High-precision Adjuvant Radiotherapy for Early-stage Breast Cancer Patients to Reduce Toxicity and Improve Survival

The risk of long-term toxicity of radiation treatment for early-stage breast cancer can be reduced by using partial breast irradiation, lungsparing and a non-coplanar beam set-up. The drift of the patient during irradaition and the motion of markers relative to the treatment target are important factors for the calculation of the margin required for partial breast irradiation

Progression of hearing loss after LINAC-based stereotactic radiotherapy for vestibular schwannoma is associated with cochlear dose, not with pre-treatment hearing level

BACKGROUND: Although stereotactic radiotherapy (SRT) for vestibular schwannoma has demonstrated excellent local control rates, hearing deterioration is often reported after treatment. We therefore wished to assess the change in hearing loss after SRT and to determine which patient, tumor and treatment-related factors influence deterioration. METHODS: We retrospectively analyzed progression of hearing loss in patients with vestibular schwannoma who had received stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT) as a primary treatment between 2000 and 2014. SRS had been delivered as a single fraction of 12 Gy, and patients treated with FSRT had received 30 fractions of 1.8 Gy. To compare the effects of SRS and FSRT, we converted cochlear doses into EQD2. Primary outcomes were loss of functional hearing, Gardner Robertson (GR) classes I and II, and loss of baseline hearing class. These events were used in Kaplan Meier plots and Cox regression. We also calculated the rate of change in Pure Tone Average (PTA) in dB per month elapsed after radiation-a measure we use in linear regression-to assess the associations between the rate of change in PTA and age, pre-treatment hearing level, tumor size, dose scheme, cochlear dose, and time elapsed after treatment (time-to-first-audiogram). RESULTS: The median follow-up was 36 months for 67 SRS patients and 63 months for 27 FSRT patients. Multivariate Cox regression and in linear regression both showed that the cochlear V90 was significantly associated with the progression of hearing loss. But although pre-treatment PTA correlated with rate of change in Cox regression, it did not correlate in linear regression. The time-to-first-audiogram was also significantly associated, indicating time dependency of the rate of change. None of the analysis showed a significant difference between dose schemes. CONCLUSIONS: We found no significant difference between SRS and FSRT. As the deterioration in hearing after radiotherapy for vestibular schwannoma was associated with the cochlea V90, restricting the V90 may reduce progression of hearing loss. The association between loss of functional hearing and baseline PTA seems to be biased by the use of a categorized variable for hearing loss

Supine MRI for regional breast radiotherapy: Imaging axillary lymph nodes before and after sentinel-node biopsy

Regional radiotherapy (RT) is increasingly used in breast cancer treatment. Conventionally, computed tomography (CT) is performed for RT planning. Lymph node (LN) target levels are delineated according to anatomical boundaries. Magnetic resonance imaging (MRI) could enable individual LN delineation. The purpose was to evaluate the applicability of MRI for LN detection in supine treatment position, before and after sentinel-node biopsy (SNB). Twenty-three female breast cancer patients (cTis-3N0M0) underwent 1.5 T MRI, before and after SNB, in addition to CT. Endurance for MRI was monitored. Axillary levels were delineated. LNs were identified and delineated on MRI from before and after SNB, and on CT, and compared by Wilcoxon signed-rank tests. LN locations and LN-based volumes were related to axillary delineations and associated volumes. Although postoperative effects were visible, LN numbers on postoperative MRI (median 26 LNs) were highly reproducible compared to preoperative MRI when adding excised sentinel nodes, and higher than on CT (median 11, p < 0.001). LN-based volumes were considerably smaller than respective axillary levels. Supine MRI of LNs is feasible and reproducible before and after SNB. This may lead to more accurate RT target definition compared to CT, with potentially lower toxicity. With the MRI techniques described here, initiation of novel MRI-guided RT strategies aiming at individual LNs could be possible

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Fully automated VMAT treatment planning for advanced-stage NSCLC patients

Purpose: To develop a fully automated procedure for multicriterial volumetric modulated arc therapy (VMAT) treatment planning (autoVMAT) for stage III/IV non-small cell lung cancer (NSCLC) patients treated with curative intent. Materials and methods: After configuring the developed autoVMAT system for NSCLC, autoVMAT plans were compared with manually generated clinically delivered intensity-modulated radiotherapy (IMRT) plans for 41 patients. AutoVMAT plans were also compared to manually generated VMAT plans in the absence of time pressure. For 16 patients with reduced planning target volume (PTV) dose prescription in the clinical IMRT plan (to avoid violation of organs at risk tolerances), the potential for dose escalation with autoVMAT was explored. Results: Two physicians evaluated 35/41 autoVMAT plans (85%) as clinically acceptable. Compared to the manually generated IMRT plans, autoVMAT plans showed statistically significant improved PTV coverage (V95%increased by 1.1% ± 1.1%), higher dose conformity (R50 reduced by 12.2% ± 12.7%), and reduced mean lung, heart, and esophagus doses (reductions of 0.9 Gy ± 1.0 Gy, 1.5 Gy ± 1.8 Gy, 3.6 Gy ± 2.8 Gy, respectively, all p < 0.001). To render the six remaining autoVMAT plans clinically acceptable, a dosimetrist needed less than 10 min hands-on time for fine-tuning. AutoVMAT plans were also considered equivalent or better than manually optimized VMAT plans. For 6/16 patients, autoVMAT allowed tumor dose escalation of 5–10 Gy. Conclusion: Clinically deliverable, high-quality autoVMAT plans can be generated fully automatically for the vast majority of advanced-stage NSCLC patients. For a subset of patients, autoVMAT allowed for tumor dose escalation

Supine MRI for regional breast radiotherapy: Imaging axillary lymph nodes before and after sentinel-node biopsy

textabstractRegional radiotherapy (RT) is increasingly used in breast cancer treatment. Conventionally, computed tomography (CT) is performed for RT planning. Lymph node (LN) target levels are delineated according to anatomical boundaries. Magnetic resonance imaging (MRI) could enable individual LN delineation. The purpose was to evaluate the applicability of MRI for LN detection in supine treatment position, before and after sentinel-node biopsy (SNB). Twenty-three female breast cancer patients (cTis-3N0M0) underwent 1.5 T MRI, before and after SNB, in addition to CT. Endurance for MRI was monitored. Axillary levels were delineated. LNs were identified and delineated on MRI from before and after SNB, and on CT, and compared by Wilcoxon signed-rank tests. LN locations and LN-based volumes were related to axillary delineations and associated volumes. Although postoperative effects were visible, LN numbers on postoperative MRI (median 26 LNs) were highly reproducible compared to preoperative MRI when adding excised sentinel nodes, and higher than on CT (median 11, p < 0.001). LN-based volumes were considerably smaller than respective axillary levels. Supine MRI of LNs is feasible and reproducible before and after SNB. This may lead to more accurate RT target definition compared to CT, with potentially lower toxicity. With the MRI techniques described here, initiation of novel MRI-guided RT strategies aiming at individual LNs could be possible

Imatinib in patients with severe COVID-19: a randomised, double-blind, placebo-controlled, clinical trial

Background The major complication of COVID-19 is hypoxaemic respiratory failure from capillary leak and alveolar oedema. Experimental and early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak. Methods This randomised, double-blind, placebo-controlled, clinical trial was done at 13 academic and non-academic teaching hospitals in the Netherlands. Hospitalised patients (aged ≥18 years) with COVID-19, as confirmed by an RT-PCR test for SARS-CoV-2, requiring supplemental oxygen to maintain a peripheral oxygen saturation of greater than 94% were eligible. Patients were excluded if they had severe pre-existing pulmonary disease, had pre-existing heart failure, had undergone active treatment of a haematological or non-haematological malignancy in the previous 12 months, had cytopenia, or were receiving concomitant treatment with medication known to strongly interact with imatinib. Patients were randomly assigned (1:1) to receive either oral imatinib, given as a loading dose of 800 mg on day 0 followed by 400 mg daily on days 1–9, or placebo. Randomisation was done with a computer-based clinical data management platform with variable block sizes (containing two, four, or six patients), stratified by study site. The primary outcome was time to discontinuation of mechanical ventilation and supplemental oxygen for more than 48 consecutive hours, while being alive during a 28-day period. Secondary outcomes included safety, mortality at 28 days, and the need for invasive mechanical ventilation. All efficacy and safety analyses were done in all randomised patients who had received at least one dose of study medication (modified intention-to-treat population). This study is registered with the EU Clinical Trials Register (EudraCT 2020–001236–10). Findings Between March 31, 2020, and Jan 4, 2021, 805 patients were screened, of whom 400 were eligible and randomly assigned to the imatinib group (n=204) or the placebo group (n=196). A total of 385 (96%) patients (median age 64 years [IQR 56–73]) received at least one dose of study medication and were included in the modified intention-to-treat population. Time to discontinuation of ventilation and supplemental oxygen for more than 48 h was not significantly different between the two groups (unadjusted hazard ratio [HR] 0·95 [95% CI 0·76–1·20]). At day 28, 15 (8%) of 197 patients had died in the imatinib group compared with 27 (14%) of 188 patients in the placebo group (unadjusted HR 0·51 [0·27–0·95]). After adjusting for baseline imbalances between the two groups (sex, obesity, diabetes, and cardiovascular disease) the HR for mortality was 0·52 (95% CI 0·26–1·05). The HR for mechanical ventilation in the imatinib group compared with the placebo group was 1·07 (0·63–1·80; p=0·81). The median duration of invasive mechanical ventilation was 7 days (IQR 3–13) in the imatinib group compared with 12 days (6–20) in the placebo group (p=0·0080). 91 (46%) of 197 patients in the imatinib group and 82 (44%) of 188 patients in the placebo group had at least one grade 3 or higher adverse event. The safety evaluation revealed no imatinib-associated adverse events. Interpretation The study failed to meet its primary outcome, as imatinib did not reduce the time to discontinuation of ventilation and supplemental oxygen for more than 48 consecutive hours in patients with COVID-19 requiring supplemental oxygen. The observed effects on survival (although attenuated after adjustment for baseline imbalances) and duration of mechanical ventilation suggest that imatinib might confer clinical benefit in hospitalised patients with COVID-19, but further studies are required to validate these findings