Development of an FRα Companion Diagnostic Immunohistochemical Assay for Mirvetuximab Soravtansine.

CONTEXT.­: Folate receptor-α (FRα, encoded by the FOLR1 gene) is overexpressed in several solid tumor types, including epithelial ovarian cancer (EOC), making it an attractive biomarker and target for FRα-based therapy in ovarian cancer. OBJECTIVE.­: To describe the development, analytic verification, and clinical performance of the VENTANA FOLR1 Assay (Ventana Medical Systems Inc) in EOC. DESIGN.­: We used industry standard studies to establish the analytic verification of the VENTANA FOLR1 Assay. Furthermore, the VENTANA FOLR1 Assay was used in the ImmunoGen Inc-sponsored SORAYA study to select patients for treatment with mirvetuximab soravtansine (MIRV) in platinum-resistant EOC. RESULTS.­: The VENTANA FOLR1 Assay is highly reproducible, demonstrated by a greater than 98% overall percent agreement (OPA) for repeatability and intermediate precision studies, greater than 93% OPA for interreader and greater than 96% for intrareader studies, and greater than 90% OPA across all observations in the interlaboratory reproducibility study. The performance of the VENTANA FOLR1 Assay in the SORAYA study was evaluated by the overall staining acceptability rate, which was calculated using the number of patient specimens that were tested with the VENTANA FOLR1 Assay that had an evaluable result. In the SORAYA trial, data in patients who received MIRV demonstrated clinically meaningful efficacy, and the overall staining acceptability rate of the assay was 98.4%, demonstrating that the VENTANA FOLR1 Assay is safe and effective for selecting patients who may benefit from MIRV. Together, these data showed that the assay is highly reliable, consistently producing evaluable results in the clinical setting. CONCLUSIONS.­: The VENTANA FOLR1 Assay is a robust and reproducible assay for detecting FRα expression and identifying a patient population that derived clinically meaningful benefit from MIRV in the SORAYA study.

Traumatic surfing injuries in New Zealand: a descriptive epidemiology study.

BACKGROUND: New Zealand (NZ) has nearly 14,000 km of coastline and a surfing population of approximately 315,000 surfers. Given its popularity, surfing has a high frequency of injury claims, however, there remains a lack of data on traumatic surfing-related injuries from large population studies. The primary purpose of this study was to examine traumatic surfing injuries in NZ specific to injury incidence, duration, location, type, mechanism of injury and associated risk factors. METHODS: A sample of self-identified surfers currently living in NZ participated in an online retrospective cross-sectional survey between December 2015 and July 2016. Demographic and surfing injury data were collected and analysed. RESULTS: The survey yielded 1,473 respondents (18.3% female); a total of 502 surfers reported 702 major traumatic injuries with an overall incidence proportion of 0.34 (95% CI [0.32-0.37]). When comparing the number of injured surfers who sustained an injury at various body locations, a significantly higher proportion of competitive surfers, compared to recreational surfers, had an injury at the neck (6.8% vs 4%, χ 2 (1,1473) = 5.84, P = 0.019); shoulder (7.4% vs 4.3%, χ 2 (1,1473) = 6.34, P = 0.017), upper back (1% vs 2.4%, χ 2 (1,1473) = 4.77, P = 0.043), lower back (7% vs 3.1%, χ 2 (1,1473) = 11.98, P = 0.001) and knee (7% vs 3.4%, χ 2 (1,1473) = 9.67, P = 0.003). A significantly higher proportion of surfers who performed aerial manoeuvres compared to those who did not reported a higher proportion of knee injuries (9.7% vs 3.9%, χ 2 (1,1473) = 13.00, P = 0.001). With respect to injury duration, the shoulder represented the largest proportion of chronic injuries (>3 months) (44.4%), and the head and face represented the largest proportion of acute injuries (≤3 months) (88%). Muscle and tendon injuries were reported most frequently (25.6%) and direct contact injuries accounted for 58.1% of all injury mechanisms. Key risk factors for traumatic injury included: competitive compared to recreational status (41.0% vs 30.1%, Relative Risk (RR) = 1.36, P < 0.001), ability to perform aerial manoeuvres (48.1% vs 31.8%, RR = 1.51, P < 0.001) and intermediate or above skill level surfers compared to beginner surfers (35.8% vs 22.7%, RR = 1.58, P < 0.001). CONCLUSION: One third of recreational surfers sustained a major traumatic injury in the previous 12 months. For competitive or aerialist surfers the risk was greater, with this proportion approximately half. Overall, the head/face was the most common location of traumatic injury, with competitive surfers being more likely to sustain a neck, shoulder, lower back, and knee injury compared to recreational surfers. The shoulder was associated with the highest proportion of injuries of chronic duration. Future research should investigate injury mechanisms and causation using prospective injury monitoring to better underpin targeted injury prevention programs.

Epidemiology of Acute Injuries in Surfing: Type, Location, Mechanism, Severity, and Incidence: A Systematic Review.

Prospective and retrospective studies have examined traumatic injuries within competitive and recreational surfers worldwide using online surveys and health care facility (HCF; e.g., hospital, emergency department, medical record) data. However, few studies have provided a synthesis of all available literature. The purpose of this study was to obtain, critique and synthesise all literature specific to acute surfing injuries, and evaluate differences in injury type, mechanism and location between HCF and survey data. A systematic literature review design was used to identify relevant articles from three major databases. Peer-reviewed epidemiological studies of musculoskeletal surfing injuries were included. A modified AXIS tool was used for critical appraisal, and objective data was extracted and synthesized by lead researchers. Overall frequencies for injury location, type and mechanism were calculated from raw injury data. A total of 19 cross-sectional articles of fair to good quality (Modified AXIS 54.2-83.3%) were included in this study; 17 were National Health and Medical Research Council (NHMRC) level III-2 (retrospective) and two were level II (prospective). Articles examined competitive, recreational and combined populations. Injury data from Australia, Brazil, UK, USA, Portugal, Japan, Norway, and worldwide were represented. Skin (46.0%; HCF 50.1%, survey 43.8%) and being struck by own surfboard (38.6%; HCF 73.4%, survey 36.7%) were the most common injury type and mechanism. Head, face and neck injuries were most common in HCF (43.1%) versus lower limb injuries (36.4%) in survey data. Incidence proportion was highest in aerialists (0.48). Incidence rate (number of injuries per 1000 h) ranged from 0.74 in Australian surfers (Melbourne) to 6.6 in international contest surfers from medical record data. This review highlights the prevalence of skin, board-related, head, face and neck, and lower limb surfing injuries across available literature. Proposed use of protective equipment and foam-based surfboards in dangerous or crowded surf locations may reduce injury risk.

A Phase I/Ib Trial of the VEGFR-Sparing Multikinase RET Inhibitor RXDX-105.

RET fusions are oncogenic drivers of various tumors, including non-small cell lung cancers (NSCLC). The safety and antitumor activity of the multikinase RET inhibitor RXDX-105 were explored in a phase I/Ib trial. A recommended phase II dose of 275 mg fed daily was identified. The most common treatment-related adverse events were fatigue (25%), diarrhea (24%), hypophosphatemia (18%), maculopapular rash (18%), and nonmaculopapular rash (17%). In the phase Ib cohort of RET inhibitor-naïve patients with RET fusion-positive NSCLCs, the objective response rate (ORR) was 19% (95% CI, 8%-38%, n = 6/31). Interestingly, the ORR varied significantly by the gene fusion partner (P < 0.001, Fisher exact test): 0% (95% CI, 0%-17%, n = 0/20) with KIF5B (the most common upstream partner for RET fusion-positive NSCLC), and 67% (95% CI, 30%-93%, n = 6/9) with non-KIF5B partners. The median duration of response in all RET fusion-positive NSCLCs was not reached (range, 5 to 18+ months). SIGNIFICANCE: Although KIF5B-RET is the most common RET fusion in NSCLCs, RET inhibition with RXDX-105 resulted in responses only in non-KIF5B-RET-containing cancers. Novel approaches to targeting KIF5B-RET-containing tumors are needed, along with a deeper understanding of the biology that underlies the differential responses observed.This article is highlighted in the In This Issue feature, p. 305.

Screening and brief intervention delivery in the workplace to reduce alcohol-related harm: a pilot randomized controlled trial.

AIM: To explore the feasibility and cost effectiveness of screening and delivery of a brief intervention for hazardous drinking employees. METHODS: A pilot randomised controlled trial of a brief intervention delivered by an Occupational Health nurse versus no delivery of brief intervention (control group) conducted in a Local Authority Council (LCA) in the United Kingdom. Changes in quality of life and economic indicators were measured by the EQ-5D. RESULTS: 627 employees were screened of whom 163 (26.01%) fulfilled the inclusion criteria with a total of 57 (35%) agreeing to participate. No significant differences were found between the groups for baseline demographics or levels/patterns of alcohol consumption. A statistically significant effect was found in the mean AUDIT scores over time (F=8.96, p=0.004) but not for group (F=0.017, p=0.896), and no significant interaction was found (F=0.148, p=0.702). The cost of each intervention was calculated at £12.48, the difference in service costs was calculated at £344.50 per person; that is there was a net saving of health and other care costs in the intervention group compared to the control group. The QALYs fell in both intervention and control groups, the difference -0.002-(-0.010) yields a net advantage of the intervention of 0.008 QALYs. CONCLUSION: The main results from this pilot study suggest that alcohol brief interventions delivered in the workplace may offer the potential to reduce alcohol-related harm and save public sector resources. A fully powered multi-centre trial is warranted to contribute to the current evidence base and explore further the potential of alcohol brief interventions in the workplace. In a full trial the recruitment method may need to be re-considered.

Assessment scales in stroke: clinimetric and clinical considerations.

As stroke care has developed, there has been a need to robustly assess the efficacy of interventions both at the level of the individual stroke survivor and in the context of clinical trials. To describe stroke-survivor recovery meaningfully, more sophisticated measures are required than simple dichotomous end points, such as mortality or stroke recurrence. As stroke is an exemplar disabling long-term condition, measures of function are well suited as outcome assessment. In this review, we will describe functional assessment scales in stroke, concentrating on three of the more commonly used tools: the National Institutes of Health Stroke Scale, the modified Rankin Scale, and the Barthel Index. We will discuss the strengths, limitations, and application of these scales and use the scales to highlight important properties that are relevant to all assessment tools. We will frame much of this discussion in the context of "clinimetric" analysis. As they are increasingly used to inform stroke-survivor assessments, we will also discuss some of the commonly used quality-of-life measures. A recurring theme when considering functional assessment is that no tool suits all situations. Clinicians and researchers should chose their assessment tool based on the question of interest and the evidence base around clinimetric properties.

School-based humanistic counseling for psychological distress in young people: pilot randomized controlled trial.

School-based humanistic counseling (SBHC) is a widely delivered intervention for psychological distress in young people, particularly in the UK. This study piloted a set of procedures for evaluating SBHC and obtaining indications of effect. Psychologically distressed young people (aged 13-16) were randomized to either 12 weeks of SBHC or a waiting list control. The primary outcome was psychological distress at the 12-week endpoint, as measured by the Young Person's CORE. Those allocated to counseling (n=16) showed significantly greater reductions in psychological distress than participants in the control group (n=17), with an effect size (ES) (g) of 1.14 on the primary outcome and a mean ES across all four outcome measures of 0.73 at endpoint. The findings indicate that SBHC may be an effective means of reducing psychological distress in young people.

Proteasome regulator marizomib (NPI-0052) exhibits prolonged inhibition, attenuated efflux, and greater cytotoxicity than its reversible analogs.

The present study was undertaken to compare the cellular transport characteristics of [(3)H]NPI-0052 (1R,4R,5S)-4-(2-chloroethyl)-1-((S)-((S)-cyclohex-2-enyl)(hydroxy)methyl)-5-methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione (marizomib; salinosporamide A) and [(3)H]NPI-0047 (1R,4R, 5S)-1-((S)-((S)-cyclohex-2-enyl)(hydroxy)methyl)-4-ethyl-5-methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione in RPMI 8226 multiple myeloma and PC-3 prostate adenocarcinoma cells to determine whether these properties explain differences in the cytotoxic potencies of these chemical analogs. The results indicate that marizomib, which possesses a chemical-leaving group, is more cytotoxic to both cell lines and inhibits proteasome activity more completely at lower concentrations than NPI-0047, a nonleaving-group analog. Moreover, it was found that both compounds accumulate in these cells by simple diffusion and the same carrier-mediated transport system. Although the rate of uptake is similar, the cellular efflux, which does not seem to be mediated by a major ATP-binding cassette (ABC)-efflux transporter, is more rapid for NPI-0047 than for marizomib. Experiments revealed that the irreversible binding of marizomib to the proteasome is responsible for its slower efflux, longer duration of action, and greater cytotoxicity compared with NPI-0047. The discovery that major ABC transporters of the multidrug resistance-associated protein family do not seem to be involved in the accumulation or removal of these agents suggests they may not be affected by multidrug resistance mechanisms during prolonged administration.

Randomised controlled trial of school-based humanistic counselling for emotional distress in young people: feasibility study and preliminary indications of efficacy.

AIMS: The purpose of this study was to test the feasibility of a randomised controlled trial comparing six weeks of humanistic school-based counselling versus waiting list in the reduction of emotional distress in young people, and to obtain initial indications of efficacy. METHODS: Following a screening procedure, young people (13 - 15 years old) who experienced emotional distress were randomised to either humanistic counselling or waiting list in this multi-site study. Outcomes were assessed using a range of self-report mental health measures, with the emotional symptoms subscale of the Strengths and Difficulties Questionnaire (SDQ) acting as the primary outcome indicator. RESULTS: Recruitment procedures were successful, with 32 young people consenting to participate in the trial and 27 completing endpoint measures. Trial procedures were acceptable to all involved in the research. No significant differences were found between the counselling and waiting list groups in reductions in levels of emotional symptoms (Hedges' g = 0.03), but clients allocated to counselling showed significantly greater improvement in prosocial behaviour (g = 0.89) with an average effect size (g) across the nine outcome measures of 0.25. Participants with higher levels of depressive symptoms showed significantly greater change. CONCLUSION: This study suggested that a randomised controlled trial of counselling in schools is acceptable and feasible, although initial indications of efficacy are mixed. TRIAL REGISTRATION: Current Controlled Trials ISRCTN68290510.

Snapshots of the fluorosalinosporamide/20S complex offer mechanistic insights for fine tuning proteasome inhibition.

Many marketed drugs contain fluorine, reflecting its ability to modulate a variety of biological responses. The unique 20S proteasome inhibition profile of fluorosalinosporamide compared to chlorinated anticancer agent salinosporamide A (NPI-0052) is exemplary and relates to each halogen's leaving group potential. Crystal structures of fluoro-, hydroxy-, and bromosalinosporamide in complex with the yeast 20S proteasome core particle (CP) provide mechanistic insights into ligand binding and leaving group elimination and the ability to fine-tune the duration of proteasome inhibition. Fluorosalinosporamide/CP crystal structures determined over time offer striking snapshots of the ligand trapped with an intact fluoroethyl group in anticipation of fluoride elimination, followed by complete nucleophilic displacement of fluoride to give the highly stabilized cyclic ether found for salinosporamide A and bromosalinosporamide. This two-step reaction pathway is consistent with a mechanism for partially reversible proteasome inhibition by fluorosalinosporamide. Proteasome catalyzed fluoride displacement provides preliminary insights into the active site Thr1N pK(a).

Leaving groups prolong the duration of 20S proteasome inhibition and enhance the potency of salinosporamides.

Salinosporamide A ( 1 (NPI-0052)) is a potent, monochlorinated 20S proteasome inhibitor in clinical trials for the treatment of cancer. To elucidate the role of the chlorine leaving group (LG), we synthesized analogues with a range of LG potentials and determined their IC 50 values for inhibition of chymotrypsin-like (CT-L), trypsin-like (T-L), and caspase-like (C-L) activities of 20S proteasomes. Proteasome activity was also determined before and after attempted removal of the inhibitors by dialysis. Analogues bearing substituents with good LG potential exhibited the greatest potency and prolonged duration of proteasome inhibition, with no recovery after 24 h of dialysis. In contrast, activity was restored after

Lynamicins A-E, chlorinated bisindole pyrrole antibiotics from a novel marine actinomycete.

A series of chlorinated bisindole pyrroles, lynamicins A-E (1-5), was discovered from a novel marine actinomycete, NPS12745, which was isolated from a marine sediment collected off the coast of San Diego, California. Close to full length 16S rRNA sequence analysis indicated that NPS12745 is a novel strain of a recently described marine actinomycete with the proposed genus name Marinispora. The antimicrobial spectrum of these compounds was evaluated against a panel of 11 pathogens, which demonstrated that these substances possess broad-spectrum activity against both Gram-positive and Gram-negative organisms. Significantly, compounds 1-5 were active against drug-resistant pathogens such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium.

Enantioselective total synthesis of (-)-Salinosporamide A (NPI-0052).

A novel enantioselective total synthesis of 20S proteasome inhibitor Salinosporamide A (NPI-0052; 1) is presented. Key features include intramolecular aldol cyclization of 6 to simultaneously generate the three chiral centers of advanced intermediate 5, cyclohexene ring addition using B-2-cyclohexen-1-yl-9-BBN, and inversion of the C-5 stereocenter by oxidation followed by enantioselective enzymatic reduction.

An integrative complexity analysis of cognitive behaviour therapy sessions for borderline personality disorder.

OBJECTIVES: Integrative complexity (IC), a measure of cognitive style, was used to analyse discourse in Cognitive Behaviour Therapy (CBT) sessions from patients with borderline personality disorder treated in the BOSCOT trial. It was predicted that patients' level of integrative complexity would be positively associated with the outcome of therapy. That is, an increase in patients' level of integrative complexity would be associated with good outcome. We also predicted that therapists would also show an increase in the level of complexity associated with their patient's increase in integrative complexity and good outcome. DESIGN: Ten patients who received CBT were categorized according to the outcome, good (N=5) and poor (N=5), using an algorithm that incorporated the number of suicide attempts and magnitude of change in severity of depression during therapy. METHOD: For each patient and their therapist, an early and a late therapy session were transcribed and coded for integrative complexity (IC) (N=20 sessions transcribed). IC scores for patients and therapists were compared across early and late therapy sessions and for good and poor outcomes of therapy. RESULTS: The majority of discourse was at the lower levels of IC. Higher levels of IC at baseline were related to depression and anxiety. Good outcome was not associated with a change in the level of IC between earlier and later CBT sessions. Therapists, however, showed an increase in IC when patient's outcome was poor. In addition, an increase in patient's IC was associated with improvement in social functioning. CONCLUSIONS: Therapists may overcompensate for patient's poor outcome by giving more complex explanations to patients. Higher complexity does not necessarily lead to better outcomes.

Unique butyric acid incorporation patterns for salinosporamides A and B reveal distinct biosynthetic origins.

Feeding sodium butyrate (0.25-1 mg/ml) to cultures of Salinispora tropica NPS21184 enhanced the production of salinosporamide B (NPI-0047) by 319% while inhibiting the production of salinosporamide A (NPI-0052) by 26%. Liquid chromatography mass spectrometry analysis of the crude extract from the strain NPS21184 fed with 0.5 mg/ml sodium [U-(13)C(4)]butyrate indicated that butyrate was incorporated as a contiguous four-carbon unit into NPI-0047 but not into NPI-0052. Nuclear magnetic resonance analysis of NPI-0047 and NPI-0052 purified from the sodium [U-(13)C(4)]butyrate-supplemented culture extract confirmed this incorporation pattern. The above finding is the first direct evidence to demonstrate that the biosynthesis of NPI-0047 is different from NPI-0052, and NPI-0047 is not a precursor of NPI-0052.

Effects of halogens on the production of salinosporamides by the obligate marine actinomycete Salinispora tropica.

We examined the effects of halogens on the production of salinosporamide A (NPI-0052) by the obligate marine actinomycete Salinispora tropica NPS465, specifically the production of analogs containing halogens other than chlorine. Adding NaF, NaBr and NaI directly to the production medium prepared in seawater containing -3% NaCl did not induce the production of the corresponding analogs. Replacing seawater with 2-3% NaI in the production medium enhanced the production of NPI-0052 by 2.1 fold. Replacing seawater with 2-3% NaBr in the production medium suppressed the production of NPI-0052 but induced the production of a brominated analog at very low yield. Using a stepwise enrichment of bromide in the seed cultures in order to reduce the chloride ion carried over to the production medium, the production of the brominated analog was enhanced by 4 fold. We also demonstrated that the growth of this obligate marine actinomycete is dependent upon sodium concentration, not chloride concentration.