ALBERT

Description: Introduction: Rituximab (R) is an integral component of therapy for B-cell lymphoid malignancies; bortezomib (Btz) has shown provocative single agent activity in Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL) and Waldenström’s Macroglobulinaemia (WM), providing the rationale for investigating the combination. Patients+Methods: Forty-five adult patients (pts.) (30 men, 15 women) with histologically confirmed recurrent CD20+ve FL, MCL or WM, median age 60 years (range 45-79), FL: 17, MCL: 18, WM: 10, stage III/IV 40 (93%), bone marrow (BM) infiltration 32 (73%), elevated LDH 22 (49%), performance status ≥1 22 (49%), were enrolled in a randomised trial comparing 2 schedules of Brz+R: Arm A (twice weekly) Btz: 1.3mg/m2 (on days 1, 4, 8, 11 of a 21-day cycle) and R: 375mg/m2 (on day 1) for 8 cycles, or Arm B (weekly) Btz: 1.6mg/m2 (on days 1, 8, 15, 22 of a 35-day cycle) and R: 375mg/m2 (on days 1, 8, 15, 22 of cycles 1 and 4) for 6 cycles (23 arm A, 22 arm B). The median number of previous treatments was 2 (range 1-7). Seventeen pts. had received a R-containing regimen, with response lasting 〉6 months, and 8 high-dose treatment. Response was evaluated using the IWR criteria (Cheson et al, JCO17: 1244, 1999) and the updated response criteria from the 3rd International Workshop on WM (Treon et al, Blood107: 3442, 2006) Results: Ability to deliver the therapy, toxicity and efficacy were equivalent in both arms. The median number of cycles given in arm A was 4 and 5 in arm B. Haematological toxicity (grade≥3: anaemia 0%, neutropenia 25%, thrombocytopenia 22%) was significantly influenced by the high percentage of pts. with BM infiltration and concomitant cytopenia on entry to the trial. The most common non-haematological adverse events were fatigue (76%), nausea (56%), diarrhoea (56%), lethargy (46%). Neurotoxicity occurred in 19 pts. (46%) (10 pts. grade 1, 7 pts. grade 2, 2 pts. grade 3). Btz dose was reduced in 7 pts.; 5 doses were omitted because of neuro or haematological toxicity. In 16 pts., treatment was delayed by 1-14 days and in 24 pts. treatment was stopped prematurely. The reasons for stopping treatment were: treatment-related toxicity 11 pts., progressive disease 9 pts., patient’s preference 3 pts., myocardial infarction 1 pt. One pt. was excluded having been found ineligible post randomisation. Thirty-nine pts. (21 arm A, 18 arm B) are evaluable for response so far, one having only received 1 cycle of therapy, which had to be discontinued because of excessive toxicity. 15/32 were in remission (CR, CRu, PR) at the completion of therapy, 7/7 at “mid-therapy” assessment, and 5 have yet to be evaluated. Thus the overall response rate (RR) presently is 22/39 (56%) (CR, CRu, PR), FL 44%, MCL 46%, WM 90%. Conclusions: The combination was active in pts. with recurrent NHL especially WM (RR 90%), despite multiple previous treatments, The weekly schedule is preferable being more convenient, as efficacious and no more toxic. Further investigation is warranted, despite not insignificant therapy compromising toxicity.

Description: Background: FL is a common NHL that has a broad spectrum of clinical outcomes. Over time some pts will transform to an aggressive histology (Tly) associated with inferior survival. In 2004, the LLMPP constructed a model that was predictive of overall survival (OS) based on the gene expression profiles (GEP) of 191 specimens taken from pts with untreated FL. The genes associated with survival were derived from the non-neoplastic immune response (IR) cells. However the risk of developing Tly was not addressed in this study. Thus we re-analyzed the GEP with updated clinical data. Our goal was to validate our previous model with extended follow-up and to create a model that would predict the risk of developing TLy. Methods: 170 of 191 previously untreated FL pts had updated clinical information but only 142 had transformation outcome. Transformation was defined as biopsy proven DLBCL or clinically based on the presence of at least one of the following: hypercalcemia, a sudden rise in LDH 〉twice baseline, unusual extranodal growth or rapid discordant nodal growth. Raw CEL files from Affymetrix U133A arrays were pre-processed and normalized using Bioconductor’s GCRMA package. Models were developed using SignS package (http://signs/bioinfo.cnio.es/), with 10 times cross-validation. All gene lists produced in these analyses were then re-tested for association with outcome using Bioconductor’s Globaltest package. Over Representation Analysis of signature components was performed using Dchip. Results: The median OS of these patients was 8 yrs. A new 7-component survival model (85 genes) was developed that was significantly associated with survival (p= 2.9×10−13). In Globaltest, these gene lists were associated with survival at a level of (p=2.6×10−5). The previous model using IR-1 and IR-2 signatures was associated with survival at a level of p=2.6×10−4. Although there is little overlap between the 2 models, the new model confirms the importance of IR genes and extracellular matrix genes as being prognostically important. Interestingly, one component containing 10 genes on chromosome 6q was associated with a superior survival (p1 cross validation run. These were significantly enriched in genes important in immune response like T cell and macrophage activation. Conclusion: Our survival model is stable and confirms the importance of key genes involved in the immune response and lymph node remodeling. It also introduces new genes that are potentially important for survival. Our transformation model may shed light on the mechanisms involved in the progression of FL to DLBCL but it is less stable and less reliable than our survival model at predicting outcome.

Description: The WASP consortium is conducting an ultra-wide field survey of stars between 8–15 mag from both hemispheres. Our primary science goal is to detect extra-solar ‘hot-Jupiter’-type planets that eclipse (or transit) bright host stars and for which further detailed investigation will be possible. We summarize the design of the SuperWASP instruments and describe the first results from our northern station SW-N, sited in La Palma, Canary Islands. Our second station, which began operations this year, is located at the South African Astronomical Observatory. Between April and September, 2004, SW-N continuously observed ~6.7 million stars. The consortium's custom-written, fully automated data reduction pipeline has been used to process these data, and the information is now stored in the project archive, held by the Leicester database and archive service (LEDAS). We have applied a sophisticated, automated algorithm to identify the low-amplitude (~0.01 mag), brief (~few hours) signatures of transiting exoplanets. In addition, we have assessed each candidate in the light of all available catalogue information in order to reject data artefacts and astrophysical false positive detections. The highest priority candidates are currently being subjected to further observations in order to select the true planets. Once the exoplanets are confirmed, a host of exciting opportunities are open to us. In this paper, we describe two techniques that exploit the transits in order to detect other objects within the same system. The first involves determining precise epochs for a sequence of transit events in order to detect the small timing variations caused by the gravitational pull of other planets in the same system. The second method employs ultra-high precision photometry of the transits to detect the deviations caused by the presence of exoplanetary moons. Both of these techniques are capable of detecting objects the size of terrestrial planets.