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Abstract: Surface integrity of nickel-based superalloys after machining operations has become a topic of major interest in the aerospace sector. In the present work, the characteristics of nickel-based alloys (Alloy 718, Waspaloy, Alloy 720Li, and RR1000) subjected to abusive drilling conditions have been investigated using experimental methods such as FEG-SEM, EBSD, XRD, TEM and nano-indentation. The results indicated the presence of nano-sized grains typical of severe plastic deformation in the machined surface while the presence of plastic slip bands was observed in the sub-surface layers. Correlations between the thermo-mechanical properties of the nickel-based alloys and the severe plastic deformation features of the machined surfaces are presented. [Copyright &y& Elsevier]

Purpose: To investigate predictive factors in the development of symptomatic radiation injury after treatment with linear accelerator–based stereotactic radiosurgery for intracerebral arteriovenous malformations and relate the findings to the conclusions drawn by Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC). Methods and Materials: Archived plans for 73 patients who were treated at the British Columbia Cancer Agency were studied. Actuarial estimates of freedom from radiation injury were calculated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards models were used for analysis of incidence of radiation injury. Log–rank test was used to search for dosimetric parameters associated with freedom from radiation injury. Results: Symptomatic radiation injury was exhibited by 14 of 73 patients (19.2%). Actuarial rate of symptomatic radiation injury was 23.0% at 4 years. Most patients (78.5%) had mild to moderate deficits according to Common Terminology Criteria for Adverse Events, version 4.0. On univariate analysis, lesion volume and diameter, dose to isocenter, and a Vx for doses ≥8 Gy showed statistical significance. Only lesion diameter showed statistical significance (p < 0.05) in a multivariate model. According to the log–rank test, AVM volumes >5 cm3 and diameters >30 mm were significantly associated with the risk of radiation injury (p < 0.01). The V12 also showed strong association with the incidence of radiation injury. Actuarial incidence of radiation injury was 16.8% if V12 was <28 cm3 and 53.2% if >28 cm3 (log–rank test, p = 0.001). Conclusions: This study confirms that the risk of developing symptomatic radiation injury after radiosurgery is related to lesion diameter and volume and irradiated volume. Results suggest a higher tolerance than proposed by QUANTEC. The widely differing findings reported in the literature, however, raise considerable uncertainties. [Copyright &y& Elsevier]

Purpose: To identify subgroups of patients with carcinoma of the prostate treated with radical radiotherapy that have improved overall survival when disease is biochemically controlled. Methods and Materials: A cohort of 1,060 prostate cancer patients treated with radical radiotherapy was divided into nine subgroups based on National Comprehensive Cancer Network risk category and estimated 10-year overall survival (eOS 10y) derived from the age adjusted Charlson Comorbidity Index. Patients with and without biochemical control were compared with respect to overall survival. Actuarial estimates of overall survival were calculated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards models were used for analysis of overall survival. Results: Median follow-up was 125 months (range, 51–176 months). Only the subgroups with high or intermediate risk disease and an eOS 10y of >90% had a statistically significantly improved overall survival when prostate cancer was biochemically controlled. In all other groups, biochemical control made no significant difference to overall survival. In the subgroup with high-risk disease and eOS 10y >90%, actuarial overall survival was 86.3% (95% confidence interval [CI] 78.5%–94.1%) and 62.1% (95% CI 52.9%–71.3%) for patients with biochemical control and biochemical relapse respectively (p = 0.002). In the intermediate risk group with eOS >90%, actuarial overall survival was 95.3% (95% CI 89.0%–100%) and 79.8% (95% CI 68.0%–91.6%) for biochemically controlled and biochemically relapsed patients (p = 0.033). On multivariate analysis, National Comprehensive Cancer Network risk group (p = 0.005), biochemical control (p = 0.033) and eOS 10y (p < 0.001) were statistically significant. Conclusion: Biochemical control translates into improved overall survival in patients with high or intermediate risk disease and an estimated 10-year overall survival of >90%. [Copyright &y& Elsevier]

Abstract: Background and purpose: To evaluate outcome in patients with Gleason 7 prostate cancer treated with iodine-125 brachytherapy at the British Columbia Cancer Agency. Materials and methods: Between 20th July 1998 and 7th February 2006, 1500 patients underwent I-125 prostate brachytherapy without supplemental external beam radiation therapy. Of these, 439 had Gleason 7 disease; 362 had Gleason 3+4 and 77 had 4+3 disease. Generally, patients received 6months of androgen suppression. We compared biochemical no evidence of disease (bNED) between patients with Gleason ⩽6 and Gleason 7 and between Gleason 3+4 and 4+3 using the Phoenix definition of biochemical recurrence. Results: Median follow-up was 60months. Estimated 5year bNED was 97% for patients with Gleason score ⩽6 and 94% for patients with Gleason 7 disease (p =0.037). Estimated bNED was 95% and 94% for 3+4 and 4+3, respectively (p =0.791). There was no difference in bNED between implants achieving D90⩾versus

Purpose: To determine whether patients with Grade 3 early breast cancer have an inferior rate of local disease control at 10 years with hypofractionated radiotherapy compared with more conventionally fractionated schedules. Methods and Materials: Local relapse rates were compared between patients receiving hypofractionated radiotherapy or conventionally fractionated radiotherapy to the whole breast in a population-based cohort of women with early-stage (T1-T2, N0, M0) Grade 3 breast cancers diagnosed between 1990 and 2000 and referred to the British Columbia Cancer Agency. Cumulative rates of local relapse were estimated using a competing risk method, and factors significant on univariate analysis were included with fractionation group in a multivariate model. The primary end point was local control at 10 years. Results: A total of 1,335 patients with Grade 3 tumors were treated with adjuvant radiotherapy, 252 with conventional fractionation, and 1,083 with a hypofractionated schedule. The 10-year cumulative incidence of local relapse was 6.9% in the hypofractionated group and 6.2% in the conventionally fractionated group (p = 0.99). Conclusions: There is no evidence that hypofractionation is inferior to conventional fractionation for breast conserving therapy in patients with Grade 3 breast cancer in this large population-based series after 10 years of follow-up. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: The British Columbia Cancer Agency has been performing iodine-125 prostate brachytherapy since 1998, initially using loose seeds and phasing into the exclusive use of RAPIDStrand (RS) (Oncura Inc., Plymouth Meeting, PA) by November 2000. The aim of this study was to investigate rates of biochemical no evidence of disease (bNED) in patients treated with loose seeds compared with RS from this population-based cohort. Methods and materials: Between July 1998 and February 2006, 1500 implants were performed (327 loose and 1173 RS). Biochemical failure is reported using the Phoenix definition and prostate-specific antigen (PSA) >0.4ng/mL at ≥48 months postimplant. Actuarial estimates were calculated by the Kaplan–Meier method. Analysis was repeated with the first 100 loose and stranded implants excluded to assess the learning curve effect. Log-rank test was used to evaluate differences in bNED. Variables showing association with bNED were included in a multivariate model. Results: There was no difference between loose and stranded seeds. Estimated rate of bNED was 93.5% (95% confidence interval [CI], 90.6–96.4) at 7 years for patients treated with loose seeds and 94.0% (95% CI, 91.8–96.2) for patients treated with RS according to Phoenix definition (p =0.846). Using the PSA >0.4ng/mL definition, estimated rates were 91.3% (95% CI, 88.0–94.6) and 91.9% (95% CI, 89.7–94.1) for loose and stranded seeds, respectively (p =0.871). Exclusion of the first 100 loose and stranded implants also revealed no difference in bNED. Conclusion: This study of 1500 patients treated with iodine-125 brachytherapy demonstrates no difference in bNED between loose and stranded seeds, using either Phoenix or PSA >0.4ng/mL definitions of biochemical failure. [Copyright &y& Elsevier]

Patients with glioblastoma who are older or have poor performance status (PS) experience particularly poor clinical outcomes. At the time of study initiation, these patients were treated with short-course radiation therapy (40 Gy in 15 fractions). Olaparib is an oral inhibitor of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP) that is well tolerated as a single agent but exacerbates acute radiation toxicity in extracranial sites. Preclinical data predicted that PARP inhibitors would enhance radiosensitivity in glioblastoma without exacerbating adverse effects on the normal brain. Phase 1 of the PARADIGM trial was a 3+3 dose-escalation study testing olaparib in combination with radiation therapy (40 Gy 15 fractions) in patients with newly diagnosed glioblastoma who were unsuitable for radical treatment either because they were aged 70 years or older (World Health Organization PS 0-1) or aged 18 to 69 years with PS 2. The primary outcome was the recommended phase 2 dose of olaparib. Secondary endpoints included safety and tolerability, overall survival, and progression-free survival. Effects on cognitive function were assessed via the Mini Mental State Examination. Of 16 eligible patients (56.25% male; median age, 71.5 years [range, 44-78]; 75% PS 0-1), 1 dose-limiting toxicity was reported (grade 3 agitation). Maximum tolerated dose was not reached and the recommended phase 2 dose was determined as 200 mg twice daily. Median overall survival and progression-free survival were 10.8 months (80% CI, 7.3-11.4) and 5.5 months (80% CI, 3.9-5.9), respectively. Mini Mental State Examination plots indicated that cognitive function was not adversely affected by the olaparib–radiation therapy combination. Olaparib can be safely combined with hypofractionated brain radiation therapy and is well tolerated in patients unsuitable for radical chemoradiation. These results enabled initiation of a randomized phase 2 study and support future trials of PARP inhibitors in combination with radiation therapy for patients with brain tumors. [ABSTRACT FROM AUTHOR]

The aim of the study was to assess the impact of treatment with adjuvant vemurafenib monotherapy on health-related quality of life (HRQOL) in patients with resected stage IIC–IIIC melanoma. The phase 3 BRIM8 study (NCT01667419) randomised patients with BRAF V600 mutation–positive resected stage IIC–IIIC melanoma to 960 mg of vemurafenib twice daily or matching placebo for 52 weeks (13 × 28-day cycles). Patients completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) version 3 at baseline, cycle 1 (days 1, 15 and 22), cycle 2 (days 1 and 15), day 1 of every subsequent 4-week cycle, the end-of-treatment visit and each visit during the follow-up period. Completion rates for the EORTC QLQ-C30 questionnaire were high (>80%). There was a mean decline in the global health status (GHS)/quality of life (QOL) score of 17.4 (±22.9) and 17.3 (±24.1) points at days 15 and 22 of cycle 1, respectively, among vemurafenib-treated patients who recovered to approximately 10 points below baseline for the remainder of the treatment period. A similar trend was observed in all functional scales except for cognitive function (<10-point change from baseline at all visits) and in the symptom scores for appetite loss, fatigue and pain. As observed for the GHS/QOL score, all scores rapidly returned to baseline after completion of planned vemurafenib treatment or treatment discontinuation. The schedule of HRQOL assessments allowed for an accurate and complete evaluation of the impact of acute treatment-related symptoms. Vemurafenib-treated patients experience clinically meaningful moderate worsening in some treatment- or disease-related symptoms and GHS/QOL that resolve over time. • Maintaining quality of life (QOL) during adjuvant treatment for melanoma is the key. • Early-onset adverse events with vemurafenib coincide with initial QOL deterioration. • QOL improvement 4 weeks after treatment start reflects adverse event resolution. • Timing of QOL assessment is critical to capture acute treatment effects. • This study exemplifies considerations for an optimal schedule of QOL assessments. [ABSTRACT FROM AUTHOR]

Background: Systemic adjuvant treatment might mitigate the high risk of disease recurrence in patients with resected stage IIC-III melanoma. The BRIM8 study evaluated adjuvant vemurafenib monotherapy in patients with resected, BRAFV600 mutation-positive melanoma.Methods: BRIM8 was a phase 3, international, double-blind, randomised, placebo-controlled study that enrolled 498 adults (aged ≥18 years) with histologically confirmed stage IIC-IIIA-IIIB (cohort 1) or stage IIIC (cohort 2) BRAFV600 mutation-positive melanoma that was fully resected. Patients were randomly assigned (1:1) by an interactive voice or web response system to receive twice-daily adjuvant oral vemurafenib 960 mg tablets or matching placebo for 52 weeks (13 × 28-day cycles). Randomisation was done by permuted blocks (block size 6) and was stratified by pathological stage and region in cohort 1 and by region in cohort 2. The investigators, patients, and sponsor were masked to treatment assignment. The primary endpoint was disease-free survival in the intention-to-treat population, evaluated separately in each cohort. Hierarchical analysis of cohort 2 before cohort 1 was prespecified. This trial is registered with ClinicalTrials.gov, number NCT01667419.Findings: The study enrolled 184 patients in cohort 2 (93 were assigned to vemurafenib and 91 to placebo) and 314 patients in cohort 1 (157 were assigned to vemurafenib and 157 to placebo). At the time of data cutoff (April 17, 2017), median study follow-up was 33·5 months (IQR 25·9-41·6) in cohort 2 and 30·8 months (25·5-40·7) in cohort 1. In cohort 2 (patients with stage IIIC disease), median disease-free survival was 23·1 months (95% CI 18·6-26·5) in the vemurafenib group versus 15·4 months (11·1-35·9) in the placebo group (hazard ratio [HR] 0·80, 95% CI 0·54-1·18; log-rank p=0·26). In cohort 1 (patients with stage IIC-IIIA-IIIB disease) median disease-free survival was not reached (95% CI not estimable) in the vemurafenib group versus 36·9 months (21·4-not estimable) in the placebo group (HR 0·54 [95% CI 0·37-0·78]; log-rank p=0·0010); however, the result was not significant because of the prespecified hierarchical prerequisite for the primary disease-free survival analysis of cohort 2 to show a significant disease-free survival benefit. Grade 3-4 adverse events occurred in 141 (57%) of 247 patients in the vemurafenib group and 37 (15%) of 247 patients in the placebo group. The most common grade 3-4 adverse events in the vemurafenib group were keratoacanthoma (24 [10%] of 247 patients), arthralgia (17 [7%]), squamous cell carcinoma (17 [7%]), rash (14 [6%]), and elevated alanine aminotransferase (14 [6%]), although all keratoacanthoma events and most squamous cell carcinoma events were by default graded as grade 3. In the placebo group, grade 3-4 adverse events did not exceed 2% for any of the reported terms. Serious adverse events were reported in 40 (16%) of 247 patients in the vemurafenib group and 25 (10%) of 247 patients in the placebo group. The most common serious adverse event was basal cell carcinoma, which was reported in eight (3%) patients in each group. One patient in the vemurafenib group of cohort 2 died 2 months after admission to hospital for grade 3 hypertension; however, this death was not considered to be related to the study drug.Interpretation: The primary endpoint of disease-free survival was not met in cohort 2, and therefore the analysis of cohort 1 showing a numerical benefit in disease-free survival with vemurafenib versus placebo in patients with resected stage IIC-IIIA-IIIB BRAFV600 mutation-positive melanoma must be considered exploratory only. 1 year of adjuvant vemurafenib was well tolerated, but might not be an optimal treatment regimen in this patient population.Funding: F Hoffman-La Roche Ltd. [ABSTRACT FROM AUTHOR]