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HERMES: Randomized Trial of 2-Fraction or 5-Fraction Magnetic Resonance Imaging-Guided Adaptive Prostate Radiation Therapy.
No full textPURPOSE: To demonstrate the safety and feasibility of 2-fraction stereotactic body radiation therapy (SBRT) for prostate cancer. METHODS AND MATERIALS: This single-center, noncomparative, phase 2/R-IDEAL 2b trial randomized 46 patients with intermediate/lower high-risk prostate cancer with visible gross tumor volume on multiparametric magnetic resonance imaging to receive 36.25 Gy in 5 fractions over 10 days or 24 Gy in 2 fractions with a gross tumor volume boost up to 27 Gy over 8 days. All treatment was delivered on a magnetic resonance linac with daily adaptive replanning. The primary endpoint was acute grade ≥2 (G2+) genitourinary (GU) toxicity (Common Terminology Criteria for Adverse Events version 5.0). Secondary endpoints include gastrointestinal (GI) toxicity and patient-reported outcomes. RESULTS: G2+ GU acute toxicity was observed in 6 of 22 patients (27.3%; 95% CI, 0.11-0.50) in the 2-fraction group and 7 of 24 patients (29.2%; 95% CI, 0.13-0.50) in the 5-fraction group. There were no grade 3 GU toxicities. G2+ urinary frequency rose from 4.5% (1 of 22) at week 2 to 13.6% (3 of 22) at week 4 in 2-fraction SBRT. G2+ urinary frequency peaked earlier in 5-fraction SBRT at 16.7% (4 of 24) in week 2, falling to 12.5% (3 of 24) at week 4. At 12 weeks, median Expanded Prostate Cancer Index Composite-26 urinary incontinence score was 85.5 (IQR, 75-100) for 2-fraction SBRT and 100 (IQR, 93.8-100) for 5-fraction SBRT. Urinary irritative-obstructive scores were higher at 12 weeks in the 2-fraction group (93.8; IQR, 87.5-100) than in the 5-fraction group (87.5; IQR, 81.3-93.8). Peak International Prostate Symptoms Score was lower in the 2-fraction group (8; IQR, 4-11) than in the 5-fraction group (13.5; IQR, 10-17). G2+ GI acute toxicity occurred in 3 of 24 (6.8%) after 5-fraction SBRT, but none after 2-fraction SBRT. CONCLUSIONS: Acceptable acute GU toxicity was seen after 2-fraction SBRT. Acute GI toxicity was low. Randomized trials are warranted to explore late toxicity and biochemical control
Predictive factors of radioiodine ablation success: results from a MEDIRAD prospective clinical study for thyroid cancer.
No full textOBJECTIVE: Serum thyroglobulin measurements are used in the long-term management of patients with differentiated thyroid cancer following thyroidectomy and radioiodine therapy. The use of predictive biomarkers, such as post-operative stimulated thyroglobulin levels and absorbed dose, may help to identify patients at risk of disease recurrence or an unsuccessful initial treatment. METHODS: Differentiated thyroid cancer patients treated with 1.1 or 3.7 GBq of radioiodine using recombinant human thyrotropin stimulation or thyroid hormone withdrawal were recruited into observational clinical studies in France, Germany and the UK with aligned study endpoints (MEDIRAD). The maximum absorbed dose to the thyroid remnant was determined and compared to post-operative stimulated thyroglobulin with respect to its ability to predict ablation success. Radioiodine therapy success was defined as unstimulated or stimulated thyroglobulin level of <0.2 or <1.0 ng/mL 9-12 months post-radioiodine. RESULTS: Ninety-four patients had follow-up data and negative antithyroglobulin antibody tests. Seventy-eight patients (83%) were deemed excellent biochemical responders. Post-operative thyroglobulin and maximum absorbed dose predicted ablation success with receiver operating characteristic area under the curves of 0.83 ± 0.05 (P < 0.001) and 0.64 ± 0.08 (P = 0.12). A dose-response relationship between maximum absorbed dose and ablation success was found for patients with a post-operative stimulated thyroglobulin of ≥1 ng/mL. CONCLUSIONS: Predictions of ablation success using post-operative stimulated thyroglobulin or the absorbed dose to the thyroid remnant could inform personalisation of management of differentiated thyroid cancer and identify patients where further treatments or more intensive follow-up are required. Patients with a post-operative stimulated Tg of <1 ng/mL likely do not benefit from radioiodine
A retrospective study of the impact of comorbidity, polypharmacy and demographic factors on patient inclusion and healthcare delivery in phase I oncology trials.
No full textBACKGROUND: Phase I trials include patients with metastatic cancer and complex health conditions. Understanding baseline comorbidity and demographic features is critical to improving trial design. METHODS: We used electronic patient records to study the association of comorbidity, polypharmacy, and demographic factors on trial recruitment, time on trial, and health service utilisation. RESULTS: A cohort of 1671 patients was considered for allocation to a phase I study, of whom 518 patients were recruited to a phase I study and 1153 patients were not. A multivariable analysis revealed polypharmacy was associated with lower recruitment to phase I trials with an odds ratio of 0.95 (95% CI: [0.92, 0.99], p = 0.01), and a greater number of emergency admissions with a risk ratio of 1.1 (95% CI: [1.03, 1.17], p = 0.01). Interestingly, comorbidity was not associated with lower recruitment but was associated with a lower time on trial with a hazard ratio of 0.75 (95% CI: [0.62, 0.90], p ≤ 0.001). Demographic factors, including ethnicity, distance of residence from the hospital, and index of multiple deprivation, did not significantly influence these parameters. CONCLUSION: Polypharmacy and comorbidity should be considered both in the design of phase I oncology trials and in planning for healthcare utilisation during these trials
A large-scale retrospective study in metastatic breast cancer patients using circulating tumour DNA and machine learning to predict treatment outcome and progression-free survival.
No full textMonitoring levels of circulating tumour-derived DNA (ctDNA) provides both a noninvasive snapshot of tumour burden and also potentially clonal evolution. Here, we describe how applying a novel statistical model to serial ctDNA measurements from shallow whole genome sequencing (sWGS) in metastatic breast cancer patients produces a rapid and inexpensive predictive assessment of treatment response and progression-free survival. A cohort of 149 patients had DNA extracted from serial plasma samples (total 1013, mean samples per patient = 6.80). Plasma DNA was assessed using sWGS and the tumour fraction in total cell-free DNA estimated using ichorCNA. This approach was compared with ctDNA targeted sequencing and serial CA15-3 measurements. We identified a transition point of 7% estimated tumour fraction to stratify patients into different categories of progression risk using ichorCNA estimates and a time-dependent Cox Proportional Hazards model and validated it across different breast cancer subtypes and treatments, outperforming the alternative methods. We used the longitudinal ichorCNA values to develop a Bayesian learning model to predict subsequent treatment response with a sensitivity of 0.75 and a specificity of 0.66. In patients with metastatic breast cancer, a strategy of sWGS of ctDNA with longitudinal tracking of tumour fraction provides real-time information on treatment response. These results encourage a prospective large-scale clinical trial to evaluate the clinical benefit of early treatment changes based on ctDNA levels
Quantifying the tumour vasculature environment from CD-31 immunohistochemistry images of breast cancer using deep learning based semantic segmentation.
No full textBACKGROUND: Tumour vascular density assessed from CD-31 immunohistochemistry (IHC) images has previously been shown to have prognostic value in breast cancer. Current methods to measure vascular density, however, are time-consuming, suffer from high inter-observer variability and are limited in describing the complex tumour vasculature morphometry. METHODS: We propose a method for automatically measuring a range of vascular parameters from CD-31 IHC images, which together provide a detailed description of the vasculature morphology. We first used a U-Net based convolutional neural network, trained and validated using 36 partially annotated whole slide images from 27 patients, to segment vessel structures and tumour regions from which the measurements are taken. The model also segments the vascular smooth muscle, benign epithelium, adipose tissue, stroma, lymphocyte clusters, nerves and CD-31 positive leukocytes, and we applied it to an additional 21 images from 15 patients. Using these segmentations, we investigated the relationship between the various tissue types and the vasculature and studied the relationship of various vascular parameters with clinical parameters. We also performed a 3D histology analysis on a separate tumour sample as a proof of principle, providing a more comprehensive visualization of vasculature morphology compared to the standard 2D cross-section of a tissue sample. RESULTS: Using two-way cross-validation, we show that vessels were accurately segmented, with Dice scores of 0.875 and 0.856, and were accurately identified, with F1 scores of 0.777 and 0.748. All vascular parameters exhibit strong ( r > 0.7 ) and significant (p<0.001) correlations with measurements taken from the manual ground truth vessel segmentations. A significant relationship between the major/minor axis ratio, a measure of elongation, and the tumour grade was found. CONCLUSION: Our proposed method shows promise as a tool for studying the tumour vasculature and its relationship with surrounding cells and tissue types. Furthermore, the correlation with tumour grade highlights the clinical relevance of our approach. These findings suggest that our method could have substantial implications for improving prognostic assessments and personalizing therapeutic strategies in breast cancer treatment
APC I1307K and clinical management: insights from UK Biobank association analysis of colorectal and other cancer risks in Ashkenazi and non-Ashkenazi whites.
No full textBACKGROUND: APC c.3920T>A; p.Ile1307Lys (I1307K), prevalent in individuals of Ashkenazi Jewish (AJ) origin, has been associated with a modestly increased colorectal cancer (CRC) risk. Clinical recommendations for I1307K heterozygotes vary across countries and expert groups, reflecting differences in population frequencies, modest risk estimates and limited data in non-AJ individuals. METHODS: We analysed UK Biobank data comprising 466 315 individuals (8944 with CRC), using genomic analysis to classify AJ and non-AJ ancestries. RESULTS: I1307K was identified in 7.1% of AJ and 0.08% of non-AJ white participants. No significant association with CRC was observed in AJ (OR: 0.71; 95% CI: 0.17 to 2.95) or non-AJ white individuals (OR: 1.05; 95% CI: 0.50 to 2.22). The previously established OR of 1.7-1.8 for AJ individuals lies within our 95% CI, indicating underpowered results due to limited CRC cases. No significant associations were detected for other cancers. Unbiased, adequately powered CRC case-control studies in non-AJ populations would require cohorts far larger than current resources for feasible analysis. CONCLUSION: Clinical actionability of I1307K should prioritise risk stratification based on overall CRC risk and ancestry-dependent variant detection rates. However, management strategies need not differ by ancestry once a carrier is identified, as the biological impact of I1307K should be consistent across populations
The human RIF1-Long isoform interacts with BRCA1 to promote recombinational fork repair under DNA replication stress.
No full textRIF1 is a multifunctional protein that regulates DNA replication and repair. RIF1-deficient cells are hypersensitive to DNA replication stress. Of the two alternatively spliced RIF1 isoforms, called RIF1-Short and RIF1-Long, the RIF1-Long isoform is more capable than RIF1-Short in supporting cell recovery from replication stress. Examining replication stress resistance mechanisms specific to RIF1-Long, we find that prolonged replication stress unexpectedly induces interaction of RIF1-Long with BRCA1. Mechanistically, a phosphorylated SPKF motif unique to the RIF1-Long isoform binds the tandem BRCT domain of BRCA1. BRCA1-RIF1-Long interaction is strongly down-regulated through dephosphorylation by RIF1-associated Protein Phosphatase 1. BRCA1-RIF1-Long interaction requires ATR signaling, and occurs predominantly during S phase. Loss of RIF1-Long impairs the formation of RAD51 foci, and reduces the efficiency of homology-mediated repair at broken replication forks. In summary, our investigation establishes RIF1-Long as a new functional binding partner of the BRCA1-BRCT domain, crucial to protect cells from extended DNA replication stress by enabling RAD51-dependent repair of broken replication forks
Phase I and II Clinical Studies of the STING Agonist Ulevostinag with and without Pembrolizumab in Participants with Advanced or Metastatic Solid Tumors or Lymphomas.
No full textPURPOSE: We report results from two clinical trials of the cyclic dinucleotide stimulator of IFN genes (STING) agonist ulevostinag. PATIENTS AND METHODS: In a phase I study (NCT03010176) with an accelerated titration design/modified toxicity probability interval method, participants with advanced/metastatic solid tumors or lymphomas received intratumoral ulevostinag (±intravenous pembrolizumab). In an expansion phase, participants with head and neck squamous cell carcinoma (HNSCC) or triple-negative breast cancer received the combination. Primary objectives were safety/tolerability and identifying the recommended phase II dose; biomarkers were exploratory. In a randomized phase II study (NCT04220866), participants with untreated metastatic or unresectable, recurrent HNSCC received intravenous pembrolizumab (±ulevostinag 540 µg). The primary objective was antitumor activity. Pembrolizumab 200 mg was administered every 3 weeks in both studies. RESULTS: In the phase I study (NCT03010176; N = 156), the most common adverse event was pyrexia (70%). Plasma ulevostinag concentrations increased dose-dependently. Circulating levels of C-X-C motif chemokine 10, IFNγ, and IL-6 showed elevation at 2 to 4 hours, peak at 6 to 8 hours, and plateau/partial resolution at 24 hours but, beyond the 540 µg dose, did not show a clear dose-effect relationship. Ten participants experienced dose-limiting toxicities; the recommended phase II dose for intratumoral ulevostinag was 540 µg. In the phase II study (NCT04220866), 4 of 8 participants treated with combination therapy and 1 of 10 treated with pembrolizumab monotherapy had a complete or partial response. The most common adverse event was pyrexia (n = 5). CONCLUSIONS: Intratumoral ulevostinag (±pembrolizumab) had manageable toxicity, dose-dependent pharmacokinetics, and evidence of STING activation and target engagement. Combination therapy showed antitumor activity in participants with untreated metastatic or unresectable, recurrent HNSCC
The accessory type III secretion system effectors collectively shape intestinal inflammatory infection outcomes.
No full textInjection of effectors via a type III secretion system (T3SS) is an infection strategy shared by various Gram-negative bacterial pathogens, many infecting mucosal surfaces. While individual T3SS effectors are well characterized, their network-level organization and the distinction between core and accessory effectors remain incompletely understood. Here, by systematically dissecting the T3SS effector network of the enteric mouse pathogen Citrobacter rodentium (CR) we identified a subset of 12 accessory effectors that, while dispensable for colonization, significantly alter infection outcomes. A strain lacking the accessory effectors (CRM12) remained virulent in susceptible mouse hosts yet resulted in reduced epithelial barrier damage, inflammation, and immune cell infiltration in resistant mice. Deep proteomic analysis specifically targeting CR-attached colonic epithelial cells revealed that, despite lacking 39% of its effector repertoire, infection with CRM12 results in similar changes to global protein expression as seen in mice infected with the wild-type strain, though key regulators of barrier integrity were differentially expressed. Using a host with impaired barrier repair (Il22- /- mice), we confirmed that accessory effectors collectively shape infection outcomes without significantly impacting virulence. This study refines the concept of core and accessory effectors, providing a basis for further studies into effector-driven host adaptation
Ablative Techniques for Lung Metastases: Patient Selection and Outcomes Following Treatment with Stereotactic Radiotherapy or Radiofrequency Ablation.
No full textStereotactic radiotherapy (SBRT) and radiofrequency ablation (RFA) are common ablative techniques for lung metastases. A retrospective review of all patients treated with either modality at a single institution between 2011 and 2019 was conducted. Baseline characteristics and outcomes were compared. Local and distant progression, and overall survival were estimated using the Kaplan-Meier method. Univariable analysis was carried out using Cox regression; this was followed by multivariable modelling. In total, 106 patients treated with RFA and 70 treated with SBRT were identified. Tumours treated with SBRT were larger (median size 18 mm vs. 11 mm) and primarily oligometastatic (91.4% vs. 20%). Median progression-free survival (PFS) was 12.5 months for SBRT and 7.9 months for RFA (p = 0.009). Median OS was similar (p = 0.66). In multivariable analysis, lesion size > 20 mm was predictive of adverse local PFS (p = 0.001), PFS (p = 0.0034) and OS (p = 0.001). A statistically significant interaction effect suggested that RFA was associated with better local PFS within colorectal primary patients (p = 0.035). This study highlights differences in patient selection and outcomes for RFA or SBRT in the treatment of lung metastases at our institution. Future studies for SBRT should focus on the optimum dose schedules required for different histologies. For less-radiosensitive tumours, RFA may offer a superior alternative where dose-escalated SBRT is not possible