Dosimetric parameters for the surrogate urethra (SU), contoured urethra, bladder, bladder trigone (BT), and rectum were extracted from available computed tomography planning scans of PACE-B SBRT patients. The SU and BT were retrospectively delineated. Dose levels analyzed included maximum point dose (Dmax), D2, D50, and D95, where D(n) represents the dose (Gy) to (n)% of the structure. Baseline characteristics and planning dosimetry between the CK-SBRT and CL-SBRT cohorts were compared using Mann-Whitney U tests, t tests, and χ2 tests. RESULTS: Of the 414 patients who received SBRT, 169 (41%) were treated with CK-SBRT and 245 (59%) with CL-SBRT, with dosimetric parameters available for 94% of patients (390/414). There was a nonstatistically significant trend toward more low-risk prostate cancer in the CK-SBRT cohort (12% vs 6% P = .02 [nonsignificant]). Margins were similar between platforms, except posteriorly, where CK-SBRT had smaller margins. CK-SBRT plans had significantly higher median SU Dmax (45.9 Gy vs 42.8 Gy, P < .0001), D2%, and D50% compared with CL-SBRT plans. Additionally, CK-SBRT plans had significantly higher median BT Dmax (43.4 Gy vs 41.6 Gy, P < .0001), D2%, and D95%, as well as higher median bladder Dmax, D50%, and D95%. CK-SBRT plans had lower median rectal D2% (35.5 Gy vs 36.0 Gy, P < .0001) but higher rectal D50% and D95%. CONCLUSIONS: Although the CK-SBRT cohort showed lower urinary toxicity, the planned doses to urinary substructures were actually higher, likely due to heterogeneous dose planning. Factors like intrafraction tracking or other confounding variables may explain the differences in toxicity outcomes between the treatment platforms
Sub-3 Å resolution protein structure determination by single-particle cryo-EM at 100 keV.
No full textCryoelectron microscopy (cryo-EM) has transformed structural biology by providing high-resolution insights into biological macromolecules. We report sub-3 Å resolution structures using the 100 keV Tundra cryo-TEM, equipped with the Falcon C direct electron detector (DED). This system combines advanced optics, extreme-brightness field emission gun (XFEG), and SP-TWIN lens to enhance coherence and resolution. The semi-automated loader reduced contamination and drift, enabling extended data collection, while the high detective quantum efficiency (DQE) of Falcon C improved signal-to-noise ratio. We validated performance by determining structures of biological samples, including apoferritin (2.1 Å), T20S proteasome (2.7 Å), GABAA receptor (2.8 Å), hemoglobin (5.0 Å), transthyretin (3.5 Å), and AAV9 capsid (2.8 Å), spanning 50 kDa-3.9 MDa. This work highlights the potential of 100 keV transmission electron microscopes (TEMs) to make cryo-EM more accessible. It sets a precedent for using lower voltage TEMs not only for screening, but also for high-resolution protein structure determination
PD-1 Blockade Mitigates Surgery-Induced Immunosuppression and Increases the Efficacy of Photodynamic Therapy for Pleural Mesothelioma.
No full textUNLABELLED: Lung-sparing radical pleurectomy with intraoperative photodynamic therapy (PDT) demonstrates remarkable survival for patients with pleural mesothelioma. Nevertheless, most patients treated with this multimodal approach will develop local tumor recurrence. An understanding of potential causes of treatment failure is central to developing mitigation strategies. Surgery importantly reduces disease burden but also produces tumor-promoting inflammation, as demonstrated through transcriptomic analysis of pleural mesothelioma specimens. Using preclinical models in the setting of combination therapy, we separated the benefit of surgical resection from its counterproductive effects on therapeutic outcome. Specifically, we evaluated mechanisms by which surgically induced inflammation can be therapy-limiting in a murine model of tumor incision (TI) introduced by a surgical cut across the tumor. In this TI model, we identified distinct TI-altered patterns in innate and adaptive inflammatory cells in murine mesothelioma tumors, and we studied changes in these patterns with the addition of PDT. TI introduction of an immunosuppressive environment is established via upregulation of PD-1/PD-L1 expression on tumor cells, T cells, and myeloid cells that is partially resolved by PDT. Immune dysfunction is further mitigated by the addition of PD-1 blockade, leading to curative potential in a process that requires Ly6G+ neutrophils and CD8+ T cells. Overall, these studies suggest that, without PDT, surgical modulation of immune cell trafficking and functionality leads to systemic immunosuppression. This immunosuppressive state potentially interferes with the generation of antitumor immunity by PDT. However, targeted inhibition of surgery-induced signaling in the PD-l/PD-L1 pathway counteracts surgery's immunosuppressive outcomes to enhance PDT efficacy in the intraoperative setting. SIGNIFICANCE: Surgery combined with PDT extends survival for patients with mesothelioma, but these patients are still at risk for tumor recurrence, in part due to the immunosuppressive effects of surgery. We find, in a mouse model, that combining surgery, PDT, and immune checkpoint blockade maximizes the efficacy of these therapies
Excised DNA circles from V(D)J recombination promote relapsed leukaemia.
No full textExtrachromosomal DNA amplification is associated with poor cancer prognoses1. Large numbers of excised signal circles (ESCs) are produced as by-products of antigen receptor rearrangement during V(D)J recombination2,3. However, current dogma states that ESCs are progressively lost through cell division4. Here we show that ESCs replicate and persist through many cell generations and share many properties in common with circular extrachromosomal DNAs. Increased ESC copy numbers at diagnosis of B cell precursor acute lymphoblastic leukaemia were highly correlated with subsequent relapse. By taking advantage of the matching recombination footprint that is formed upon the generation of each ESC, we measured ESC persistence and replication and found increased ESC replication in patients who later relapsed. This increased replication is controlled by cell-intrinsic factors and corresponds to increased expression of DNA replication- and repair-associated genes. Consistent with high ESC levels having a role in disease progression, the number of mutations typical of those caused by the V(D)J recombinase-ESC complex was significantly increased at diagnosis in patients who later relapsed. The number of such mutations in genes associated with relapse increased between diagnosis and relapse, and corresponded to clonal expansion of cells with high ESC copy numbers. These data demonstrate that the by-product of V(D)J recombination, when increased in abundance, potently associates with the V(D)J recombinase to cause adverse disease outcomes
Associations between degree of food processing and all-cause and cause-specific mortality: a multicentre prospective cohort analysis in 9 European countries.
No full textBACKGROUND: Ultra-processed food (UPF) consumption has been linked with higher risk of mortality. This multi-centre study investigated associations between food intake by degree of processing, using the Nova classification, and all-cause and cause-specific mortality. METHODS: This study analyzed data from the European Prospective Investigation into Cancer and Nutrition. All-cause mortality and cause-specific mortality due to cancer, circulatory diseases, digestive diseases, Parkinson's disease, and Alzheimer's disease served as endpoints. Hazard ratios (HRs) and 95% CIs were estimated using multivariable Cox proportional hazards regression models. Substitution analyses were also performed. FINDINGS: Overall, 428,728 (71.7% female) participants were included in the analysis and 40,016 deaths were documented after 15.9 years of follow-up. UPFs (in percentage grams per day [g/d]) were positively associated with all-cause mortality (HRs per 1-SD: 1.04; 95% CI: 1.02,1.05), as well as mortality from circulatory diseases (1.09; 95% CI: 1.07,1.12), cerebrovascular disease (1.11; 95% CI: 1.05,1.17), ischemic heart disease (1.10; 95% CI: 1.06,1.15), digestive diseases (1.12; 95% CI: 1.05,1.20), and Parkinson's disease (1.23; 95% CI: 1.06,1.42). No associations were found between UPFs and mortality from cancer or Alzheimer's disease. Replacing processed and UPFs with unprocessed/minimally processed foods was associated with lower mortality risk. INTERPRETATION: In this pan-European analysis, higher UPF consumption was associated with greater mortality from circulatory diseases, digestive diseases, and Parkinson's disease. The results support growing evidence that higher consumption of UPFs and lower consumption of unprocessed foods may have a negative impact on health. FUNDING: l'Institut National du Cancer, and World Cancer Research Fund International
Stromal lipid species dictate melanoma metastasis and tropism.
No full textCancer cells adapt to signals in the tumor microenvironment (TME), but the TME cues that impact metastasis and tropism are still incompletely understood. We show that abundant stromal lipids from young subcutaneous adipocytes, including phosphatidylcholines, are taken up by melanoma cells, where they upregulate melanoma PI3K-AKT signaling, fatty acid oxidation, oxidative phosphorylation (OXPHOS) leading to oxidative stress, resulting in decreased metastatic burden. High OXPHOS melanoma cells predominantly seed the lung and brain; decreasing oxidative stress with antioxidants shifts tropism from the lung to the liver. By contrast, the aged TME provides fewer total lipids but is rich in ceramides, leading to lower OXPHOS and high metastatic burden. Aged TME ceramides taken up by melanoma cells activate the S1P-STAT3-IL-6 signaling axis and promote liver tropism. Inhibiting OXPHOS in the young TME or blocking the IL-6 receptor in the aged TME reduces the age-specific patterns of metastasis imposed by lipid availability
Simulation-free radiotherapy on the MR-linac in prostate cancer.
No full textOBJECTIVES: The radiotherapy (RT) pathway faces bottlenecks. The Rapid Adaptive and Cost-Effective Radiotherapy (RACE) study evaluates the feasibility of using diagnostic MRI (dMRI) scans for planning prostate MRI-guided adaptive RT (MRIgART). METHODS: We audited prostate cancer patients treated with 5-fraction (#) stereotactic body radiotherapy (SBRT) between March 2023 and January 2024, assessing dMRI for RT planning suitability. Planning suitability required a T2-weighted sequence for target/organs at risk (OAR) delineation and a large field-of-view (LFOV). Scans were classified as RT plan suitable or as having specific issues (incomplete body coverage or slice thickness >10 mm). Workflow analysis from RT referral to first fraction estimated potential time savings with simulation-free RT (SFRT). Case studies illustrated identified issues and proposed solutions. RESULTS: dMRIs were available for 93% of patients, with scans originating from various hospitals and conducted on 1.5 Tesla (T) or 3 T MRI scanners. Ideal image characteristics for RT planning were met in 38% of MRIs. Issues such as cropped field of view (FOV) and low slice resolution were identified, but proposed solutions could increase the number of patients with suitable scans to 87%. CONCLUSIONS: The findings suggest that with appropriate technical solutions, most dMRI scans can be adapted for RT planning purposes. ADVANCES IN KNOWLEDGE: The study highlights the potential of SFRT to reduce treatment delays and improve cost-effectiveness