ALBERT

Description: Ecologists are increasingly recognizing the conservation significance of microrefugia, but it is inherently difficult to locate these small patches with unusual climates, and hence they are also referred to as cryptic refugia. Here we introduce a new methodology to quantify and locate potential microrefugia using fine-scale topoclimatic grids that capture extreme conditions, stable climates, and distinct differences from the surrounding matrix. We collected hourly temperature data from 150 sites in a large (200 km by 300 km) and diverse region of New South Wales, Australia, for a total of 671 days over 2 years. Sites spanned a range of habitats including coastal dune shrublands, eucalypt forests, exposed woodland ridges, sheltered rainforest gullies, upland swamps, and lowland pastures. Climate grids were interpolated using a regional regression approach based on elevation, distance to coast, canopy cover, latitude, cold-air drainage, and topographical exposure to winds and radiation. We identified extreme temperatures on two separate climatic gradients: the 5th percentile of minimum temperatures and the 95th percentile of maximum temperatures. For each gradient, climatic stability was assessed on three different time scales (intra-seasonal, intra-annual and inter-annual). Differences from the matrix were assessed using a moving window with a 5 km radius. We averaged the Z-scores for these extreme, stable and isolated climates to identify potential locations of microrefugia. We found that our method successfully predicted the location of communities that were considered to occupy refugia, such as rainforests that have progressively contracted in distribution over the last 2.5 million years, and alpine grasslands that have contracted over the last 15 thousand years. However, the method was inherently sensitive to the gradient selected and other aspects of the modelling process. These uncertainties could be dealt with in a conservation planning context by repeating the methodology with various parameterizations and identifying areas that were consistently identified as microrefugia.

Description: The development of fine-resolution climate grids is an important priority in explaining species' distributions at the regional scale and predicting how species may respond to variable and changing climates. Recent studies have demonstrated advantages of producing these grids using large networks of inexpensive climate loggers, as the resulting grids can capture local climatic variations over a range of environments. In this study we extend these methods to develop innovative fine-resolution (25 m) climate grids for a large region (∼200 × 300 km) of New South Wales, Australia. The key aspects of these grids is that they: (1) are based on near-surface (5 cm) observations to better reflect where many species live; (2) cover a wide variety of habitats including forests, woodlands and grasslands so that they are broadly applicable; (3) include both temperature and humidity, the latter of which has often been neglected in similar studies; (4) are developed using a variety of climate-forcing factors rather than relying only on elevation and geographic location; and (5) they focus on the extreme temperatures and humidities regardless of when these occur. Analyses showed that elevation was the dominant factor explaining mild temperatures (low maximums, high minimums), but cold air drainage, distance from coast, canopy cover and topographic exposure had more effect on the extreme maximum and minimum temperatures. Humidities were predominately determined by distance to coast, elevation, canopy cover and topography; however, the relationships were nonlinear and varied in both shape and effect size between dry and moist extremes. Extreme climates occur under specific weather conditions, and our results highlight how averaging climates over seasons or periods of consecutive days will include different weather patterns and obscure important trends. Regional-scale climate grids can potentially be further improved through a better understanding of how the effects of different climate-forcing factors vary under different weather conditions. Copyright © 2011 Royal Meteorological Society

Description: Ecologists are increasingly recognising the conservation significance of microrefugia, but it is inherent difficult to locate these small patches with unusual climates, and hence they are also referred to as cryptic refugia. Here we introduce a new methodology to quantify and locate potential microrefugia using fine-scale topoclimatic grids that capture extreme conditions, stable climates, and distinct differences from the surrounding matrix. We collected hourly temperature data from 150 sites in a large (200km by 300km) and diverse region of New South Wales, Australia, for a total of 671 days over two years. Sites spanned a range of habitats including coastal dune shrublands, eucalypt forests, exposed woodland ridges, sheltered rainforest gullies, upland swamps, and lowland pastures. Climate grids were interpolated using a regional regression approach based on elevation, distance to coast, canopy cover, latitude, cold-air drainage and topographic exposure to winds and radiation. We identified extreme temperatures on two separate climatic gradients: the 5 th percentile of minimum temperatures and the 95 th percentile of maximum temperatures. For each gradient, climatic stability was assessed on three different time scales (intra-seasonal, intra-annual and inter-annual). Differences from the matrix were assessed using a moving window with a 5km radius. We averaged the Z-scores for these extreme, stable and isolated climates to identify potential locations of microrefugia. We found that our method successfully predicted the location of communities that were considered to occupy refugia, such as rainforests that have progressively contracted in distribution over the last 2.5 million years, and alpine grasslands that have contracted over the last 15 thousand years. However, the method was inherently sensitive to the gradient selected and other aspects of the modelling process. These uncertainties could be dealt with in a conservation planning context by repeating the methodology with various parameterisations and identifying areas that were consistently identified as microrefugia.

Description: Journal of the American Chemical Society DOI: 10.1021/jacs.5b09053

Description: Introduction: Inhibitor development in Mild Haemophilia A (MHA) is an uncommon complication, occurring in approximately 15% of MHA patients. Risk factors associated with the development of inhibitors in MHA include change in recombinant factor VIII (rFVIII), intensive replacement therapy, immunological challenges and missense mutations in the FVIII gene, including Tyr2105Cys mutation on exon 22. Only few reports have addressed the therapeutic options to eradicate these inhibitors, either by immune tolerance or immunosuppressive protocols. Patient: We present a case report of a 36-year-old MHA patient (original factor VIII activity of 17.5% (10–20%) with a Tyr2105Cys mutation. He developed a low titre inhibitor after intensive exposure to rFVIII to cover for spinal epidural steroid injection, switch of recombinant product (full length rFVIII to B-domain deleted rFVIII) and intensive antiviral treatment (pegylated interferon and ribavarin) for Hepatitis C. His quality of life was very poor due to recurrent spontaneous bleeds - ecchymoses, haematomas and haemarthroses. His baseline factor VIII activity dropped to 1% with an initial inhibitor titre of 2.6 BU and factor VIII recovery of less than 25%. Results: The patient responded positively when started on an immune tolerance protocol with a low dose of high purity FVIII/vWF complex concentrate. All clinical parameters improved two weeks after commencing 50 IU/kg on alternate days of the high purity FVIII/vWF product. FVIII recovery levels improved to 50% and he was asymptomatic in terms of bleeding manifestations for the following 17 weeks. Inhibitor titres stabilised at 3.5 BU. Recently, the recovery levels dropped to 26% and the frequency of bleeds increased, necessitating treatment with additional doses. The immune tolerance dose of the high purity FVIII/vWF was increased to 100IU/kg/day. Haemostatic and clinical parameters again recovered (factor VIII recovery levels of 43%) with no further spontaneous bleeds. Conclusions: The use of recombinant factor VIII, especially high intensity replacement may pose a risk of inhibitor development and bleeding complications during the management of MHA patients with Tyr2105Cys mutation. An immune tolerance protocol with FVIII/vWF concentrate is effective in the management of MHA patients with inhibitors and can improve the quality of life soon after the start of the treatment. There is no anamnestic response observed. Though low dose immune-tolerance protocol may be effective, the benefits may be short-lasting, necessitating treatment with high daily dose protocol.

Description: Abstract 5035 Rationale: Recent studies demonstrate superiority of bortezomib-containing regimens over standard therapy at improving response rates and durability of responses in patients with multiple myeloma (MM). However, limited data exist for the feasibility of delivering bortezomib-containing regimens to patients with MM over the age of 70 years. We therefore conducted a retrospective review of administration of bortezomib in combination with pulsed Dexamethasone (Bort-Dex) in elderly patients to determine the feasibility and toxicity of delivery. Methods: Patients 〉70 years with MM who had received at least one prior line of treatment but had not been previously exposed to bortezomib, were assessed for their predicted tolerance to Bort-Dex: bortezomib 1.3mg/m2 IV on days 1, 4, 8 and 11 (standard) on a 21 day-cycle or on days 1, 8, 15 and 22 (modified) on a 35 day cycle, in association with dexamethasone 20mg on the day of and day after bortezomib. Treatment was discontinued at maximal disease response, if refractory disease or if treatment-related toxicity precluded further cycles. A control cohort comprised patients

Description: Cancer patients have historically had a very poor outcome following ICU admission. Outcome has however improved over the last decade. We aim to identify factors that predict survival for critically ill patients with hematological malignancy and which can be readily identified prior to admission. This would improve selection of patients suitable for ICU admission, which represents a limited resource. We also assessed the ability of the APACHE II score to predict prognosis in these patients. Since the ICU admission case mix will vary between hospitals, one non-surgical admission within +/− 1 week of each hematological admission acted as a control group. Factors which might affect outcome were assessed by multivariate regression analysis. Factors included were age, hematological diagnosis (acute or chronic leukemia, myeloma, lymphoma), time from hematological diagnosis to ICU admission (0–6 months, 6–12 months, 〉12 months), degree of prior treatment (admission prior to diagnosis, during first line therapy, after first line), remission status, prior stem cell transplant, documented infection and length of neutropenia (none, 1–10 days, 〉10 days). For hematology patients, predicted hospital mortality was calculated from the APACHE II score by the formula of Knaus et al (Critical Care Medicine 1985). The APACHE scores of hematology patients were compared to controls by a two-sample t test. Predicted and actual mortalities were compared using a one sample test of proportion. The impact of mechanical ventilation (MV) on mortality was assessed by risk ratios. We identified 111 patients with hematological malignancy (acute leukemia n=42, chronic leukemia n=11, myeloma n=19 and lymphoma n=39) admitted to ICU in one teaching and three district general hospitals (November 2000 - January 2006). Median age of hematological patients was 59 years (range 17–84) and M: F ratio 1.22:1. Control patients (n=111) were similar with median age 63 years (range 17–86) and M: F ratio 1.09:1. For control patients, overall ICU and hospital survival rates were 70% and 55% respectively while survival for hematology patients was approximately half at 44% and 24% respectively. In multivariate regression analysis, only increasing age predicted poor outcome (p=0.016). There was a trend to poor outcome if patients were not in complete remission (p=0.066) or had documented infection (p=0.06). All other variables were not significant. APACHE scores were significantly higher in hematology patients (median 27) compared to controls (median 19) p

Description: Introduction. The impact of therapy in the management of disease relapse in patients with myeloma (MM) needs to be balanced with the impact on quality of life (QoL). The benefit of a salvage autologous stem cell transplant (ASCT2) has been demonstrated in terms of durability of response over non-transplant consolidation (NTC) (G Cook, et al., Lancet Oncology, 2013 Vol. 15, No. 8, p874-885). However, the impact of ASCT2 on patient reported outcomes (PRO) has not been reported to date. Therefore, patients' experience of pain and global measures of QoL, as part of a systematic assessment of PRO were measured at key points before, during and after randomisation in this multi-centre national phase III trial. Methods. 174 patients were randomised and data are presented on 171 who completed self-rated QoL assessments using EORTC QLQ-C30 and the EORTC myeloma module (MY-20). Pain assessments using BPI-SF were also incorporated. Genomic DNA was prepared from PBMNC using standardised GLP methods. Results. Completion rates for EORTC QoL and BPI-SF assessments were 83.3% and 77.1% at registration, and 59.6% and 53.8% at randomisation, respectively. Over half of patients reaching 1 year post-randomisation completed both assessments. EORTC QoL and BPI-SF forms had average 6% and 10% missing data, respectively. These completion rates are commensurate with previous longitudinal studies. EORTC QLQ-C30 Global health status/QoL subscale scores were significantly higher (better) in the NTC arm at 100 days and 6 month post-randomisation (P=0.0496), but not at later time points. BPI-SF pain scores showed significantly higher pain severity in the NTC (4.3/10) than the ASCT2 (2.9/10) patients only at 2 years post-randomisation. However, for pain interference with aspects of daily living, NTC patients reported significantly lower scores at 6 months (P=0.0155), 1 year post-randomisation (P=0.0466) and 2 years post-randomisation (P=0.0348). The MY-20 assessment showed that at 100 days and 6 months post-randomisation, the subscale scores for Side-effects of treatment were significantly higher in the ASCT2 arm than in the NTC arm, but not at later time points up to 2 years. Kaplan-Meier estimate of time-to-progression (TTP) by randomised allocation suggested that patients with an EORTC global QoL score greater than median (ie better QoL) at randomisation and who received ASCT2 had a significant TTP advantage over those receiving NTC (HR 0.3 (95% CI 0.15-0.61), p=0.006). However, with multivariate Cox regression analysis accounting for stratification factors this difference was not significant. Patients who reported a lower (ie better) than median level of concern on the Side-effects of treatment subscale and who received ASCT2 had a significant TTP advantage over those receiving NTC (Kaplan-Meier HR 0.24 (95% CI (0.10-0.55), p=0.003). This survival difference was still observed after multivariate Cox regression analysis (HR 5.02 (95% CI 1.00-25.20), p= 0.0499). We tested for genomic associations of SNPs from key genes reported to be involved in pain perception and analgesic responsiveness, and subjective outcomes. There were no significant associations for the opioid mu-receptor (OPRM1) and pain or QoL. However, the rs2236861 SNP in the opioid delta-receptor (OPRD1) showed nominally significant associations with worst pain (p=0.022), average pain (p=0.03) and pain interference (p=0.02) at baseline. The rs1045642 SNP in the ABCB1 drug transporter gene was nominally associated with worst pain (p=0.047) and average pain (p=0.019) after bortezomib-based induction therapy. A SNP rs13361160 in the chaperonin CCT5 gene was associated with worst pain (p=0.033), least pain (p=0.006) and pain interference (p=0.03). It was also associated with self-reported global QoL (P=0.014). Conclusions. We report the first PROs using self-reported QoL and pain assessments in myeloma patients having salvage ASCT or NTC. Global QoL was worse and side-effects of treatment higher after ASCT2 for up to 6 months post-randomisation but then equalised. Pain caused less interference with daily living after NTC but became more severe at 2 years, possibly associated with relapse. Patients who reported lower concerns about side-effects of treatment after ASCT2 had a significant TTP advantage. The genomic analyses suggest a potential inherited predisposition that influences both pain and quality of life and warrants further exploration. Disclosures Ahmedzai: Mundipharma: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Grunenthal: Consultancy, Research Funding, Speakers Bureau. Snowden:Sanofi: Consultancy; MSD: Consultancy, Other: Educational support, Speakers Bureau; Janssen: Other: Educational support, Speakers Bureau; Celgene: Other: Educational support, Speakers Bureau. Williams:Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau. Cavenagh:Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Parrish:Janssen: Speakers Bureau; Celgene: Speakers Bureau. Yong:Amgen: Honoraria; Novartis: Consultancy; Takeda: Honoraria; BMS: Honoraria; Janssen: Honoraria; Autolous: Consultancy. Cavet:Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau. Bird:Celgene: Speakers Bureau; Janssen: Other: Educational support; Amgen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Ashcroft:Janssen: Consultancy, Other: Educational support. Brown:Bayer: Research Funding; Roche: Research Funding; Celgene: Research Funding; Janssen: Research Funding. Morris:Celgene: Other: Meeting support; Janssen: Other: Meeting support. Cook:Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy; Takeda Oncology: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau.

Description: Abstract 311 Introduction: MRC Myeloma IX (N = 1,960) included intensive and non-intensive pathways and 2 bisphosphonates (BPs; zoledronic acid [ZOL] and clodronate [CLO]) in patients (pts) with newly diagnosed multiple myeloma. The trial is unique in having investigated both overall survival (OS) and bone endpoints in the context of BP treatment and a thalidomide (Thal), alkylating agent, and steroid induction regimen; and maintenance Thal. We have shown that ZOL significantly reduces skeletal-related events (SREs) and improves OS independent of its effect on SREs, suggesting potential antimyeloma activity (Morgan et al. ASCO 2010, #8021). Early comparisons between antimyeloma regimens demonstrated superiority of Thal-containing regimens for induction (Morgan et al. ASH 2009, #352) and maintenance. Here we present important new data on interactions between BPs, Thal, and standard induction regimens used in terms of response, progression-free survival (PFS), OS, and on the bone endpoints included in SREs. Methods: The intensive pathway randomized pts to 4 to 6, 3-wk cycles of CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) or CTD (cyclophosphamide, Thal, dexamethasone) as induction therapy, followed by high-dose melphalan treatment and ASCT. The non-intensive pathway randomized pts to 4-wk cycles of melphalan and prednisolone (MP) or attenuated CTD (CTDa). Each treatment arm also was randomized to ZOL (4 mg IV q 3–4 wk, dose-adjusted based on renal function) or CLO (1600 mg/d) continued at least until disease progression. After induction, pts in both pathways were offered entry to a maintenance Thal or no maintenance randomization. Endpoints included PFS, OS, and response. SREs include fractures, spinal cord compression, radiation or surgery to bone, and new osteolytic lesions at disease progression. Time to first SRE was assessed using cumulative incidence function, and OS was estimated using the Kaplan-Meier method. Cox analysis was used to assess hazard ratio (HR) and associated 95% CI for SRE risk, adjusting for effects of treatment regimen, minimization factors, and SRE history at baseline (stratified by pathway). Diagnosis of bone lesions was not a study-entry requirement; BP use may be off-label outside the UK in some pts. Results: With a median follow-up of 3.7 yr and 1,960 evaluable pts, ZOL and Thal-containing regimens produced multiple treatment benefits. Overall, there was a trend for more pts with complete response (CR; P = .15), fewer early deaths (within 60 days of randomization; P = .06), and improved OS for ZOL vs CLO (P = .04). SRE risk was significantly reduced with ZOL vs CLO (HR = 0.74, P = .0004), and—for the first time—SRE risk also proved lower for CTDa vs MP (HR = 0.74, P = .021), but was similar for CTD vs CVAD (HR = 1.03; P = .80). In the intensive pathway (n = 1,111; median age 59 yr), CR or very-good-partial response (VGPR) was achieved after induction therapy by 43.2% of pts with CTD and 27.5% of pts with CVAD. Similar proportions of pts achieved CR/VGPR with ZOL and CLO (36.0% vs 34.7%). OS and PFS were slightly better for ZOL vs CLO (OS: HR = 0.84; 95% CI, 0.68–1.03; PFS: HR = 0.90; 95% CI, 0.78–1.05; P 〉 .05 for both). In both the CVAD and CTD arms, fewer ZOL- vs CLO-treated pts had SREs (overall intensive: 27.9% vs 36.3%; log-rank P = .034). In the nonintensive pathway (n = 849; median age 73 yr), pts randomized to CTDa had a significantly higher CR rate (13.1% vs 2.4%; P 〈 .0001) and CR/VGPR (30.0% vs 4.0%; P 〈 .0001) vs MP. In each treatment arm, the ZOL group had higher rates of CR/VGPR vs CLO (MP: 6% vs 2%; CTDa: 34% vs 26%, respectively; P = .03 overall). ZOL significantly reduced risk of death by 17% vs CLO (HR = 0.83; P = .049). Time to first SRE was significantly longer for CTDa vs MP (P = .021) and ZOL vs CLO (log-rank P = .008). In modeling analyses we show that the impact of achieving a CR and of CTDa on SREs may not be independent, suggesting that the improved response is important in reducing bone disease. ZOL prolonged the median time to first SRE vs CLO in both the MP and CTDa arms. In the maintenance randomization (n = 820), ZOL significantly reduced SREs compared with CLO. Conclusions: We demonstrate that ZOL provided benefits beyond CLO, improving OS and response status, and preventing potentially debilitating SREs. Pts receiving regimens containing Thal and ZOL had the best clinical outcomes, being associated with better response, survival, and lower SRE risk. Disclosures: Morgan: Celgene: Honoraria, Research Funding; Ortho Biotech: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Boehringer Ingelheim: Research Funding; Pharmion: Research Funding; Chugai: Research Funding. Off Label Use: Diagnosis of bone lesions was not a study-entry requirement; Therefore bisphosphonate use may be off-label outside the UK in some patients. Davies:Celgene: Honoraria; Ortho Biotech: Honoraria; Novartis: Honoraria. Cook:Orthobiotec: Consultancy, Speakers Bureau. Jackson:Celgene: Honoraria; Janssen-Cilag: Honoraria.

Description: Introduction Although ASCT in MM is standard consolidative therapy in first line treatment definitive evidence for its use in salvage therapy is lacking. The principal aim of this multi-centre phase III randomised controlled trial was to evaluate the durability of response (DuR) of a second ASCT compared with a less intensive alkylating agent consolidation, after a bortezomib-containing re-induction strategy. Patients and Methods Eligible patients with MM relapsing after a prior ASCT were enrolled. All patients were re-induced with PAD therapy (Bortezomib 1.3mg/m2 iv D1, 4, 8 & 11; Doxorubicin 9mg/m2/day iv D1-4; Dexamethasone 40mg/day PO D1-4: additionally D8-11 & D15-18 on cycle 1 only) delivered in 4-6 21-day cycles before 1:1 randomization to either a second ASCT (Melphalan 200mg/m2 iv; ASCT2 supported by either stored stem cells or remobilized stem cells) or low dose consolidation with weekly cyclophosphamide 400mg/m2 PO for 12 weeks (C-weekly). Response assessment (by IMWG criteria) was analyzed after re-induction and 100 days post-randomization and time-to-disease progression (TTP) determined. Patients were stratified by β2microglobulin (β2M) at trial entry and response to re-induction and analyzed according to cytogenetic abnormalities by iFISH (unfavorable: t(4,14), t(14,16) and del17p). The primary endpoint was Time-to-progression (TTP) with secondary endpoints of OS, overall response rate (to PAD and randomized intervention), feasibility of stem cell mobilization in salvage therapy, safety & quality of life. Results The Data and Safety Monitoring Board (DSMB) recommended randomization closure and early result release owing to the primary end-point having been met. 297 patients were entered into the study and 174 randomized from April 2008 to November 2012: ASCT2 n = 89, C-weekly n = 85. Median age was 61 (range 38 -75) with 73.6% of patients relapsing more than 24 months from first ASCT. ORR to re-induction therapy was 79.4%% with 16.0% sCR/CR rate. Post-randomization, sCR/CR was significantly higher in ASCT2 (39.3%, 95% CI 29.1, 50.3) than C-weekly (22.4%, 95% CI 14.0, 32.7) cohorts with more patients upgrading response to sCR/CR in the ASCT2 (n = 22) than C-weekly (n = 7) cohorts. At the time of analysis, 125 of 174 patients have progressed, 57 in the ASCT2 (64%) and 68 in the C-weekly (80%) cohorts. Median TTP was 19 months (95% CI 16, 25) for ASCT2 compared with 11 months (95% CI 9, 12) for C-weekly (HR 0.36 95% CI 0.25, 0.53; Cox regression analysis p