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Summary Background Whole breast irradiation delivered once per day over 3–5 weeks after breast conserving surgery reduces local recurrence with good cosmetic results. Accelerated partial breast irradiation (APBI) delivered over 1 week to the tumour bed was developed to provide a more convenient treatment. In this trial, we investigated if external beam APBI was non-inferior to whole breast irradiation. Methods We did this multicentre, randomised, non-inferiority trial in 33 cancer centres in Canada, Australia and New Zealand. Women aged 40 years or older with ductal carcinoma in situ or node-negative breast cancer treated by breast conserving surgery were randomly assigned (1:1) to receive either external beam APBI (38·5 Gy in ten fractions delivered twice per day over 5–8 days) or whole breast irradiation (42·5 Gy in 16 fractions once per day over 21 days, or 50 Gy in 25 fractions once per day over 35 days). Patients and clinicans were not masked to treatment assignment. The primary outcome was ipsilateral breast tumour recurrence (IBTR), analysed by intention to treat. The trial was designed on the basis of an expected 5 year IBTR rate of 1·5% in the whole breast irradiation group with 85% power to exclude a 1·5% increase in the APBI group; non-inferiority was shown if the upper limit of the two-sided 90% CI for the IBTR hazard ratio (HR) was less than 2·02. This trial is registered with ClinicalTrials.gov , NCT00282035 . Findings Between Feb 7, 2006, and July 15, 2011, we enrolled 2135 women. 1070 were randomly assigned to receive APBI and 1065 were assigned to receive whole breast irradiation. Six patients in the APBI group withdrew before treatment, four more did not receive radiotherapy, and 16 patients received whole breast irradiation. In the whole breast irradiation group, 16 patients withdrew, and two more did not receive radiotherapy. In the APBI group, a further 14 patients were lost to follow-up and nine patients withdrew during the follow-up period. In the whole breast irradiation group, 20 patients were lost to follow-up and 35 withdrew during follow-up. Median follow-up was 8·6 years (IQR 7·3–9·9). The 8-year cumulative rates of IBTR were 3·0% (95% CI 1·9–4·0) in the APBI group and 2·8% (1·8–3·9) in the whole breast irradiation group. The HR for APBI versus whole breast radiation was 1·27 (90% CI 0·84–1·91). Acute radiation toxicity (grade ≥2, within 3 months of radiotherapy start) occurred less frequently in patients treated with APBI (300 [28%] of 1070 patients) than whole breast irradiation (484 [45%] of 1065 patients, p Interpretation External beam APBI was non-inferior to whole breast irradiation in preventing IBTR. Although less acute toxicity was observed, the regimen used was associated with an increase in moderate late toxicity and adverse cosmesis, which might be related to the twice per day treatment. Other approaches, such as treatment once per day, might not adversely affect cosmesis and should be studied. Funding Canadian Institutes for Health Research and Canadian Breast Cancer Research Alliance.

Purpose To determine the impact on overall survival with different salvage therapies, including no treatment, reirradiation, systemic therapy, or radiation and systemic therapy, in participants of a phase 3 clinical trial evaluating dose-dense versus standard-dose temozolomide for patients with newly diagnosed glioblastoma. Methods and Materials This analysis of patients from Trial RTOG 0525 investigated the effect of reirradiation or systemic treatment after tumor progression. Survival from first progression was compared between patients receiving no therapy, systemic therapy alone, radiation alone, and both modalities. The Cox proportional hazards model was used to compare the mortality hazard, controlling for potential confounders. Results The analysis included 637 patients who progressed and had information on their management, excluding those who died less than half a month after progression. A total of 267 patients (42%) received neither reirradiation nor systemic treatment at progression, 24 (4%) received radiation alone, 282 (44%) received systemic treatment only, and 64 (10%) received both radiation and systemic therapy. Patients who received no treatment had a median survival of 4.8 months, lower than with radiation treatment alone (8.2 months), systemic therapy alone (10.6 months), and both radiation and systemic therapy (12.2 months). In survival models controlling for potential confounders, those who received radiation alone had modestly better survival (hazard ratio HR 0.74, 95% confidence interval [CI] 0.43-1.28), whereas those who underwent systemic therapy either without (HR 0.42, 95% CI 0.34-0.53) or with radiation therapy (HR 0.44, 95% CI 0.30-0.63) had better survival. There was no significant survival difference between patients who received radiation only and those who received systemic therapy (either with radiation or alone). Conclusions Patients who received no salvage treatment had poorer survival than those who received radiation, chemotherapy, or the combination. However, patient selection for no treatment likely reflects poorer expected prognosis. There was no significant survival difference among those receiving radiation therapy, systemic therapy, or both. Ongoing clinical trials will help define the role of reirradiation after glioblastoma progression.

Purpose Long-term work disability due to common mental disorders (CMDs) is a growing problem. Yet optimal interventions remain unclear and little is known about implementation challenges in everyday practice. This study aimed to support and evaluate, in real time, the development and implementation of a work rehabilitation program (WRP) designed to promote post-CMD return-to-work (RTW). Methods A 2-year developmental evaluation was performed using a participatory approach. At program outset, the researchers held five work meetings to revise the program’s logic model and discuss its underlying change theory with clinicians. Data collection tools used throughout the study period were structured charts of activities conducted with workers (n = 41); in-depth interviews with program clinicians and managers (n = 9); and participant observation during work meetings. Quantitative data were analyzed using descriptive statistics. Qualitative data underwent thematic analysis using a processual approach. Results Three types of activity were developed and implemented: individual and group interventions targeting workers, and joint activities targeting partners (physicians, employers, others). While worker-targeted activities were generally implemented as planned, joint activities were sporadic. Analysis of the implementation process revealed five challenges faced by clinicians. Determinants included clinicians, host organization, sociopolitical context and resources provided by the evaluation. Conclusion The program studied is original in that it is based on the best available scientific knowledge, yet adapted to contextual particularities. The identified implementation challenges highlight the need for greater importance to be placed on the external, non-program context to ensure sustainable implementation in everyday practice.

Introduction In Canada, few early work rehabilitation services are offered to prevent long-term work disability due to common mental disorders (CMD), despite population-level needs. Our study aimed to support and evaluate the implementation and effects of an innovative program designed to promote post-CMD return-to-work (RTW) in primary healthcare. Methods A developmental evaluation approach (Patton, 2011) was retained. Main implementation strategies consisted of periodically revising the program’s logic model and discussing its underlying theory of change with clinicians. Data collection tools included: dashboards of activities conducted with participants (n=41); interviews with participants upon discharge (n=26) and 6 months post-discharge (n=24); questionnaires completed by attending physicians (n=18). Quantitative data underwent descriptive statistical analyses, while qualitative data underwent thematic analysis. Results were presented and discussed periodically with clinicians to ensure their credibility. Result The implemented program included group interventions, one-on-one interventions, and concerted actions with partners. Participants began the program after 5 months of sick leave on average, and participated for 10±2 weeks. 80% of cases included concerted actions, usually with insurers and rarely attending physicians. However, virtually all the physicians saw the program as meeting needs and promoting RTW. Active components identified by participants concerned primarily the interventions’ group format, but also activities, and clinicians themselves. In terms of the program’s final expected outcome, 69% of the participants returned to work upon discharge and 79% were at work 6 months post-discharge. Discussion The program studied is based on the best scientific evidence and is feasible in a primary healthcare context. Results suggest that it facilitates a sustainable RTW of workers with a CMD and that it supports physicians in their interventions with this population. While additional work is required to demonstrate its effectiveness, current results suggest that a group format is an important intervention component for this target population.

Summary Background Rindopepimut (also known as CDX-110), a vaccine targeting the EGFR deletion mutation EGFRvIII, consists of an EGFRvIII-specific peptide conjugated to keyhole limpet haemocyanin. In the ACT IV study, we aimed to assess whether or not the addition of rindopepimut to standard chemotherapy is able to improve survival in patients with EGFRvIII-positive glioblastoma. Methods In this randomised, double-blind, phase 3 trial, we recruited patients aged 18 years and older with glioblastoma from 165 hospitals in 22 countries. Eligible patients had newly diagnosed glioblastoma confirmed to express EGFRvIII by central analysis, and had undergone maximal surgical resection and completion of standard chemoradiation without progression. Patients were stratified by European Organisation for Research and Treatment of Cancer recursive partitioning analysis class, MGMT promoter methylation, and geographical region, and randomly assigned (1:1) with a prespecified randomisation sequence (block size of four) to receive rindopepimut (500 μg admixed with 150 μg GM-CSF) or control (100 μg keyhole limpet haemocyanin) via monthly intradermal injection until progression or intolerance, concurrent with standard oral temozolomide (150–200 mg/m 2 for 5 of 28 days) for 6–12 cycles or longer. Patients, investigators, and the trial funder were masked to treatment allocation. The primary endpoint was overall survival in patients with minimal residual disease (MRD; enhancing tumour 2 post-chemoradiation by central review), analysed by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01480479. Findings Between April 12, 2012, and Dec 15, 2014, 745 patients were enrolled (405 with MRD, 338 with significant residual disease [SRD], and two unevaluable) and randomly assigned to rindopepimut and temozolomide (n=371) or control and temozolomide (n=374). The study was terminated for futility after a preplanned interim analysis. At final analysis, there was no significant difference in overall survival for patients with MRD: median overall survival was 20·1 months (95% CI 18·5–22·1) in the rindopepimut group versus 20·0 months (18·1–21·9) in the control group (HR 1·01, 95% CI 0·79–1·30; p=0·93). The most common grade 3–4 adverse events for all 369 treated patients in the rindopepimut group versus 372 treated patients in the control group were: thrombocytopenia (32 [9%] vs 23 [6%]), fatigue (six [2%] vs 19 [5%]), brain oedema (eight [2%] vs 11 [3%]), seizure (nine [2%] vs eight [2%]), and headache (six [2%] vs ten [3%]). Serious adverse events included seizure (18 [5%] vs 22 [6%]) and brain oedema (seven [2%] vs 12 [3%]). 16 deaths in the study were caused by adverse events (nine [4%] in the rindopepimut group and seven [3%] in the control group), of which one—a pulmonary embolism in a 64-year-old male patient after 11 months of treatment—was assessed as potentially related to rindopepimut. Interpretation Rindopepimut did not increase survival in patients with newly diagnosed glioblastoma. Combination approaches potentially including rindopepimut might be required to show efficacy of immunotherapy in glioblastoma. Funding Celldex Therapeutics, Inc.

Purpose To prospectively investigate the coronary artery status using coronary CT angiography (CCTA) in patients with Hodgkin lymphoma treated with combined modalities and mediastinal irradiation. Methods and Materials All consecutive asymptomatic patients with Hodgkin lymphoma entered the study during follow-up, from August 2007 to May 2012. Coronary CT angiography was performed, and risk factors were recorded along with leukocyte telomere length (LTL) measurements. Results One hundred seventy-nine patients entered the 5-year study. The median follow-up was 11.6 years (range, 2.1-40.2 years), and the median interval between treatment and the CCTA was 9.5 years (range, 0.5-40 years). Coronary artery abnormalities were demonstrated in 46 patients (26%). Coronary CT angiography abnormalities were detected in nearly 15% of the patients within the first 5 years after treatment. A significant increase (34%) occurred 10 years after treatment ( P =.05). Stenoses were mostly nonostial. Severe stenoses were observed in 12 (6.7%) of the patients, entailing surgery with either angioplasty with stent placement or bypass grafting in 10 of them (5.5%). A multivariate analysis demonstrated that age at treatment, hypertension, and hypercholesterolemia, as well as radiation dose to the coronary artery origins, were prognostic factors. In the group of patients with LTL measurements, hypertension and LTL were the only independent risk factors. Conclusions The findings suggest that CCTA can identify asymptomatic individuals at risk of acute coronary artery disease who might require either preventive or curative measures. Conventional risk factors and the radiation dose to coronary artery origins were independent prognostic factors. The prognostic value of LTL needs further investigation.

Resume Objectif Evaluation de l’optimisation du concept de l’« involved-node radiotherapy » par la radiotherapie conformationnelle avec modulation d’intensite (RCMI) dans la maladie de Hodgkin localisee sus-diaphragmatique. Patients et methodes Les patients etaient atteints de maladie de Hodgkin localisee sus-diaphragmatique. Le traitement a consiste en une chimiotherapie puis une radiotherapie conformationnelle avec modulation d’intensite « involved-node ». Resultats Quarante-sept patients ont ete traites de janvier 2003 a decembre 2010. L’âge median etait de 31 ans (extremes : 17–62). Trente patients etaient atteints d’une maladie de stade I-IIA, 14 de stade I-IIB et trois de rechute. Quarante-deux ont recu de trois a six cycles de chimiotherapie associant l’adriamycine, la bleomycine, la vinblastine et la dacarbazine (ABVD). Les trois patients en situation de rechute ont ete autogreffes avant la radiotherapie. La dose mediane prescrite etait de 36 Gy (20–40). Le suivi median est de 57,4 mois (5,4–94,3). Pour les 44 patients atteints d’une maladie de Hodgkin primitive (44 patients), la probabilite de survie a cinq ans et celle de survie sans progression a cinq ans etaient de 96 % (intervalle de confiance a 95 % : 80–99) et de 92 % (intervalle de confiance a 95 % : 78–97), respectivement. Aucun des trois patients traites en situation de rechute n’a ete atteint de nouvelle rechute (avec un suivi de 85, 12 et neuf mois). Trois maladies de Hodgkin ont rechute, une en plein territoire irradie et deux en dehors. Il n’y a eu qu’un cas de toxicite de grade 3, une pneumopathie regressive sous corticotherapie. Conclusion Ces resultats encourageants sont en faveur de l’utilisation du concept de radiotherapie conformationnelle avec modulation d’intensite « involved-node ».

BACKGROUND: There is limited evidence regarding which salvage treatment approach may be of most benefit for glioblastoma patients who progress following standard chemo-radiation treatment. METHODS: This secondary analysis of RTOG 0525 investigated the effect of reirradiation or systemic treatment in patients with tumor progression. Survival time was calculated from date of progression. Survival from first progression was estimated and compared between patients receiving neither radiation or systemic therapy, systemic therapy alone, or any radiation treatment. Patient characteristics were compared between groups and the Cox proportional hazards model was used to compare hazard of death controlling for potential confounders. RESULTS: A total of 637 patients who progressed with recorded information on their non-protocol therapy, excluding those who died less than half a month after progression, were analyzed. 267 patients (42%) received neither radiation or systemic treatment at progression. 88 patients (14%) received some form of radiation treatment. 282 patients (44%) received systemic treatment only. Patients who received no treatment had a median survival (MS) of 4.8 months, lower than radiation treatment (11.3 months), or systemic therapy (10.6 months). However, there was no survival difference between patients who received systemic therapy and those who received radiotherapy (p = 0.3808). Cox models, controlling for potential confounders, demonstrate no difference in hazard of death (1.13, 95% CI 0.8-1.5) between treatment arms. Patients receiving neither therapy had a statistically significant increased hazard of death (2.45, 95% CI: 1.9-3.1). CONCLUSIONS: Salvage treatments after GBM tumor progression were highly variable. Patients who received radiation with or without systemic therapy had a similar MS as those receiving systemic therapy only. Either treatment was statistically significantly better than no treatment. However, this may be the result of poorer functional status of untreated patients. SUPPORT: This project was supported by grants U10CA21661, U10CA180868, U10CA180822 and U10CA37422 from the NCI and Merck.

In Modern English, adverbs are generally derived from an adjectival root to which the suffix -ly is added. However, -ly is also found in other kinds of words such as adjectives and even a few substantives. Therefore, the problem of the English suffix ?ly lies in the fact that it is generally considered an adverbial suffix even though it is used to form other types of words. The suffix apparently has many uses which would endow it with many functions and meanings. To complicate matters further, some -ty adjectives and adverbs have bare counterparts, and they form adjectival and adverbial pairs. The adverbial pairs are made up of two adverbs derived from the same adjectival root, and one adverb is characterized by the -ly suffix, whereas the other adverb is bare, meaning that it is identical in form to the root. Here is an example: He thought deeply about religious matters, and He plunged deep into the ocean. An example of an adjectival pair would be a kind man and a kindly heart. Interestingly, in a good number of adverbial pairs, the -ly adverb and the bare adverb are not interchangeable, as is the case for deep and deeply, mentioned above. This suggests that there is a semantic difference between the two types of adverbs, and that this difference would probably be explained by the presence of the suffix. Since the -ly suffixes, be they adverbial, adjectival, or substantival, are morphologically identical and since they have a common etymological root, the question of whether a definition exists that could be generalized to all uses of the suffix can be raised. If such a semantic link existed, this would mean that -ly does far more than, as many grammars claim, simply generate adverbs. The goal of this thesis is to show that -ly is a consistently meaningful suffix that tells us something about the nature of the genesis of the lexical content of whatever part of speech the word may belong to. In other words, it will be proposed that there exists a unique semantic value of the suffix in tongue which would explain all of its uses in discourse.