Involvement of DNA polymerase μ in the repair of a specific subset of DNA double-strand breaks in mammalian cells

The repair of DNA double-strand breaks (DSB) requires processing of the broken ends to complete the ligation process. Recently, it has been shown that DNA polymerase μ (polμ) and DNA polymerase λ (polλ) are both involved in such processing during non-homologous end joining in vitro. However, no phenotype was observed in animal models defective for either polμ and/or polλ. Such observations could result from a functional redundancy shared by the X family of DNA polymerases. To avoid such redundancy and to clarify the role of polμ in the end joining process, we generated cells over-expressing the wild type as well as an inactive form of polμ (polμD). We observed that cell sensitivity to ionizing radiation (IR) was increased when either polμ or polμD was over-expressed. However, the genetic instability in response to IR increased only in cells expressing polμD. Moreover, analysis of intrachromosomal repair of the I-SceI-induced DNA DSB, did not reveal any effect of either polμ or polμD expression on the efficiency of ligation of both cohesive and partially complementary ends. Finally, the sequences of the repaired ends were specifically affected when polμ or polμD was over-expressed, supporting the hypothesis that polμ could be involved in the repair of a DSB subset when resolution of junctions requires some gap filling

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Involved-field radiotherapy for patients with mantle cell lymphoma

Introduction: Retrospective analysis was performed at a single institution to assess the responsiveness of mantle cell lymphoma (MCL) to involved-field radiotherapy (IFRT). Methods: All patients treated with IFRT to at least one site of MCL between 1998 and 2012 were included. There were 25 patients who received radiotherapy to 60 disease sites. Primary endpoint was overall response rate (ORR) infield for the first site of MCL treated per patient. Predictors of ORR were analysed for the primary endpoint. Time to local progression (TLP) infield and progression-free survival were calculated from the start of the first treatment course. Analysis of all sites collectively was also undertaken. Survival analysis was conducted by the Kaplan-Meier method. Results: ORR rate was 84% for the first site treated per patient. Complete response and partial response rates were 68% and 16% respectively. Median TLP following radiotherapy to the first site was not reached. Infield control rate was 91% at 12 months (95% confidence interval 69-97%). When analysis was performed on all 60 sites, ORR was 85%. Symptomatic improvement occurred after IFRT to 93% of all sites. Systemic progression outside the radiotherapy field was the predominant form of failure following IFRT. Conclusion: Radiotherapy generally induced a clinical response at all levels of dose administered, ranging from 3 to 36Gy. However, increased durability of local control was suggested with higher doses. Radiotherapy is an effective treatment for palliation of MCL with objective and symptomatic responses seen over a range of radiotherapy doses

Dosimetric comparison of optimization methods for multichannel intracavitary brachytherapy for superficial vaginal tumors

Purpose: Multichannel vaginal applicators allow treatment of a more conformal volume compared with a single, central vaginal channel. There are several optimization methods available for use with multichannel applicators, but no previous comparison of these has been performed in the treatment of superficial vaginal tumors. Accordingly, a feasibility study was completed to compare inverse planning by simulated annealing (IPSA), dose point optimization (DPO), and graphical optimization for high-dose-rate brachytherapy using a multichannel, intracavitary vaginal cylinder. Methods and Materials: This comparative study used CT data sets from five patients with superficial vaginal recurrences of endometrial cancer treated with multichannel intracavitary high-dose-rate brachytherapy. Treatment plans were generated using DPO, graphical optimization, surface optimization with IPSA (surf IPSA), and two plans using volume optimization with IPSA. The plans were evaluated for target coverage, conformal index, dose homogeneity index, and dose to organs at risk. Results: Best target coverage was achieved by volume optimization with IPSA 2 and surf IPSA with mean V100 values of 93.89% and 91.87%, respectively. Doses for the most exposed 2-cm³ of the bladder (bladder D2cc) was within tolerance for all optimization methods. Rectal D2cc was above tolerance for one DPO plan. All volume optimization with IPSA plans resulted in higher vaginal mucosa doses for all patients. Greatest homogeneity within the target volume was seen with surf IPSA and DPO. Highest conformal indices were seen with surf IPSA and graphical optimization. Conclusions: Optimization with surf IPSA was user friendly for the generation of treatment plans and achieved good target coverage, conformity, and homogeneity with acceptable doses to organs at risk

Implications for dosimetric changes when introducing MR-guided brachytherapy for small volume cervix cancer: a comparison of CT and MR-based treatments in a single centre

To evaluate cervix brachytherapy dosimetry with the introduction of magnetic resonance (MR) based treatment planning and volumetric prescriptions and propose a method for plan evaluation in the transition period. The treatment records of 69 patients were reviewed retrospectively. Forty one patients were treated using computed tomography (CT)-based, Point A-based prescriptions and 28 patients were treated using magnetic resonance (MR)-based, volumetric prescriptions. Plans were assessed for dose to Point A and organs at risk (OAR) with additional high-risk clinical target volume (HR-CTV) dose assessment for MR-based brachytherapy plans. ICRU-38 point doses and GEC-ESTRO recommended volumetric doses (D2_cc for OAR and D₁₀₀, D₉₈ and D₉₀ for HR-CTV) were also considered. For patients with small HR-CTV sizes, introduction of MR-based volumetric brachytherapy produced a change in dose delivered to Point A and OAR. Point A doses fell by 4.8 Gy (p = 0.0002) and ICRU and D2cc doses for OAR also reduced (p < 0.01). Mean Point A doses for MR-based brachytherapy treatment plans were closer to those of HR-CTV D₁₀₀ for volumes less than 20 cm³ and HR-CTV D₉₈ for volumes between 20 and 35 cm³, with a significant difference (p < 0.0001) between Point A and HR-CTV D₉₀ doses in these ranges. In order to maintain brachytherapy dose consistency across varying HR-CTV sizes there must be a relationship between the volume of the HR-CTV and the prescription dose. Rather than adopting a ‘one size fits all’ approach during the transition to volume-based prescriptions, this audit has shown that separating prescription volumes into HR-CTV size categories of less than 20 cm³, between 20 and 35 cm³, and more than 35 cm³ the HR-CTV can provide dose uniformity across all volumes and can be directly linked to traditional Point A prescriptions

Optimal single 3T MR imaging sequence for HDR brachytherapy of cervical cancer

Purpose: The superior image quality of 3 tesla (3T) magnetic resonance (MR) imaging in cervical cancer offers the potential to use a single image set for brachytherapy. This study aimed to determine a suitable single sequence for contouring tumour and organs at risk, applicator reconstruction, and treatment planning. Material and methods: A 3T (Skyra, Siemens Healthcare AG, Germany) MR imaging system with an 18 channel body matrix coil generated HDR cervical cancer brachytherapy planning images on 20 cases using plastic-based treatment applicators. Seven different T2-weighted Turbo Spin Echo (TSE) sequences including both 3D and contiguous 2D scans based on sagittal, axial (transverse), and oblique planes were analysed. Each image set was assessed for total scanning time and usefulness in tumour localization via inter- and intra-observer analysis of high-risk clinical target volume (HR CTV) contouring. Applicator reconstruction in the treatment planning system was also considered. Results: The intra-observer difference in HR CTV volumes between 2D and 3D axial-based image sets was low with an average difference of 3.1% for each observer. 2D and 3D sagittal image sets had the highest intra- and inter observer differences (over 15%). A 2D axial 'double oblique' sequence was found to produce the best intra- (average difference of 0.6%) and inter-observer (mean SD of 9.2%) consistency and greatest conformity (average 0.80). Conclusions: There was little difference between 2D and 3D-based scanning sequences; however the increased scanning time of 3D sequences have potential to introduce greater patient motion artifacts. A contiguous 2D sequence based on an axial T2-weighted turbo-spin-echo (TSE) sequence orientated in all planes of the treatment applicator provided consistent tumour delineation whilst allowing applicator reconstruction and treatment planning

Intensity-modulated radiation therapy:not a dry eye in the house

Inverse planned intensity-modulated radiation therapy (IMRT) has been applied to patients in a conformal fashion in order to avoid the lacrimal gland. In the present study, we report a patient in which a potential planned dose of 63 Gy to the lacrimal gland for a conventional plan was reduced to 12 Gy to the lacrimal gland for the IMRT plan. Dose objective inverse planning was provided using a Pinnacle treatment planning computer and treatment was delivered using a Varian dynamic multileaf collimator (MLC) on a Varian linear accelerator. Because multiple MLC segments are used to deliver the modulated treatment, conventional dose checks by manual calculation are not practical. To aid in an alternative dosimetric verification process, the Pinnacle planning computer has two unique dose tools, which provide axial and beams eye view doses on user-specified check phantoms. The combined field axial dose tool matched our ion chamber dose checks within +/- 2.4% at the isocentre. The individual beams eye view dose tool matched film dose maps within +/- 3% in the umbra

Spinal multiparametric MRI and DEXA changes over time in men with prostate cancer treated with androgen deprivation therapy: a potential imaging biomarker of treatment toxicity

Objectives: To explore changes in bone mineral density (BMD) measured by DEXA and MRS fat fraction (FF), Dixon FF, and ADC in lower spinal vertebral bodies in men with prostate cancer treated with androgen deprivation therapy (ADT). Methods: Twenty-eight men were enrolled onto a clinical trial. All received ADT. DEXA imaging was performed at baseline and 12\ua0months. L-spine MRI was done at baseline and 6\ua0months. Results: The number of patients who underwent DEXA, Dixon, ADC, and MRS at baseline/follow-up were 28/27, 28/26, 28/26, and 22/20. An increase in FF was observed from T11 to S2 (average 1\ua0%/vertebra). There was a positive correlation between baseline MRS FF and Dixon FF (r = 0.85, p 5\ua0% BMD loss after 1\ua0year had triple the percentage increase in MRS FF at 6\ua0months (61.1\ua0% vs. 20.9\ua0%, p = 0.19). Conclusions: Changes are observed on L-spine MRI after 6\ua0months of ADT. Further investigation is warranted of MRS change as a potential predictive biomarker for later BMD loss. Key Points: • Spinal marrow fat fraction increases after 6\ua0months of androgen deprivation therapy. • More inferior vertebral bodies tend to have higher fat fractions. • MRS fat fraction changes were associated with later changes in DEXA BMD