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Highlights • Complete tumor response of an L-LCNEC to radiotherapy and immunotherapy. • There is a possible synergetic effect of radiotherapy with immunotherapy. • Immunotherapy seems to be efficient in carcinoma-LCNEC. • Immunotherapy could be effective in the neoadjuvant setting in L-LCNEC. Abstract Lung large-cell neuroendocrine carcinoma (L-LCNEC) is a rare subset of lung carcinoma associated with poor overall survival. Due to its rarity, little has been established about its optimal treatment in the advanced stage. We report the case of a 41-year-old woman diagnosed with an unresectable locally advanced L-LCNEC who presented an impressive tumor response to immunotherapy with nivolumab after non-curative thoracic radiotherapy. Salvage surgery was then performed, and pathologic analysis of the resected piece revealed the absence of residual viable tumor cells. Based on this case report, we discuss the literature regarding the efficacy of inhibitors of programmed death-1 protein (PD-1) in L-LCNEC and their use in association with radiotherapy and in the neoadjuvant setting. [ABSTRACT FROM AUTHOR]

• The collection of quality indicators on a national level is a valuable process in steering quality improvement initiatives. • Radiotherapy specific quality indicators have been collected on a yearly and national basis in Belgium from 2016 until now. • The feasibility of collecting radiotherapy specific quality indicators on a national basis was demonstrated with a high level of participation. • Personalized feedback of the collected QIs have shown to guide departments in setting up quality improvement initiatives. To promote best practice and quality of care, the Belgian College of Physicians for Radiotherapy Centers established a set of radiotherapy specific quality indicators for benchmarking on a national level. This paper describes the development, the collected QIs, the observed trends and the departments' evaluation of this initiative. The Donabedian approach was used, focussing on structural, process and outcome QIs. The criteria for QI selection were availability, required for low-threshold regular collection, and applicability to guidelines and good practice. The QIs were collected yearly and individualized reports were sent out to all RT departments. In 2021, a national survey was held to evaluate the ease of data collection and submission, and the perceived importance and validity of the collected QIs. 18 structural QI and 37 process and outcome parameters (n = 25 patients/pathology/department) were collected. The participation rate amounted to 95 % overall. The analysis gave a national overview of RT activity, resources, clinical practice and reported acute toxicities. The individualized reports allowed departments to benchmark their performance. The 2021 survey indicated that the QIs were overall easy to collect, relevant and reliable. The collection of acute recorded toxicities was deemed a weak point due to inter-observer variabilities and lack of follow-up time. QI collection on a national level is a valuable process in steering quality improvement initiatives. The feasibility and relevance was demonstrated with a high level of participation. The national initiative will continue to evolve as a quality monitoring and improvement tool. [ABSTRACT FROM AUTHOR]

Background and purpose Cardiac disease has been related to heart dose after left-sided breast radiotherapy. This trial evaluates the heart sparing ability and feasibility of deep inspiration breath hold (DIBH) in the prone position for left-sided whole breast irradiation (WBI). Materials and methods Twelve patients underwent CT-simulation in supine shallow breathing (SB), supine DIBH, prone SB and prone DIBH. A validation cohort of 38 patients received prone SB and prone DIBH CT-scans; the last 30 patients were accepted for prone DIBH treatment. WBI was planned with a prescription dose of 40.05 Gy. Results DIBH was able to reduce ( p < 0.001) heart dose in both positions, with results for prone DIBH at least as favorable as for supine DIBH. Mean heart dose was lowered from 2.2 Gy for prone SB to 1.3 Gy for prone DIBH ( p < 0.001), while preserving the lung sparing ability of prone positioning. Moreover prone DIBH nearly consistently reduced mean heart dose to less then 2 Gy, regardless of breast volume. All patients were able to perform the simulation procedure, 28/30 patients were treated with prone DIBH. Conclusions This trial demonstrates the ability and feasibility of prone DIBH to acquire optimal heart and lung sparing for left-sided WBI. [ABSTRACT FROM AUTHOR]

Background and purpose Delineation of clinical target volumes (CTVs) is a weak link in radiation therapy (RT), and large inter-observer variation is seen in breast cancer patients. Several guidelines have been proposed, but most result in larger CTVs than based on conventional simulator-based RT. The aim was to develop a delineation guideline obtained by consensus between a broad European group of radiation oncologists. Material and methods During ESTRO teaching courses on breast cancer, teachers sought consensus on delineation of CTV through dialogue based on cases. One teacher delineated CTV on CT scans of 2 patients, followed by discussion and adaptation of the delineation. The consensus established between teachers was sent to other teams working in the same field, both locally and on a national level, for their input. This was followed by developing a broad consensus based on discussions. Results Borders of the CTV encompassing a 5 mm margin around the large veins, running through the regional lymph node levels were agreed, and for the breast/thoracic wall other vessels were pointed out to guide delineation, with comments on margins for patients with advanced breast cancer. Conclusion The ESTRO consensus on CTV for elective RT of breast cancer, endorsed by a broad base of the radiation oncology community, is presented to improve consistency. [ABSTRACT FROM AUTHOR]

Summary Background Since the introduction of breast-conserving treatment, various radiation doses after lumpectomy have been used. In a phase 3 randomised controlled trial, we investigated the effect of a radiation boost of 16 Gy on overall survival, local control, and fibrosis for patients with stage I and II breast cancer who underwent breast-conserving treatment compared with patients who received no boost. Here, we present the 20-year follow-up results. Methods Patients with microscopically complete excision for invasive disease followed by whole-breast irradiation of 50 Gy in 5 weeks were centrally randomised (1:1) with a minimisation algorithm to receive 16 Gy boost or no boost, with minimisation for age, menopausal status, presence of extensive ductal carcinoma in situ, clinical tumour size, nodal status, and institution. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. The trial is registered with ClinicalTrials.gov , number NCT02295033 . Findings Between May 24, 1989, and June 25, 1996, 2657 patients were randomly assigned to receive no radiation boost and 2661 patients randomly assigned to receive a radiation boost. Median follow-up was 17·2 years (IQR 13·0–19·0). 20-year overall survival was 59·7% (99% CI 56·3–63·0) in the boost group versus 61·1% (57·6–64·3) in the no boost group, hazard ratio (HR) 1·05 (99% CI 0·92–1·19, p=0·323). Ipsilateral breast tumour recurrence was the first treatment failure for 354 patients (13%) in the no boost group versus 237 patients (9%) in the boost group, HR 0·65 (99% CI 0·52–0·81, p<0·0001). The 20-year cumulative incidence of ipsilatelal breast tumour recurrence was 16·4% (99% CI 14·1–18·8) in the no boost group versus 12·0% (9·8–14·4) in the boost group. Mastectomies as first salvage treatment for ipsilateral breast tumour recurrence occurred in 279 (79%) of 354 patients in the no boost group versus 178 (75%) of 237 in the boost group. The cumulative incidence of severe fibrosis at 20 years was 1·8% (99% CI 1·1–2·5) in the no boost group versus 5·2% (99% CI 3·9–6·4) in the boost group (p<0·0001). Interpretation A radiation boost after whole-breast irradiation has no effect on long-term overall survival, but can improve local control, with the largest absolute benefit in young patients, although it increases the risk of moderate to severe fibrosis. The extra radiation dose can be avoided in most patients older than age 60 years. Funding Fonds Cancer, Belgium. [ABSTRACT FROM AUTHOR]

Purpose To quantify the influence on heart dose metrics of prone left-sided whole-breast irradiation in an end-inspiratory phase (Pr IN ) versus an end-expiratory phase (Pr EX ). Patients and methods Twenty patients underwent CT-simulation in Pr IN and Pr EX . Dynamic intensity-modulated radiotherapy was planned for whole-breast irradiation with a median prescription dose of 40.05 Gy in 15 fractions and maximal sparing of the organs at risk. Dose–volume parameters were analyzed for heart, left anterior descending coronary artery, ipsilateral lung and both breasts. Results Pr IN consistently reduced ( P < 0.001) heart and left anterior descending coronary artery dose metrics compared to Pr EX . Population averages for maximum and mean heart dose were 6.2 Gy and 1.3 Gy for Pr IN versus 21.4 Gy and 2.5 Gy for Pr EX , respectively. Moreover, a maximum heart dose less than 10 Gy was achieved in 80% of patients for Pr IN . Target dose distribution, ipsilateral lung and contralateral breast sparing by radiation dose were similar for both procedures. Conclusions Inspiratory gating consistently reduced heart dose metrics pointing to a possible benefit of breathing-adapted radiotherapy for prone left-sided whole-breast irradiation. [ABSTRACT FROM AUTHOR]

Current antiviral agents can control but not eliminate hepatitis B virus (HBV), because HBV establishes a stable nuclear covalently closed circular DNA (cccDNA). Interferon-α treatment can clear HBV but is limited by systemic side effects. We describe how interferon-α can induce specific degradation of a the nuclear viral DNA without hepatotoxicity and propose lymphotoxin-β receptor activation as therapeutic alternative. Interferon-α and lymphotoxin-β receptor activation up-regulated APOBEC3A and APOBEC3B cytidine deaminases, respectively, in HBV-infected cells, primary hepatocytes, and human liver needle biopsies. HBV core protein mediated the interaction with nuclear cccDNA, resulting in cytidine deamination, apurinic/apyrimidinic site formation, and finally cccDNA degradation that prevented HBV reactivation. Genomic DNA was not affected. Thus, inducing nuclear deaminases--for example, by lymphotoxin-β receptor activation--allows the development of new therapeutics that, in combination with existing antivirals, may cure hepatitis B. [ABSTRACT FROM AUTHOR]

Abstract: In this work, we aimed to build a 3D-model of NIK and to study the binding of pyrazolo[4,3-c]isoquinolines with a view to highlight the structural elements responsible for their inhibitory potency. However, in the course of this work, we unexpectedly found that the pyrazolo[4,3-c]isoquinolines initially reported as NIK inhibitors were neither inhibitors of this enzyme nor of the alternative NF-κB pathway, but were in fact inhibitors of another kinase, the TGF-β activated kinase 1 (TAK1) which is involved in the classical NF-κB pathway. [Copyright &y& Elsevier]

Abstract: Purpose: This work describes the clinical validation of an automatic segmentation algorithm in CT-based radiotherapy planning for prostate cancer patients. Material and methods: The validated auto-segmentation algorithm (Smart Segmentation, version 1.0.05) is a rule-based algorithm using anatomical reference points and organ-specific segmentation methods, developed by Varian Medical Systems (Varian Medical Systems iLab, Baden, Switzerland). For the qualitative analysis, 39 prostate patients are analysed by six clinicians. Clinicians are asked to rate the auto-segmented organs (prostate, bladder, rectum and femoral heads) and to indicate the number of slices to correct. For the quantitative analysis, seven radiation oncologists are asked to contour seven prostate patients. The individual clinician contour variations are compared to the automatic contours by means of surface and volume statistics, calculating the relative volume errors and both the volume and slice-by-slice degree of support, a statistical metric developed for the purposes of this validation. Results: The mean time needed for the automatic module to contour the four structures is about one minute on a standard computer. The qualitative evaluation using a score with four levels (“not acceptable”, “acceptable”, “good” and “excellent”) shows that the mean score for the automatically contoured prostate is “good”; the bladder scores between “excellent” and “good”; the rectum scores between “acceptable” and “not acceptable”. Using the concept of surface and volume degree of support, the degree of support given to the automatic module is comparable to the relative agreement among the clinicians for prostate and bladder. The slice-by-slice analysis of the surface degree of support pinpointed the areas of disagreement among the clinicians as well as between the clinicians and the automatic module. Conclusion: The efficiency and the limits of the automatic module are investigated with both a qualitative and a quantitative analysis. In general, with efficient correction tools at hand, the use of this auto-segmentation module will lead to a time gain for the prostate and the bladder; with the present version of the algorithm, modelling of the rectum still needs improvement. For the quantitative validation, the concept of relative volume error and degree of support proved very useful. [Copyright &y& Elsevier]

Abstract: Background and purposes: The appropriate application of 3-D conformal radiotherapy, intensity modulated radiotherapy or image guided radiotherapy for patients undergoing radiotherapy for prostate cancer requires a standardisation of target delineation as well as clinical quality assurance procedures. Patients and methods: Pathological and imaging studies provide valuable information on tumour extension. In addition, clinical investigations on patient positioning and immobilisation as well as treatment verification data offer an abundance of information. Results: Target volume definitions for different risk groups of prostate cancer patients based on pathological and imaging studies are provided. Available imaging modalities, patient positioning and treatment preparation studies as well as verification procedures are collected from literature studies. These studies are summarised and recommendations are given where appropriate. Conclusions: On behalf of the European Organisation for Research and Treatment of Cancer (EORTC) Radiation Oncology Group this article presents a common set of recommendations for external beam radiotherapy of patients with prostate cancer. [Copyright &y& Elsevier]

Summary Concomitant hepatocyte apoptosis and regeneration is a hallmark of chronic liver diseases (CLDs) predisposing to hepatocellular carcinoma (HCC). Here, we mechanistically link caspase-8-dependent apoptosis to HCC development via proliferation- and replication-associated DNA damage. Proliferation-associated replication stress, DNA damage, and genetic instability are detectable in CLDs before any neoplastic changes occur. Accumulated levels of hepatocyte apoptosis determine and predict subsequent hepatocarcinogenesis. Proliferation-associated DNA damage is sensed by a complex comprising caspase-8, FADD, c-FLIP, and a kinase-dependent function of RIPK1. This platform requires a non-apoptotic function of caspase-8, but no caspase-3 or caspase-8 cleavage. It may represent a DNA damage-sensing mechanism in hepatocytes that can act via JNK and subsequent phosphorylation of the histone variant H2AX. [ABSTRACT FROM AUTHOR]

In 1973 R.C. Lyneham and others warned against the possible epileptogenic effect of prostaglandins. We studied the influence of this substance on the electroencephalogram of 53 subject (31 non-epileptics and 22 epileptics) before and during the administration of PG E2. Forty-eight tracings remained unchanged, four showed a slight improvement and one showed some worsening during infusion of PG E2. One patient, suffering from daily psychomotor attacks had, accidentally a fit during the trial. It can be concluded that PG E2 does not alter the electroencephalogram in a significant way and that it does not induce epileptic seizures.

A case is presented of a young woman with a serious addiction to levodopa who over the years developed an extrapyramidal syndrome and chronic paranoid psychotic behaviour. The possible pathophysiological mechanism is discussed.