A phase Ib/II dose expansion study of subcutaneous sasanlimab in patients with locally advanced or metastatic non-small-cell lung cancer and urothelial carcinoma.

BACKGROUND: Sasanlimab is an antibody to the programmed cell death protein 1 receptor. We report updated data of subcutaneous sasanlimab in non-small-cell lung cancer (NSCLC) and urothelial carcinoma dose expansion cohorts from a first-in-human phase Ib/II study. PATIENTS AND METHODS: Patients were ≥18 years of age with NSCLC or urothelial carcinoma, and no prior immunotherapies, who progressed on or were intolerant to systemic therapy, or for whom systemic therapy was refused or unavailable. Patients received subcutaneous sasanlimab at 300 mg every 4 weeks (q4w). Primary objectives were to evaluate safety, tolerability, and clinical efficacy by objective response rate (ORR). RESULTS: Sixty-eight and 38 patients with NSCLC and urothelial carcinoma, respectively, received subcutaneous sasanlimab. Overall, sasanlimab was well tolerated; 13.2% of patients experienced grade ≥3 treatment-related adverse events. Confirmed ORR was 16.4% and 18.4% in the NSCLC and urothelial carcinoma cohorts, respectively. ORR was generally higher in patients with high programmed death-ligand 1 (PD-L1) expression (≥25%) and high tumor mutational burden (TMB; >75%). In the NSCLC and urothelial carcinoma cohorts, median progression-free survival (PFS) was 3.7 and 2.9 months, respectively; corresponding median overall survival (OS) was 14.7 and 10.9 months. Overall, longer median PFS and OS correlated with high PD-L1 expression and high TMB. Longer median PFS and OS were also associated with T-cell inflamed gene signature in the urothelial carcinoma cohort. CONCLUSIONS: Subcutaneous sasanlimab at 300 mg q4w was well tolerated with promising clinical efficacy observed. Phase II and III clinical trials of sasanlimab are ongoing to validate clinical benefit. Subcutaneous sasanlimab may be a potential treatment option for patients with NSCLC or urothelial carcinoma.

MRI Features of Histologically Diagnosed Supratentorial Primitive Neuroectodermal Tumors and Pineoblastomas in Correlation with Molecular Diagnoses and Outcomes: A Report from the Children's Oncology Group ACNS0332 Trial.

BACKGROUND AND PURPOSE: Supratentorial primitive neuroectodermal tumors and pineoblastomas have traditionally been grouped together for treatment purposes. Molecular profiling of these tumors has revealed a number of distinct entities and has led to the term "CNS-primitive neuroectodermal tumors" being removed from the 2016 World Health Organization classification. The purpose of this study was to describe the MR imaging findings of histologically diagnosed primitive neuroectodermal tumors and pineoblastomas and correlate them with molecular diagnoses and outcomes. MATERIALS AND METHODS: Histologically diagnosed primitive neuroectodermal tumors and pineoblastomas were enrolled in this Children's Oncology Group Phase III trial, and molecular classification was retrospectively completed using DNA methylation profiling. MR imaging features were systematically studied and correlated with molecular diagnoses and survival. RESULTS: Of the 85 patients enrolled, 56 met the inclusion criteria, in whom 28 tumors were in pineal and 28 in nonpineal locations. Methylation profiling revealed a variety of diagnoses, including pineoblastomas (n = 27), high-grade gliomas (n = 17), embryonal tumors (n = 7), atypical teratoid/rhabdoid tumors (n = 3), and ependymomas (n = 2). Thus, 39% overall and 71% of nonpineal tumor diagnoses were discrepant with histopathology. Tumor location, size, margins, and edema were predictors of embryonal-versus-nonembryonal tumors. Larger size and ill-defined margins correlated with poor event-free survival, while metastatic disease by MR imaging did not. CONCLUSIONS: In nonpineal locations, only a minority of histologically diagnosed primitive neuroectodermal tumors are embryonal tumors; therefore, high-grade glioma or ependymoma should be high on the radiographic differential. An understanding of molecularly defined tumor entities and their relative frequencies and locations will help the radiologist make more accurate predictions of the tumor types.

Expansion Thoracoplasty in Rabbit Model: Effect of Timing on Preserving Pulmonary Growth and Correcting Spine Deformity.

STUDY DESIGN: In a treatment-control animal study expansion thoracoplasty (ET) was performed in a juvenile rabbit model of thoracic insufficiency syndrome (TIS) and benefits to thoracic development and respiratory function quantified. Rabbits treated early versus late were compared to age-matched normal and disease control rabbits through to skeletal maturity. OBJECTIVE: Evaluate (1) how ET changes the natural TIS disease trajectory and (2) how timing of ET affects changes in spine growth, lung growth, and respiratory mechanics. SUMMARY OF BACKGROUND DATA: Pulmonary growth potential is thought to diminish with age; thus, early therapeutic intervention may increase pulmonary growth in children with TIS. However, no direct empirical evidence exists to support this treatment paradigm. METHODS: Convex left scoliosis and resultant TIS was induced in 3-week-old rabbits via surgical rib tethering. We compare the efficacy of ET performed at 7 weeks and expanded at 11 weeks (early, n = 7) versus only at 11 weeks of age (late, n = 7) in preserving lung growth and respiratory function relative to normal (n = 8) and disease (n = 10) rabbits. Sequential computed tomography images and pulmonary function testing was performed to quantify spine curvature, lung growth, and respiratory volumes. At 28 weeks of age chest wall elastance was measured in vivo then acinar complexity analyzed histologically via radial alveolar counts. RESULTS: ET performed early or late altered the predicted trajectory of spine deformity, pulmonary growth inhibition, and respiratory dysfunction seen in disease rabbits. Growth was not significantly different between early and late rabbits and post-treatment gains remained below those of age-matched normal rabbits. Chest wall elastance was impaired by ET and more so in early rabbits, there were no differences in pulmonary elastance. CONCLUSION: ET interrupted the natural progression of deformity and pulmonary hypoplasia associated with spine curvature in disease rabbits. However, growth benefits are only seen in cases of the most severe initial deformity and must be balanced against the further impairment to chest wall function associated with repetitive surgery. LEVEL OF EVIDENCE: N/A.

Phase I dose-escalation study of copanlisib in combination with gemcitabine or cisplatin plus gemcitabine in patients with advanced cancer.

BACKGROUND: Copanlisib is a pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant PI3K-α/δ activity that has demonstrated clinical activity and manageable safety when administered as monotherapy in a phase II study. Combination therapy may overcome compensatory signalling that could occur with PI3K pathway inhibition, resulting in enhanced inhibitory activity, and preclinical studies of copanlisib with gemcitabine have demonstrated potent anti-tumour activity in vivo. METHODS: A phase I, open-label, dose-escalation study to evaluate the safety, tolerability and recommended phase II dose (RP2D) of copanlisib with gemcitabine or with cisplatin plus gemcitabine (CisGem) in patients with advanced malignancies, including an expansion cohort in patients with biliary tract cancer (BTC) at the RP2D of copanlisib plus CisGem. Copanlisib and gemcitabine were administered on days 1, 8 and 15 of a 28-day cycle; maximum tolerated dose (MTD) and RP2D of copanlisib were determined. Copanlisib plus CisGem was administered on days 1 and 8 of a 21-day cycle; pharmacokinetics and biomarkers were assessed. RESULTS: Fifty patients received treatment as follows: dose-escalation cohorts, n=16; copanlisib plus CisGem cohort, n=14; and BTC expansion cohort, n=20. Copanlisib 0.8 mg kg-1 plus gemcitabine was the MTD and RP2D for both combinations. Common treatment-emergent adverse events included nausea (86%), hyperglycaemia (80%) and decreased platelet count (80%). Copanlisib exposure displayed a dose-proportional increase. No differences were observed upon co-administration of CisGem. Response rates were as follows: copanlisib plus gemcitabine, 6.3% (one partial response in a patient with peritoneal carcinoma); copanlisib plus CisGem, 12% (one complete response and three partial responses all in patients with BTC (response rate 17.4% in patients with BTC)). Mutations were detected in PIK3CA (1 out of 43), KRAS (10 out of 43) and BRAF (2 out of 22), with phosphate and tensin homologue protein loss in 41% (12 out of 29). CONCLUSIONS: Copanlisib plus CisGem demonstrated a manageable safety profile, favourable pharmacokinetics, and potentially promising clinical response.

Hyperspectral data processing improves PpIX contrast during fluorescence guided surgery of human brain tumors.

Fluorescence guided surgery (FGS) using aminolevulinic-acid (ALA) induced protoporphyrin IX (PpIX) provides intraoperative visual contrast between normal and malignant tissue during resection of high grade gliomas. However, maps of the PpIX biodistribution within the surgical field based on either visual perception or the raw fluorescence emissions can be masked by background signals or distorted by variations in tissue optical properties. This study evaluates the impact of algorithmic processing of hyperspectral imaging acquisitions on the sensitivity and contrast of PpIX maps. Measurements in tissue-simulating phantoms showed that (I) spectral fitting enhanced PpIX sensitivity compared with visible or integrated fluorescence, (II) confidence-filtering automatically determined the lower limit of detection based on the strength of the PpIX spectral signature in the collected emission spectrum (0.014-0.041 µg/ml in phantoms), and (III) optical-property corrected PpIX estimates were more highly correlated with independent probe measurements (r = 0.98) than with spectral fitting alone (r = 0.91) or integrated fluorescence (r = 0.82). Application to in vivo case examples from clinical neurosurgeries revealed changes to the localization and contrast of PpIX maps, making concentrations accessible that were not visually apparent. Adoption of these methods has the potential to maintain sensitive and accurate visualization of PpIX contrast over the course of surgery.

Identification of a 10/10 matched donor for patients with an uncommon haplotype is unlikely.

BACKGROUND: Despite over 6 million subjects contributing to the National Marrow Donor Program human leukocyte antigen (HLA) haplotype frequency reference data (HFD), haplotypes cannot be predicted from the HLA assignments of some patients searching for an unrelated donor (URD) in the Be The Match Registry®. We aimed to determine the incidence of these patient searches and whether haplotypes lacking from the HFD can be found among the low-resolution typed URD pool. MATERIALS AND METHODS: New NMDP searches with uncommon patient haplotypes (UPH), defined as a lack of haplotype pairs in any single ethnic group in the HFD based upon HLA-A˜C˜B˜DRB1˜DQB1, were identified. Each search had up to 20 potential 10/10 or 8/8 URDs typed to determine the likelihood of an allele match. RESULTS: The incidence of patient searches without haplotype pairs in a single ethnic group in the HFD was 1.2% (N=144 out of 12,172) and a majority of these patients (117; 81%) had one uncommon haplotype previously uncharacterized in the HFD. Non-White patients had the highest incidence of UPH. Importantly, no patients with UPH had a 10/10 URD identified. The transplant rate among UPH patients was 15%, and a majority of these patients utilized cord blood units as their transplant stem cell source. CONCLUSION: Therefore, the HLA HFD that informs the HapLogic matching algorithm is thorough as UPH patient searches were infrequent. Since such patients are highly unlikely to have a fully 10/10 matched URD identified, this study supports the identification of alternative stem cell sources including cord blood or a mismatched URD early in the search process.

The interaction between acetylation and serine-574 phosphorylation regulates the apoptotic function of FOXO3.

The multispecific transcription factor and tumor suppressor FOXO3 is an important mediator of apoptosis, but the mechanisms that control its proapoptotic function are poorly understood. There has long been evidence that acetylation promotes FOXO3-driven apoptosis and recently a specific JNK (c-Jun N-terminal kinase)-dependent S574 phosphorylated form (p-FOXO3) has been shown to be specifically apoptotic. This study examined whether acetylation and S574 phosphorylation act independently or in concert to regulate the apoptotic function of FOXO3. We observed that both sirtuins 1 and 7 (SIRT1 and SIRT7) are able to deacetylate FOXO3 in vitro and in vivo, and that lipopolysaccharide (LPS) treatment of THP-1 monocytes induced a rapid increase of FOXO3 acetylation, partly by suppression of SIRT1 and SIRT7. Acetylation was required for S574 phosphorylation and cellular apoptosis. Deacetylation of FOXO3 by SIRT activation or SIRT1 or SIRT7 overexpression prevented its S574 phosphorylation and blocked apoptosis in response to LPS. We also found that acetylated FOXO3 preferentially bound JNK1, and a mutant FOXO3 lacking four known acetylation sites (K242, 259, 290 and 569R) abolished JNK1 binding and failed to induce apoptosis. This interplay of acetylation and phosphorylation also regulated cell death in primary human peripheral blood monocytes (PBMs). PBMs isolated from alcoholic hepatitis patients had high expression of SIRT1 and SIRT7 and failed to induce p-FOXO3 and apoptosis in response to LPS. PBMs from healthy controls had lower SIRT1 and SIRT7 and readily formed p-FOXO3 and underwent apoptosis when similarly treated. These results reveal that acetylation is permissive for generation of the apoptotic form of FOXO3 and the activity of SIRT1 and particularly SIRT7 regulate this process in vivo, allowing control of monocyte apoptosis in response to LPS.

Design and performance of a large lumen glaucoma drainage device.

PurposeWe report the in vivo testing of a large-lumen glaucoma drainage (LL-GDD) device equipped with a flow regulator. The device's membrane can be non-invasively opened with laser in the postoperative period to adjust aqueous flow and intraocular pressure.MethodsThe initial LL-GDD prototypes were constructed using 22 G silicone angiocatheters cut down to size. A 10 nm PVDF membrane was then affixed to the end using cyanoacrylate. The LL-GDD was tested first in a model eye equipped with ports for infusion and pressure measurement and in New Zealand rabbits.ResultsNew Zealand white satin cross rabbits were used, two eyes receiving the LL-GDD and the two fellow eyes serving as the control group with no intervention performed. After the procedure, the IOP in the LL-GGD surgical group dropped an average of 5.5 mm Hg (P=0.001), which was maintained until the membrane laser procedure at week 5 resulting in an average IOP reduction of 1.8 mm Hg. At week 7, the average IOP in the surgical group was 11 mm Hg compared with 18 mm Hg in the control group (P<0.001). A second laser procedure was done to completely open the membrane face, which resulted in an immediate drop in the average IOP of the surgical group by another 2.7 mm Hg, which was maintained until the study termination at day 55.ConclusionsThe large-lumen glaucoma drainage device demonstrated an ability both to prevent immediate postoperative hypotony and to allow progressively lower IOP on demand in this proof-of-concept study.

Spaceflight-Relevant Challenges of Radiation and/or Reduced Weight Bearing Cause Arthritic Responses in Knee Articular Cartilage.

There is little known about the effect of both reduced weight bearing and exposure to radiation during spaceflight on the mechanically-sensitive cartilage lining the knee joint. In this study, we characterized cartilage damage in rat knees after periods of reduced weight bearing with/without exposure to solar-flare-relevant radiation, then cartilage recovery after return to weight bearing. Male Sprague Dawley rats (n = 120) were either hindlimb unloaded (HLU) via tail suspension or remained weight bearing in cages (GROUND). On day 5, half of the HLU and GROUND rats were 1 Gy total-body X-ray irradiated during HLU, and half were sham irradiated (SHAM), yielding 4 groups: GROUND-SHAM; GROUND-IR; HLU-SHAM; and HLU-IR. Hindlimbs were collected from half of each group of rats on day 13. The remaining rats were then removed from HLU or remained weight bearing, and hindlimbs from these rats were collected on day 62. On day 13, glycosaminoglycan (GAG) content in cartilage lining the tibial plateau and femoral condyles of HLU rats was lower than that of the GROUND animals. Likewise, on day 13, immunoreactivity of the collagen type II-degrading matrix metalloproteinase-13 (MMP-13) and of a resultant metalloproteinase-generated neoepitope VDIPEN was increased in all groups versus GROUND-SHAM. Clustering of chondrocytes indicating cartilage damage was present in all HLU and IR groups versus GROUND-SHAM on day 13. On day 62, after 49 days of reloading, the loss of GAG content was attenuated in the HLU-SHAM and HLU-IR groups, and the increased VDIPEN staining in all treatment groups was attenuated. However, the increased chondrocyte clustering remained in all treatment groups on day 62. MMP-13 activity also remained elevated in the GROUND-IR and HLU-IR groups. Increased T2 relaxation times, measured on day 62 using 7T MRI, were greater in GROUND-IR and HLU-IR knees, indicating persistent cartilage damage in the irradiated groups. Both HLU and total-body irradiation resulted in acute degenerative and pre-arthritic changes in the knee articular cartilage of rats. A return to normal weight bearing resulted in some recovery from cartilage degradation. However, radiation delivered as both a single challenge and when combined with HLU resulted in chronic cartilage damage. These findings suggest that radiation exposure during spaceflight leads to and/or impairs recovery of cartilage upon return to reloading, generating long-term joint problems for astronauts.

A phase Ib dose-escalation study of the MEK inhibitor trametinib in combination with the PI3K/mTOR inhibitor GSK2126458 in patients with advanced solid tumors.

Introduction This Phase Ib trial investigated the safety, tolerability, and recommended phase 2 dose for the pan-PI3K/mTOR inhibitor, GSK2126458 (GSK458), and trametinib combination when administered to patients with advanced solid tumors. Patients and Methods Patients with advanced solid tumors received escalating doses of GSK458 (once or twice daily, and continuous or intermittent) and trametinib following a zone-based 3 + 3 design to determine the maximum tolerated dose (MTD). Assessments included monitoring for adverse events and response, and evaluating pharmacokinetic (PK) measures. Archival tissue and circulating free DNA samples were collected to assess biomarkers of response in the PI3K and RAS pathways. Results 57 patients were enrolled onto the continuous dosing cohort and 12 patients onto an intermittent BID dosing cohort. Two MTDs were established for the continuous daily dosing: 2 mg of GSK458 with 1.0 mg of trametinib or 1.0 mg of GSK458 with 1.5 mg of trametinib; no MTD was determined in the intermittent dosing cohort. The most frequent adverse events were rash (74 %) and diarrhea (61 %). Dose interruptions due to adverse events occurred in 42 % of patients. No significant PK interaction was observed. One patient achieved partial response and 12 patients had stable disease >16 weeks. Mutations in RAS/RAF/PI3K were detected in 70 % of patients, but no pattern emerged between response and mutational status. Conclusion GSK458 plus trametinib is poorly tolerated, due to skin and GI-related toxicities. Responses were minimal, despite enrichment for PI3K/RAS pathway driven tumors, which may be due to overlapping toxicities precluding sufficient dose exposure.

Modelling the cost-effectiveness of adopting risk-stratified approaches to extended screening intervals in the national diabetic retinopathy screening programme in Scotland.

AIMS: To assess the cost-effectiveness of adopting risk-stratified approaches to extended screening intervals in the national diabetic retinopathy screening programme in Scotland. METHODS: A continuous-time hidden Markov model was fitted to national longitudinal screening data to derive transition probabilities between observed non-referable and referable retinopathy states. These were incorporated in a decision model simulating progression, costs and visual acuity outcomes for a synthetic cohort with a covariate distribution matching that of the Scottish diabetic screening population. The cost-effectiveness of adopting extended (2-year) screening for groups with no observed retinopathy was then assessed over a 30-year time horizon. RESULTS: Individuals with a current grade of no retinopathy on two consecutive screening episodes face the lowest risk of progressing to referable disease. For the cohort as a whole, the incremental cost per quality-adjusted life year gained for annual vs. biennial screening ranged from approximately £74 000 (for those with no retinopathy and a prior observed grade of mild or observable background retinopathy) to approximately £232 000 per quality-adjusted life year gained (for those with no retinopathy on two consecutive screening episodes). The corresponding incremental cost-effectiveness ratios in the subgroup with Type 1 diabetes were substantially lower; approximately £22 000 to £85 000 per quality-adjusted life year gained, respectively. CONCLUSIONS: Biennial screening for individuals with diabetes who have no retinopathy is likely to deliver significant savings for a very small increase in the risk of adverse visual acuity and quality of life outcomes. There is greater uncertainty regarding the long-term cost-effectiveness of adopting biennial screening in younger people with Type 1 diabetes.

Outcome of Adult Brain Tumor Consortium (ABTC) prospective dose-finding trials of I-125 balloon brachytherapy in high-grade gliomas: challenges in clinical trial design and technology development when MRI treatment effect and recurrence appear similar.

OBJECTIVES: The aim of this study is to define the maximal safe radiation dose to guide further study of the GliaSite balloon brachytherapy (GSBT) system in untreated newly diagnosed glioblastoma (NEW-GBM) and recurrent high-grade glioma (REC-HGG). GBST is a balloon placed in the resection cavity and later filled through a subcutaneous port with liquid I-125 Iotrex, providing radiation doses that diminish uniformly with distance from the balloon surface. METHODS: The Adult Brain Tumor Consortium initiated prospective dose-finding studies to determine maximum tolerated dose in NEW-GBM treated before standard RT or after surgery for REC-HGG. Patients were inevaluable if there was progression before the 90-day posttreatment toxicity evaluation point. RESULTS: Ten NEW-GBM patients had the balloon placed, and 2/10 reached the 90 day timepoint. Five REC-HGG enrolled and two were assessable at the 90-day evaluation endpoint. Imaging progression occurred before 90-day evaluation in 7/12 treated patients. The trials were closed as too few patients were assessable to allow dose escalation, although no dose-limiting toxicities (DLTs) were observed. Median survival from treatment was 15.3 months (95 % CI 7.1-23.6) for NEW-GBM and 12.8 months (95 % CI 4.2-20.9) for REC-HGG. CONCLUSION: These trials failed to determine a maximum tolerated dose (MTD) for further testing as early imaging changes, presumed to be progression, were common and interfered with the assessment of treatment-related toxicity. The survival outcomes in these and other related studies, although based on small populations, suggest that GSBT may be worthy of further study using clinical and survival endpoints, rather than standard imaging results. The implications for local therapy development are discussed.

Cross-species epigenetics identifies a critical role for VAV1 in SHH subgroup medulloblastoma maintenance.

The identification of key tumorigenic events in Sonic Hedgehog (SHH) subgroup medulloblastomas (MBSHH) will be essential for the development of individualized therapies and improved outcomes. However, beyond confirmation of characteristic SHH pathway mutations, recent genome-wide sequencing studies have not revealed commonly mutated genes with widespread relevance as potential therapeutic targets. We therefore examined any role for epigenetic DNA methylation events in MBSHH using a cross-species approach to candidate identification, prioritization and validation. MBSHH-associated DNA methylation events were first identified in 216 subgrouped human medulloblastomas (50 MBSHH, 28 Wnt/Wingless, 44 Group 3 and 94 Group 4) and their conservation then assessed in tumors arising from four independent murine models of Shh medulloblastoma, alongside any role in tumorigenesis using functional assessments in mouse and human models. This strategy identified widespread regional CpG hypo-methylation of VAV1, leading to its elevated expression, as a conserved aberrant epigenetic event, which characterizes the majority of MBSHH tumors in both species, and is associated with a poor outcome in MBSHH patients. Moreover, direct modulation of VAV1 in mouse and human models revealed a critical role in tumor maintenance, and its abrogation markedly reduced medulloblastoma growth. Further, Vav1 activity regulated granule neuron precursor germinal zone exit and migration initiation in an ex vivo model of early postnatal cerebellar development. These findings establish VAV1 as a critical epigenetically regulated oncogene with a key role in MBSHH maintenance, and highlight its potential as a validated therapeutic target and prognostic biomarker for the improved therapy of medulloblastoma.

Predictors of serum polychlorinated biphenyl concentrations in Anniston residents.

The Anniston Community Health Survey was a community-based cross-sectional study of Anniston, Alabama, residents who live in close proximity to a former PCB production facility to identify factors associated with serum PCB levels. The survey comprises 765 Anniston residents who completed a questionnaire interview and provided a blood sample for analysis in 2005-2007. Several reports based on data from the Anniston survey have been previously published, including associations between PCB exposure and diabetes and blood pressure. In this study we examine demographic, behavioral, dietary, and occupational characteristics of Anniston survey participants as predictors of serum PCB concentrations. Of the 765 participants, 54% were White and 45% were African-American; the sample was predominantly female (70%), with a mean age of 55 years. Serum PCB concentrations varied widely between participants (range for sum of 35 PCBs: 0.11-170.4 ng/g wet weight). Linear regression models with stepwise selection were employed to examine factors associated with serum PCBs. Statistically significant positive associations were observed between serum PCB concentrations and age, race, residential variables, current smoking, and local fish consumption, as was a negative association with education level. Age and race were the most influential predictors of serum PCB levels. A small age by sex interaction was noted, indicating that the increase in PCB levels with age was steeper for women than for men. Significant interaction terms indicated that the associations between PCB levels and having ever eaten locally raised livestock and local clay were much stronger among African-Americans than among White participants. In summary, demographic variables and past consumption of locally produced foods were found to be the most important predictors of PCB concentrations in residents living in the vicinity of a former PCB manufacturing facility.

Activation of the ACE2/Ang-(1-7)/Mas pathway reduces oxygen-glucose deprivation-induced tissue swelling, ROS production, and cell death in mouse brain with angiotensin II overproduction.

We previously demonstrated that mice which overexpress human renin and angiotensinogen (R+A+) show enhanced cerebral damage in both in vivo and in vitro experimental ischemia models. Angiotensin-converting enzyme 2 (ACE2) counteracts the effects of angiotensin (Ang-II) by transforming it into Ang-(1-7), thus reducing the ligand for the AT1 receptor and increasing stimulation of the Mas receptor. Triple transgenic mice, SARA, which specifically overexpress ACE2 in neurons of R+A+ mice were used to study the role of ACE2 in ischemic stroke using oxygen and glucose deprivation (OGD) of brain slices as an in vitro model. We examined tissue swelling, the production of reactive oxygen species (ROS), and cell death in the cerebral cortex (CX) and the hippocampal CA1 region during OGD. Expression levels of NADPH oxidase (Nox) isoforms, Nox2 and Nox4 were measured using western blots. Results show that SARA mice and R+A+ mice treated with the Mas receptor agonist Ang-(1-7) had less swelling, cell death, and ROS production in CX and CA1 areas compared to those in R+A+ animals. Treatment of slices from SARA mice with the Mas antagonist A779 eliminated this protection. Finally, western blots revealed less Nox2 and Nox4 expression in SARA mice compared with R+A+ mice both before and after OGD. We suggest that reduced brain swelling and cell death observed in SARA animals exposed to OGD result from diminished ROS production coupled with lower expression of Nox isoforms. Thus, the ACE2/Ang-(1-7)/Mas receptor pathway plays a protective role in brain ischemic damage by counteracting the detrimental effects of Ang-II-induced ROS production.

Rates of referable eye disease in the Scottish National Diabetic Retinopathy Screening Programme.

AIMS: Diabetic retinopathy screening aims to detect people at risk of visual loss due to proliferative diabetic retinopathy, but also refers cases of suspected macular oedema (maculopathy). At the introduction of screening, ophthalmology was concerned that referral rates would be unmanageable. We report yield of referable disease by referral reason for the first 5 years of the programme. METHODS: We extracted screening results from a nationwide clinical diabetes database to calculate annual referral rates to ophthalmic clinics. We used logistic regression to examine associations between clinical measures and referable disease. RESULTS: 182 397 people underwent ≥ 1successful retinal screening between 2006 and 2010. The yield of referable eye disease was highest in the first 2 years of screening (7.0% and 6.0%) before stabilising at ∼4.3%. The majority of referrals are due to maculopathy with 73% of referrals in 2010 based on a finding of maculopathy. CONCLUSIONS: The commonest cause for referral is for suspected macular oedema (maculopathy). Referral rates for retinopathy have stabilised, as predicted, at relatively low rates. However, ophthalmology workload continues to rise as new treatment options (ie, monthly intraocular injections) have unexpectedly increased the impact on ophthalmology. A review of the screening referral path for maculopathy may be timely.

Serum concentrations of polychlorinated biphenyls (PCBs) in participants of the Anniston Community Health Survey.

Serum concentrations of 35 ortho-substituted polychlorinated biphenyl congeners (PCBs) were measured in 765 adults from Anniston, Alabama, where PCBs were manufactured between 1929 and 1971. As part of the Anniston Community Health Survey (ACHS), demographic data, questionnaire information, and blood samples were collected from participants in 2005-2007. Forty-six percent of study participants were African-American, 70% were female, and the median age was 56 years. The median concentration of the sum of 35 PCB congeners (ΣPCBs) was 528 ng/g lipid, with a 90th percentile of 2,600 ng/g lipid, minimum of 17.0 ng/g lipid, and maximum of 27,337 ng/g lipid. The least square geometric mean ΣPCBs was more than 2.5 times higher for African-American participants than for White participants (866 ng/g lipid vs. 331 ng/g lipid); this difference did not change materially after adjustment for age, sex, body mass index (BMI) and current smoking. In spite of large differences in absolute PCB levels, relative contributions of individual congeners to ΣPCBs were quite similar between race groups. Nevertheless, while percent contributions to ΣPCBs for most of the most abundant penta- to heptachlorobiphenyls were higher among African-Americans, the percentages were higher in Whites for the lower-chlorinated PCBs 28 and 74 and for octa- to decachlorinated PCBs. No major differences were observed in geometric mean ΣPCBs between women and men when adjusted for age, race, BMI and current smoking (516 ng/g lipid vs. 526 ng/g lipid). Principal component analysis revealed groups of co-varying congeners that appear to be determined by chlorine substitution patterns. These congener groupings were similar between ACHS participants and the National Health and Nutrition Examination Survey (NHANES) 2003-04 sample of the general United States population, despite ACHS participants having serum concentrations of ΣPCBs two to three times higher than those in comparable age and race groups from NHANES.

Improving the economic value of photographic screening for optical coherence tomography-detectable macular oedema: a prospective, multicentre, UK study.

OBJECTIVES: To determine the best photographic surrogate markers for detecting sight-threatening macular oedema (MO) in people with diabetes attending UK national screening programmes. DESIGN: A multicentre, prospective, observational cohort study of 3170 patients with photographic signs of diabetic retinopathy visible within the macular region [exudates within two disc diameters, microaneurysms/dot haemorrhages (M/DHs) and blot haemorrhages (BHs)] who were recruited from seven study centres. SETTING: All patients were recruited and imaged at one of seven study centres in Aberdeen, Birmingham, Dundee, Dunfermline, Edinburgh, Liverpool and Oxford. PARTICIPANTS: Subjects with features of diabetic retinopathy visible within the macular region attending one of seven diabetic retinal screening programmes. INTERVENTIONS: Alternative referral criteria for suspected MO based on photographic surrogate markers; an optical coherence tomographic examination in addition to the standard digital retinal photograph. MAIN OUTCOME MEASURES: (1) To determine the best method to detect sight-threatening MO in people with diabetes using photographic surrogate markers. (2) Sensitivity and specificity estimates to assess the costs and consequences of using alternative strategies. (3) Modelled long-term costs and quality-adjusted life-years (QALYs). RESULTS: Prevalence of MO was strongly related to the presence of lesions and was roughly five times higher in subjects with exudates or BHs or more than two M/DHs within one disc diameter. Having worse visual acuity was associated with about a fivefold higher prevalence of MO. Current manual screening grading schemes that ignore visual acuity or the presence of M/DHs could be improved by taking these into account. Health service costs increase substantially with more sensitive/less specific strategies. A fully automated strategy, using the automated detection of patterns of photographic surrogate markers, is superior to all current manual grading schemes for detecting MO in people with diabetes. The addition of optical coherence tomography (OCT) to each strategy, prior to referral, results in a reduction in costs to the health service with no decrement in the number of MO cases detected. CONCLUSIONS: Compared with all current manual grading schemes, for the same sensitivity, a fully automated strategy, using the automated detection of patterns of photographic surrogate markers, achieves a higher specificity for detecting MO in people with diabetes, especially if visual acuity is included in the automated strategy. Overall, costs to the health service are likely to increase if more sensitive referral strategies are adopted over more specific screening strategies for MO, for only very small gains in QALYs. The addition of OCT to each screening strategy, prior to referral, results in a reduction in costs to the health service with no decrement in the number of MO cases detected. STUDY REGISTRATION: This study has been registered as REC/IRAS 07/S0801/107, UKCRN ID 9063 and NIHR HTA 06/402/49. SOURCE OF FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 17, No. 51. See the HTA programme website for further project information.

Varenicline for smoking cessation among methadone-maintained smokers: a randomized clinical trial.

BACKGROUND: With smoking rates far exceeding the general population, methadone-maintained (MMT) opiate-dependent smokers experience high rates of tobacco-related health consequences. Previous treatment studies have used nicotine replacement and produced low quit rates. METHODS: We test, using a three-group randomized design, the efficacy of varenicline versus placebo, in comparison with nicotine replacement therapy (NRT) that combines nicotine patch prescription plus ad libitum nicotine rescue, for smoking cessation. We recruited methadone-maintained smokers from nine treatment centers in southern New England and provided six months of treatment, and a minimal behavioral intervention at baseline (NCI's 5A's). Outcomes included carbon monoxide (CO) confirmed 7-day point smoking cessation prevalence at 6 months and self-reported change in mean cigarettes per day. RESULTS: The 315 participants had a mean age of 40, with 50% male and 79% non-Hispanic White, smoked an average of 19.6 (± 10.4) cigarettes/day, and had a mean daily methadone dose of 109 mg. Intent-to-treat analyses, with missing considered to be smoking, showed the rate of CO-confirmed 7-day abstinence at 6-months was 5.4% overall, with varenicline 3.7% compared to placebo 2.2%, and NRT 8.3% (p>.05). Adherence rates during the 7-days immediately prior to 6-month assessment were 34.2% in varenicline, 34.4% in placebo, and 48.8% in NRT. Between baseline and 6-months there was an overall self-reported mean reduction of 8.3 cigarettes/day. CONCLUSION: Varenicline did not increase quit rates over placebo. Smoking cessation rates in methadone-maintained smokers are low and novel treatment strategies are required.