Summary Background Whole brain radiotherapy (WBRT) and dexamethasone are widely used to treat brain metastases from non-small cell lung cancer (NSCLC), although there have been no randomised clinical ...trials showing that WBRT improves either quality of life or overall survival. Even after treatment with WBRT, the prognosis of this patient group is poor. We aimed to establish whether WBRT could be omitted without a significant effect on survival or quality of life. Methods The Quality of Life after Treatment for Brain Metastases (QUARTZ) study is a non-inferiority, phase 3 randomised trial done at 69 UK and three Australian centres. NSCLC patients with brain metastases unsuitable for surgical resection or stereotactic radiotherapy were randomly assigned (1:1) to optimal supportive care (OSC) including dexamethasone plus WBRT (20 Gy in five daily fractions) or OSC alone (including dexamethasone). The dose of dexamethasone was determined by the patients' symptoms and titrated downwards if symptoms improved. Allocation to treatment group was done by a phone call from the hospital to the Medical Research Council Clinical Trials Unit at University College London using a minimisation programme with a random element and stratification by centre, Karnofsky Performance Status (KPS), gender, status of brain metastases, and the status of primary lung cancer. The primary outcome measure was quality-adjusted life-years (QALYs). QALYs were generated from overall survival and patients' weekly completion of the EQ-5D questionnaire. Treatment with OSC alone was considered non-inferior if it was no more than 7 QALY days worse than treatment with WBRT plus OSC, which required 534 patients (80% power, 5% one-sided significance level). Analysis was done by intention to treat for all randomly assigned patients. The trial is registered with ISRCTN, number ISRCTN3826061. Findings Between March 2, 2007, and Aug 29, 2014, 538 patients were recruited from 69 UK and three Australian centres, and were randomly assigned to receive either OSC plus WBRT (269) or OSC alone (269). Baseline characteristics were balanced between groups, and the median age of participants was 66 years (range 38–85). Significantly more episodes of drowsiness, hair loss, nausea, and dry or itchy scalp were reported while patients were receiving WBRT, although there was no evidence of a difference in the rate of serious adverse events between the two groups. There was no evidence of a difference in overall survival (hazard ratio 1·06, 95% CI 0·90–1·26), overall quality of life, or dexamethasone use between the two groups. The difference between the mean QALYs was 4·7 days (46·4 QALY days for the OSC plus WBRT group vs 41·7 QALY days for the OSC group), with two-sided 90% CI of −12·7 to 3·3. Interpretation Although the primary outcome measure result includes the prespecified non-inferiority margin, the combination of the small difference in QALYs and the absence of a difference in survival and quality of life between the two groups suggests that WBRT provides little additional clinically significant benefit for this patient group. Funding Cancer Research UK, Medical Research Council Clinical Trials Unit at University College London, and the National Health and Medical Research Council in Australia.
International Ocean Discovery Program (IODP) Expedition 352 recovered a high-fidelity record of volcanism related to subduction initiation in the Bonin fore-arc. Two sites (U1440 and U1441) located ...in deep water nearer to the trench recovered basalts and related rocks; two sites (U1439 and U1442) located in shallower water further from the trench recovered boninites and related rocks. Drilling in both areas ended in dolerites inferred to be sheeted intrusive rocks. The basalts apparently erupted immediately after subduction initiation and have compositions similar to those of the most depleted basalts generated by rapid sea-floor spreading at mid-ocean ridges, with little or no slab input. Subsequent melting to generate boninites involved more depleted mantle and hotter and deeper subducted components as subduction progressed and volcanism migrated away from the trench. This volcanic sequence is akin to that recorded by many ophiolites, supporting a direct link between subduction initiation, fore-arc spreading, and ophiolite genesis.
ODP/IODP Hole 1256D penetrates an in situ section of ocean crust formed at the East Pacific Rise, through lavas and sheeted dikes and ∼100 m into plutonic rocks. We use mineralogy, oxygen isotopes, ...and fluid inclusions to understand hydrothermal processes. The lavas are slightly altered at low temperatures (<150°C) to phyllosilicates and iron oxyhydroxides, with a stepwise increase in grade downward to greenschist minerals in the upper dikes. This resulted from generally upwelling hydrothermal fluids in the dikes mixing with cooler seawater solutions in the lavas, also producing minor metal sulfide mineralization in the upper dikes. Alteration grade increases downward in the dikes, with increasing recrystallization to amphibole and loss of metals at higher temperatures (>350°C up to ∼600°C). Intrusion of gabbro bodies into the lower dikes resulted in contact metamorphism to granoblastic hornfels at 850°C–900°C, representing a thermal boundary layer between the axial melt lens and the overlying hydrothermal system. Downward penetration of hydrothermal fluids led to rehydration of granoblastic dikes and plutonic rocks at ∼800°C down to <300°C. Fluid inclusion and oxygen isotope data show that vein quartz formed at ∼300°C to >450°C from hydrothermal fluids that were affected by supercritical phase separation. Fluids had variable salinities and were enriched in 18O (+0.4‰ to +3.5‰) relative to seawater, similar to seafloor vent fluids. Dike margins are brecciated and mineralized, suggesting hydrothermal activity coeval with magmatism. Anhydrite formed mainly in the upper dikes when partly reacted seawater fluids were heated as they penetrated deeper into the system. Low‐temperature alteration of the volcanic section continued as cold seawater penetrated along fluid pathways, forming minor iron oxyhydroxides in the rocks. Hydrothermal processes at Site 1256 fit with current models whereby greenschist alteration of dikes at low water/rock ratios is overprinted by fracture‐controlled alteration and mineralization by upwelling hydrothermal fluids, a conductive boundary layer above gabbroic intrusions, leaching of metals from dikes and gabbros in the deep “root zone,” and stepped thermal and alteration gradients in the basement. The Site 1256 section, however, is intact and retains recharge effects (anhydrite), allowing an integrated view of processes in the subsurface.
Abstract Introduction Patients who present with locally advanced inoperable non-small cell lung cancer (NSCLC) may be suitable for radical radiotherapy. A randomised trial of 563 patients compared ...CHART and conventional radical radiotherapy (60 Gy/30f) given over 6 weeks and suggested that CHART resulted in a 9% improvement in 2-year survival (Saunders et al., 1999). RT dose escalation for both conventional and CHARTWEL (CHART-WeekEndLess) – fractionation schedules is feasible with modern 3-dimensional CT-based planning techniques and we initiated a phase I CHART dose escalation study in 2009. Methods Patients with WHO performance status 0–2 histologically confirmed, inoperable, stage I–III non-small cell lung cancer were recruited into an open phase I dose escalation trial. Three cohorts of six patients were recruited sequentially. Total dose was escalated from standard CHART radiotherapy of 54 Gy/36f/12 days to 57.6 Gy (2 × 1.8 Gy fractions on day 15, Group 1), 61.2 Gy (4 × 1.8 Gy fractions on days 15–16, Group 2) and 64.8 Gy (6 × 1.8 Gy fractions on days 15–17, Group 3). Results Between April 2010 and May 2012, 18 patients were enrolled from 5 UK centres and received escalated dose radiotherapy. 14 were male, 16 squamous cell histology and 12 were stage IIIA or IIIB. The median age was 70 years and baseline characteristics were similar across the three dose cohorts. One patient did not start escalated radiotherapy but all remaining patients completed their planned radiotherapy schedules. Of these 9 patients have died to date with a median survival of 2 years across the three cohorts. Grade 3 or 4 adverse events (fatigue, dysphagia, nausea and anorexia – classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0) were reported in 6 patients but the pre-specified dose limiting toxicities (grade 4 early oesophagitis; grade 3 cardiac, spinal cord and pneumonitis) were not observed. Conclusions CHART remains a radiotherapy schedule in routine use across the UK and in this dose escalation study no dose limiting toxicities were observed. We feel the dose of 64.8 Gy/42f/17 days should be taken forward into further clinical trials. The sample size used in this study was small so we plan a randomised phase II study that includes other radiotherapy schedules to confirm safety and select an accelerated sequential chemo-radiotherapy schedule to take into phase III studies.
Using temperature gradients measured in 10 holes at 6 sites, we generate the first high fidelity heat flow measurements from Integrated Ocean Drilling Program drill holes across the northern and ...central Lesser Antilles arc and back arc Grenada basin. The implied heat flow, after correcting for bathymetry and sedimentation effects, ranges from about 0.1 W/m2 on the crest of the arc, midway between the volcanic islands of Montserrat and Guadeloupe, to <0.07 W/m2 at distances >15 km from the crest in the back arc direction. Combined with previous measurements, we find that the magnitude and spatial pattern of heat flow are similar to those at continental arcs. The heat flow in the Grenada basin to the west of the active arc is 0.06 W/m2, a factor of 2 lower than that found in the previous and most recent study. There is no thermal evidence for significant shallow fluid advection at any of these sites. Present‐day volcanism is confined to the region with the highest heat flow.
Key Points
Heat flow in the Lesser Antilles is similar to other volcanic arcs
No evidence for subsurface fluid flow
Volcanism is confined to the region with high heat flow
Using a critical, post-modern perspective, the need for a mid-range theory is proposed regarding the risk and potential oppression caused by the socially-constructed phenomenon of perfection and its ...distorting influence on development of a nursing lens. The term, nursing lens, is analyzed from a historical perspective, defined as a concept, and differentiated from a nursing gaze. The relationship between a nursing lens and nursing gaze is explored suggesting a process for developing nursing perceptions about practice and self. The position of perfection in the industry of healthcare and nursing is examined with the Perfectibility Model as an exemplar. Perfectibility is proposed as a distortion to a nursing lens leading to unsafe practice and an unrealistic view of self. Implications are explored for fully developing the mid-range theory of Refocusing a Nursing Lens Distorted by Perfection, and testing the theory for use in education and practice. The incipient theory has potential to radically transform nursing.
To report the results from continuous, hyperfractionated, accelerated radiotherapy (CHART) used as the standard fractionation for radical RT in the management of non-small cell lung cancer (NSCLC) in ...five United Kingdom centers.
In 2005, the CHART consortium identified six U.K. centers that had continued to use CHART after the publication of the CHART study in 1997. All centers had been using CHART for >5 years and agreed to use a common database to audit their results. Patients treated with CHART between 1998 and December 2003 were identified to allow a minimum of 2 years of follow-up. Patient demographics, tumor characteristics, treatment details, and survival were recorded retrospectively. Five centers completed the data collection.
A total of 583 patients who had received CHART were identified. Of these patients, 69% were male, with a median age of 68 years (range, 31-89); 83% had performance status 0 or 1; and 43% had Stage I or II disease. Of the 583 patients, 99% received the prescribed dose. In only 4 patients was any Grade 4-5 toxicity documented. The median survival from the start of RT was 16.2 months, and the 2-year survival rate of 34% was comparable to that reported in the original study.
The results of this unselected series have confirmed that CHART is deliverable in routine clinical practice, with low levels of toxicity. Importantly, this series has demonstrated that the results of CHART reported from the randomized trial can be reproduced in routine clinical practice.
Seemingly random acts of violence are occasionally acted upon monuments, memorials, and public icons of commemoration. On occasion, however, the rhetorical topography of cities arouses dialogue and ...interaction, especially at times of national or global crisis. Drawing on the theoretical work of Boyer and Matsuda, we explore the contested dialogues of commemoration as acts that go beyond evaluation, judgment, and of utterance, to become dialogic, interventionist, and (in extremis) auto-destructive. This article uses as a case study the creation of an artwork masquerading as a temporary memorial, which was constructed by an artist as a work about commemoration rather than as a commemoration in itself. However, due to the particular circumstances of its timing, coinciding as it did with the bombing of Afghanistan by America and its allies following the Twin Towers terrorist act in New York on 11 September 2001, it took on an unanticipated function. During the course of the show the Faux Cenotaph was written on, added to, subtracted from, and eventually dismantled by unknown hands. It became a locus for numerous expressions of protest with a sequence of interventions by a largely unseen set of players, becoming a temporary version of what the Germans call a 'Denkmal': a monument that stands as a warning, causing us to meditate on the mistakes of the past, and hopefully to mend our ways. This paper sets out a number of arguments to suggest that following this sequence of unscheduled, and very radical, interventions the piece became a 'guerilla-memorial': a rejoinder to both the object and the genre of the monumental memorial itself.
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