Previous Schedule Research Articles

Long-term efficacy of (90)Y ibritumomab tiuxetan therapy in follicular non-Hodgkin lymphoma and health-related quality of life.

The aim of this study was to analyze the outcomes of 37 follicular lymphoma (FL) patients treated with (90)ytrium ibritumomab tiuxetan (90Y-IT), outside of clinical trial, according to protocol ISCRTN36210045, after ≥5 years follow-up to February 2014. Health-related quality of life (HRQoL) was evaluated with the SF-36, Spanish version, and compared with the general population of Spain. Patients had a mean age of 61.9 (range, 30-85) years and included 18 males. FLIPI, low: 25 (67.6 %), intermedium 9 (24.3 %), and low 3 (8.1 %). Previous therapy schedules >2: 48.6 % The median follow-up was 66 months, mean Time to Relapse (TTR) 71.3 months (58.8-83.8) median not reached. Thirty-four patients achieved complete response (91.8 %), and three no response. Mean overall survival: 82.3 months (71.6-92.9). Four patients presented with concomitant tumors (colon, breast, prostate, lung) after radioimmunotherapy, and three developed second primary neoplasms (esophagus, renal, and myelodysplastic syndrome in a relapsed patient who received fludarabine). Four of 10 deaths were related to lymphoma progression. Hematological toxicities were mild and easily managed. No patients required hospitalization. Negative scores were obtained in the physical and emotional roles items; however, the perception of general health and vitality were better than in the general population, with the best outcomes in non-relapsed patients. Radioimmunotherapy with 90Y-IT was safe and effective as long-term therapy in patients with FL. Early use of radioimmunotherapy could offer good, sustained responses with low toxicity over the long term and acceptable HRQoL.

Vaccination of heifers with anaflatoxin improves the reduction of aflatoxin b1 carry over in milk of lactating dairy cows.

It was previously reported that injection of anaflatoxin B1 (AnAFB1) conjugated to keyhole limpet hemocyanin (KLH), together with Freund's adjuvant, was effective in inducing in cows a long lasting titer of anti-aflatoxin B1 (AFB1) antibodies (Abs), cross-reacting with other aflatoxins, which were able to hinder, proportionally to their titer, the secretion of aflatoxin M1 (AFM1) into the milk of cows continuously fed with AFB1. According to anti-AFB1 Ab titer, 50% of the vaccinated cows were recognized as high responder animals. In an attempt to prepare a more effective formulation for vaccination of cows, it was compared the immunogenicity, in Holstein Friesian heifers, of AnAFB1 covalently conjugated to KLH or to recombinant diphtheria toxin (CRM197) molecules, and injected together with various adjuvants. This study demonstrated that injection of AnAFB1 conjugated to KLH and mixed with complete (priming) and incomplete Freund's adjuvant (boosters), as in the previous schedule of immunization, was the most effective regimen for inducing Ab responses against AFB1, although pre-calving administration could increase the effectiveness of vaccination, resulting in 100% high responder animals. After one booster dose at the beginning of the milk production cycle, anti-AFB1 Ab titers were comparable to those recorded at the end of the immunization schedule, and proved to be effective in reducing significantly AFB1 carry over, as AFM1, from feed to milk. Pre-calving vaccination of dairy heifers with conjugated AnAFB1, adjuvated with complete and incomplete Freund's adjuvant, may represent the most effective tool for preventing the public health hazard constituted by milk and cheese contaminated with aflatoxins.

Prevalence of depression and its relationship with work characteristics in a sample of public workers

Occupation is a fundamental right, enabling social interaction and financial support for the individual. However, it is an undeniable source of stress, with consequences for physical and mental health. The prevalence of depression and somatic complaints were assessed in 1,013 public workers using the Beck Depression Inventory and a questionnaire investigating for the presence of somatic problems designed by the research team. The results were related to demographic characteristics, history of previous depressive episodes, work schedule (day work, night and day rotating shift work, day rotating shift work), and duration of current work schedule. There were more cases of moderate depression in the day rotating shift workers (84%) than in those working at night (83%). More women had mild or moderate depression than men (22% and 4% versus 10% and 3%, respectively). Severe depression was found only in men. Nearly 10% of depressed individuals reported previous depressive episodes. A link between depression and somatic complaints was also found. In particular, 59% of depressed subjects reported gastrointestinal complaints and 41% did not (P<0.001). In conclusion, the occurrence of depressive symptoms could be facilitated by occupation. A history of depressive symptoms should not be neglected, given the risk of recurrence. Somatic complaints could represent a “wake-up call” regarding depression. Global assessment and effective support are fundamental for promotion of a better quality of life in the at-risk category of workers.

Single versus multiple fractions of repeat radiation for painful bone metastases: a randomised, controlled, non-inferiority trial

Although repeat radiation treatment has been shown to palliate pain in patients with bone metastases from multiple primary origin sites, data for the best possible dose fractionation schedules are lacking. We aimed to assess two dose fractionation schedules in patients with painful bone metastases needing repeat radiation therapy. We did a multicentre, non-blinded, randomised, controlled trial in nine countries worldwide. We enrolled patients 18 years or older who had radiologically confirmed, painful (ie, pain measured as ≥2 points using the Brief Pain Inventory) bone metastases, had received previous radiation therapy, and were taking a stable dose and schedule of pain-relieving drugs (if prescribed). Patients were randomly assigned (1:1) to receive either 8 Gy in a single fraction or 20 Gy in multiple fractions by a central computer-generated allocation sequence using dynamic minimisation to conceal assignment, stratified by previous radiation fraction schedule, response to initial radiation, and treatment centre. Patients, caregivers, and investigators were not masked to treatment allocation. The primary endpoint was overall pain response at 2 months, which was defined as the sum of complete and partial pain responses to treatment, assessed using both Brief Pain Inventory scores and changes in analgesic consumption. Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00080912. Between Jan 7, 2004, and May 24, 2012, we randomly assigned 425 patients to each treatment group. 19 (4%) patients in the 8 Gy group and 12 (3%) in the 20 Gy group were found to be ineligible after randomisation, and 140 (33%) and 132 (31%) patients, respectively, were not assessable at 2 months and were counted as missing data in the intention-to-treat analysis. In the intention-to-treat population, 118 (28%) patients allocated to 8 Gy treatment and 135 (32%) allocated to 20 Gy treatment had an overall pain response to treatment (p=0·21; response difference of 4·00% [upper limit of the 95% CI 9·2, less than the prespecified non-inferiority margin of 10%]). In the per-protocol population, 116 (45%) of 258 patients and 134 (51%) of 263 patients, respectively, had an overall pain response to treatment (p=0·17; response difference 6·00% [upper limit of the 95% CI 13·2, greater than the prespecified non-inferiority margin of 10%]). The most frequently reported acute radiation-related toxicities at 14 days were lack of appetite (201 [56%] of 358 assessable patients who received 8 Gy vs 229 [66%] of 349 assessable patients who received 20 Gy; p=0·011) and diarrhoea (81 [23%] of 357 vs 108 [31%] of 349; p=0·018). Pathological fractures occurred in 30 (7%) of 425 patients assigned to 8 Gy and 20 (5%) of 425 assigned to 20 Gy (odds ratio [OR] 1·54, 95% CI 0·85-2·75; p=0·15), and spinal cord or cauda equina compressions were reported in seven (2%) of 425 versus two (<1%) of 425, respectively (OR 3·54, 95% CI 0·73-17·15; p=0·094). In patients with painful bone metastases requiring repeat radiation therapy, treatment with 8 Gy in a single fraction seems to be non-inferior and less toxic than 20 Gy in multiple fractions; however, as findings were not robust in a per-protocol analysis, trade-offs between efficacy and toxicity might exist. Canadian Cancer Society Research Institute, US National Cancer Institute, Cancer Council Australia, Royal Adelaide Hospital, Dutch Cancer Society, and Assistance Publique-Hôpitaux de Paris.

OP0148 Reduced dose and frequency of anti-TNF therapy in rhemuatic diseases

BackgroundThe anti-TNFα drugs Adalimumab (ADA) and Etanercept (ETA) are given in standard doses and intervals. Many patients on these drugs achieve long-term remission or low disease activity yet continue on...

A randomized trial of single versus multiple fractions (Fx) for re-irradiation (RE-RT) of painful bone metastases (PBM): NCIC CTG SC.20.

9502 Background: The optimal RE-RT dose and fractionation schedule for PBM is uncertain. Methods: Patients (pts) with PBM after previous radiation (RT) to the same site were stratified by previous Fx schedule and pain response and randomized to 8 Gy in 1 Fx or 20 Gy in 5 Fx (8 Fx if previous RT was to spine/whole pelvis in multiple Fx). The primary endpoint was overall response rate (RR) at 2 months using the International Consensus schema (Chow 2002) which combines Brief Pain Inventory worst pain score and opioid analgesic use. We tested if 8Gy was non-inferior (NI), analyzed by intention to treat (ITT) and a per-protocol (PP) sensitivity analysis excluding those who were ineligible, inevaluable or received non-allocated therapy. Sample size was calculated using an expected RR of 70% with 20Gy and a NI margin of 10% (i.e. upper boundary of 1-sided 95% CI for the RR difference). Pts reported adverse events (AEs) by questionnaire on Day 14. Quality of life (QoL) was assessed using the EORTC QLQ C30. Results: Between 01/2004 and 06/2012, we enrolled 850 pts from 9 countries. Most common cancers were prostate (27%), breast (26%) and lung (22%). Before the 2 month assessment, 98 (11%) pts died. By ITT, the 2-month RR was available in 66% (557/850) and was 119/425 (28%) with 8Gy and 136/425 (32%) with 20Gy (P=0.2); the upper boundary of the 95% CI for RR difference = 9.2% and is less than the pre-specified NI margin. By PP analysis, 2-month RR was available in 521 and was 117/258 (45.3%) with 8Gy and 135/263 (51.3%) with 20Gy (P=0.17); the upper boundary of the 95% CI for RR difference = 13.2%, which exceeds 10% non-inferiority boundary. Day 14 AEs differing by treatment were: lack of appetite (P=0.01), vomiting (P= 0.001), diarrhea (P=0.02) and skin reddening (P=0.002); all were worse with 20Gy. There were 30 vs 20 pathological fractures and 7 vs 2 spinal cord compressions with 8Gy and 20Gy, respectively (P=NS). No difference in QoL existed between arms. Conclusions: In pts with PBM receiving RE-RT, the 2-month RR obtained with 8Gy is non-inferior to 20 Gy when assessed by ITT but findings were not robust to a PP sensitivity analysis. When choosing between options tested, trade-offs exist between pain response and acute toxicity. Clinical trial information: NCT00080912.

VMScatter

Live virtual machine migration is a technique often used to migrate an entire OS with running applications in a non-disruptive fashion. Prior works concerned with one-to-one live migration with many techniques have been proposed such as pre-copy, post-copy and log/replay. In contrast, we propose VMScatter, a one-to-many migration method to migrate virtual machines from one to many other hosts simultaneously. First, by merging the identical pages within or across virtual machines, VMScatter multicasts only a single copy of these pages to associated target hosts for avoiding redundant transmission. This is impactful practically when the same OS and similar applications running in the virtual machines where there are plenty of identical pages. Second, we introduce a novel grouping algorithm to decide the placement of virtual machines, distinguished from the previous schedule algorithms which focus on the workload for load balance or power saving, we also focus on network traffic, which is a critical metric in data-intensive data centers. Third, we schedule the multicast sequence of packets to reduce the network overhead introduced by joining or quitting the multicast groups of target hosts. Compared to traditional live migration technique in QEMU/KVM, VMScatter reduces 74.2% of the total transferred data, 69.1% of the total migration time and achieves the network traffic reduction from 50.1% to 70.3%.

RIT with 90Y Ibritumomab Tiuxetan in Agressive Non-Hodgkin Lymphoma. Evaluation of Recent Outcomes in a Single Institution

Abstract 4883Diffuse Large B Cell (DLBC) and Mantle Cell Lymphoma (MCL), are two subtypes of aggressive non-Hodgkin lymphoma (A-NHL),that frequently present as advanced systemic disease limiting the use of involved field radiation. They are also predominant in advanced age population non suitable for intensive therapy such as stem cell transplantation. Their aggressive systemic behavior, confer high rates of relapse and short overall survival. The development of radioimmunotherapy brings a new therapeutic approach for both types of A-NHL. We present the results derived from a single-institute use of 90Y-Ibritumomab Tiuxetan (90Y-IT) (Zevalin®) in DLBC and MCL, both as consolidation therapy in first complete response (C-1CR) after chemoimmunotherapy and as second line treatment in relapsed disease (RD). Patients and Methods:we included 19 patients with A-NHL, 10 MCL and 9 DLBCL, treated with 90Y-IT according to a multidisciplinary clinical protocol, between September 2005 and February 2012. Inclusion criteria were: histological confirmed CD20+ MCL or DLBCL, with absolute neutrophil count (ANC) ≥ 1.5 × 109/L, absolute platelet count (APC) ≥ 100 × 109/L, ≤ 25% bone marrow CD20+ lymphocytes, in Complete Remission (CR) after first line chemoimmunotherapy or with relapsed disease. All patients received two prior 250 mg/m2 Rituximab doses, followed by 0.4 mCi /kg IV 90Y-IT. Response was evaluated by PET/TC 12 weeks after treatment. Major endpoints were: objective response rate (ORR), overall survival (OS), progression free survival (PFS), and safety. Other clinical prognostic factors were taken into account upon their possible influence in treatment value. Results:18 of 19 patients treated with 90Y-IT completed follow-up and were taken into analysis, 10 MCL (52.6%) and 9 DLBCL (47.4%); M/F distribution 10/9 (73.6/26.4%); Overall ECOG 0–1 82.35%. Mean follow-up time: 46.8 months. 8 patients were treated as C-1CR, 4 MCL and 4 DLBCL. For MCL mean age was 66.9 (53–79) years. MIPI score distribution: 0–3 (70.0%), >3 (30.0%). Status before 90Y-IT was: C-1CR 3; relapsed in CR after chemotherapy 3; relapsed/refractory with active disease after chemotherapy (PR) 4. Previous chemotherapeutic schedules: ≤2 (50 %). Overall response (80.0%) 7 CR; 1 PR. Mean estimated OS since 90Y-IT: 57.0 months (52.4–61.6), median OS: 59 months (34.8–86.1) and mean PFS: 24.9 months (95% CI: 14.3–35.6); median PFS: 22 months (95% CI: 1.9–42.0). For DLBCL: mean age 53 (35–87) years. IPI-R score distribution: 0–2 (33.3%), >2 (66.7%). Status before 90Y-IT was: C-1CR 5; relapse/refractory with active disease after chemotherapy (PR) 4; Previous chemotherapeutic schedules ≤2 (77.8%). Overall responses (88.8%) 5 CR; 3 PR. Mean OS since 90Y-IT: 49.2 months (42.8–55.6); median OS: NR and mean PFS: 39 months (95% CI: 22.6–55.4). Until analysis 11 patients have relapsed (57.8%), 8 MCL (80%) and 3 DLBCL (37.5%). Four patients had died, 3 because of disease progression even after several chemotherapeutic treatments. In respect to safety: thrombocytopenia was the most frequent hematologic toxicity presented in 63.1%, grade 3–4 in 21%, with median time to presentation of 2.8 weeks and median time for recovery of 3 weeks. Neutropenia occurred in 52.6%, grade 3–4 in 21%, with median time for recovery of 2 weeks. 1 patient (5.2%) required red cell transfusion and 4 (21.5%) needed platelet transfusion. The most frequent non hematologic toxicity was asthenia. One MCL patient who relapsed 28 months and received 2 more chemotherapy schedules has been diagnosed, four years after 90Y-IT as lung carcinoma. Conclusions:90Y-IT is a safe and effective consolidation therapy in A-NHL, that allows sustained CR and extends PFS with a low toxicity profile. There are needed further studies to evaluate the impact of radioimmunotherapy in A-NHL.This worh has bee partially sponsored by a grant from FEHHA Disclosures:No relevant conflicts of interest to declare.

RIT with 90Y Ibritumomab Tiuxetan in Patients with Non-Hodgkin Lymphoma Over 65 Years.

Abstract 2742 Introduction:90Y Ibritumomab tiuxetan (90Y-IT) has become an efficient alternative to therapy in non-Hodgkin Lymphoma, mainly in elderly patients. The aim of this study is to analyse our updated information of patients treated with 90YIbritumomab/tiuxetan in a prospective study according clinical practice setting and to analyse treatment outcome. Subjects and Methods:39 non Hodgkin lymphoma patients were included in a clinical protocol conducted by a multidisciplinary team and treated in the same centre. According the inclusion criteria: patients over 65 years old diagnosed as CD20+ NHL with neutrophils ≥ 1,5 × 109/L, platelets ≥ 100 × 109/L, bone marrow lymphocytes CD20+ ≤ 25%. All patients received 0,3 or 0,4 mCi /kg IV (88%) of 90YIbritumomab/tiuxetan and response evaluation was performed 12 weeks after. Period of study: September 2005/July 2012. The 90Y-IT was administered as consolidation of first line therapy (Rituximab alone, R-COP, R-CHOP21) or in relapsed/refractory status. Endpoints:Objective response rate (ORR), time to relapse (PFS) overall survival (OS) and safety. Other clinical prognostic factors were observed to assess their possible influence upon treatment value. Results:Until May 2012, 39 patients had received treatment with 90YIbritumomab/tiuxetan and completed the evaluation protocol and were considered to analysis; M/F 18/21 mean age 72.8 years (65–87); ECOG 0–1 92.3%. According OMS classification: NHL-follicular 27 (69.2%), mantle cell Lymphoma 7 (17.9%), DLBCL 4 (10.3%) and 1MALT (2.6%). Score distribution: low risk 19 (48.7%), intermediate 12 (30.8.2%) and advanced 8 (20.5%). Previous therapy schedules ≤2 (66.7%), >2 (33.3%). The median follow-up time: 42.0 months (95% CI: 4.0; 62.0), mean PFS: 38.1 months (95% CI: 30.8; 45.4) median NR. 13 patients received 90Y-IT as consolidation of first line therapy (33.3%) and 26 relapsed/refractory (66.6%). ORR was 84.6 % CR: 29 (74.3%); PR 4 (10.2%) and 6 failures (15.4%) in relapsed/refractory disease. Mean estimated OS since 90Y-IT: 54.4 months (95% CI: 49.4; 59.3) and mean estimated OS since diagnosis 159 months. Median PFS was NR. The mean PFS for patients in consolidation therapy was 54.2 months (95% CI: 47.4; 61.1). Safety: thrombocytopenia being the most frequent, G3–4 (35.9%), median time to developed haematological toxicity: fourth week, and neutropenia G3–4 (41.0%), the median time to recover normal values was 4.2 and 2.6 weeks respectively. In 5 (12.9%) of patients red blood cell transfusion was required, and 10 platelet transfusions (25.6%). The most frequent non haematological toxicity was asthenia. One patient developed a severe mucositis. Four patients have concomitant associated tumours (colon, breast, lung and prostate) and two patients over 77 years developed a rectum carcinoma after 18 months of 90Y-IT and another prostate and renal tumour after 8 years. Comments:In our experience 90Y Ibritumomab tiuxetan is a safety and effective therapy in patients with NHL over 65 years. According to obtained PFS results, it seems like the use of this kind of therapy as used in early part of therapy offers good and maintained response rate with lower toxicity in this fragile population. The OS in this population was not inferior to observed in younger NHL patients. Disclosures:No relevant conflicts of interest to declare.

O3-038 - Phase II Study of S-1 Plus Leucovorin (New 1 Week Treatment Regimen Followed by 1 Week Rest Period) in Patients with Untreated Metastatic Colorectal Cancer in Japan and China

ABSTRACT Background The previous phase II study of the oral S-1 plus oral Leucovorin (LV) (2 weeks on/2 weeks off) for patients with untreated metastatic colorectal cancer (mCRC) have shown to be effective, but the grade 3 toxic effects (diarrhea, stomatitis, and anorexia) were observed with relatively high frequency. In this phase II study, we modified the administration schedule of S-1 plus LV regimens for well-tolerated toxic effects and evaluated the efficacy. Methods Patients were eligible as follows: histologically confirmed adenocarcinoma, age ≥ 20, ECOG PS 0-1, no prior chemotherapy, at least one measurable lesion by RECIST ver1.0 criteria, adequate organ function, and written informed consent. S-1 (40-60 mg b.i.d.) and LV (25 mg b.i.d.) were orally administered for 1 week, followed by 1 week rest period. Treatment was repeated until the onset of disease progression or unacceptable adverse events occurred. The primary end point was the response rate (RR), and the secondary end points were efficacy and safety. This trial was supported by Taiho Pharmaceutical CO., Ltd. ClinicalTrials.gov Identifier: NCT00891332 Results From October 2008 to June 2009, 73 patients were enrolled in Japan and China. Of the eligible 71 patients, the median age was 60 (range 27-84), male/female was 38/33, PS: 0/1 was 39/32, and Japan/China was 32/39. RR as primary end point was 53.5% (95% CI, 41.3–65.5), and disease control rate was 83.1%. With a median follow-up period of 26.4 months, the median progression-free survival was 6.5 months. Median overall survival was 24.3 months with the survival rate of 77.5% at 1 year and 53.2% at 2 years. The incidences of grade 3 adverse drug reactions were diarrhea 8.3%, stomatitis 8.3%, anorexia 2.8%, neutropenia 9.7%, and there was no treatment-related death. Conclusions The modified treatment schedule of S-1 plus LV (1w on/ 1w off) showed similar good efficacy and better tolerability compared with the previous treatment schedule (2w on/ 2w off). This therapy showed promising activity in patients with untreated mCRC without the concurrent use of irinotecan, oxaliplatin, or molecular-targeted drugs.

984P - Conservative Sensitivity Analyses of Progression-Free Survival (PFS) of Trabectedin Plus Pegylated Liposomal Doxorubicin (PLD) Vs. Pld Alone in Patients with Relapsed Ovarian Cancer: Ova-301 Study

ABSTRACT Background Sensitivity analyses are critical to understanding the strength of conclusions made in the primary analysis. A randomised phase III trial OVA-301 compared the efficacy of trabectedin 1.1 mg/m2 in combination with PLD 30 mg/m2 given every 3 weeks vs. PLD 50 mg/m2 every 4 weeks in patients with relapsed ovarian cancer. Primary endpoint was PFS based on independent radiology review (IRR) per RECIST. Secondary PFS analyses were based on independent oncologist (IO) and investigator's assessments (IA). Methods Patients were assessed symmetrically every 8 weeks in both arms. To avoid bias of the disease assessment time, two conservative sensitivity analyses of PFS were performed. Two different conservative analyses considered the scheduled date of PFS evaluation instead of the actual date of imaging moving the actual date to: #1) the last scheduled date of assessment immediately before the actual evaluation and to #2) the closest scheduled date before or after the actual evaluation. Results The treatment effect based on the actual dates of assessment in favour of the combination arm is maintained across the performed sensitivity analyses. Summary of the two sensitivity PFS analyses compared with the pre-planned PFS analysis. Analysis n Trabectedin + PLD PLD HR CI 95% LR test (p value) PFS by IR * 645 328 317 0.789 0.646-0.963 0.0190 PFS by IR ( #1 ) 645 328 317 0.813 0.666-0.993 0.0245 PFS by IR ( #2 ) 645 328 317 0.822 0.674-1.004 0.0317 PFS by IO * 671 336 335 0.724 0.599-0.876 0.0008 PFS by IO ( #1 ) 671 336 335 0.749 0.620-0.906 0.0010 PFS by IO ( #2 ) 671 336 335 0.757 0.626-0.916 0.0013 PFS by IA * 672 337 335 0.723 0.608-0.859 0.0002 PFS by IA ( #1 ) 672 337 335 0.742 0.624-0.882 0.0001 PFS by IA ( #2 ) 672 337 335 0.747 0.629-0.888 0.0001 CI, confidence interval; HR, hazard ratio; IA, investigator assessment; IO, independent oncology review; IR, independent radiology review; LR, log-rank; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin. * *Main PFS analyses. #1 #1: Conservative PFS sensitivity analysis; imputation to the previous schedule evaluation. #2 #2: Sensitivity analysis with imputation to the closest scheduled evaluation. Conclusions The consistently observed significantly better PFS for the trabectedin combination based on adjusting progression times by moving assessments to scheduled times added methodological strengths and increased reliability and interpretability of the prior findings of this phase III trial. Disclosure A. Tanovic: I am an employee at PharmaMar and stock owner. J. Gomez Garcia: I am an employee at PharmaMar and stock owner. A.M. Poveda: I received funding for research from PharmaMar. All other authors have declared no conflicts of interest.

Prevalence of Serum Bactericidal Antibody to Serogroup C Neisseria meningitidis in England a Decade after Vaccine Introduction

Serogroup C meningococcal disease incidence and carriage declined rapidly in the United Kingdom after infant serogroup C conjugate vaccination was introduced in 1999, with catch-up vaccination for children under 18 years. Antibody levels and effectiveness waned quickly in children vaccinated at 2, 3, and 4 months of age. Therefore, in 2006, the current revised schedule of doses at 3, 4, and 12 months was introduced. This study assessed age-specific protection in 2009 compared with data from historical prevaccination and early postvaccination studies. Rabbit complement serum bactericidal antibody (SBA) was measured in anonymously banked serum samples collected in England in 2009 (n = 1,174), taking titers of ≥ 8 as protective. Age-stratified proportions of SBA titers that were ≥ 8 and geometric mean titers were compared. SBA titers varied markedly by birth cohort and time since vaccination. Overall, 35% of samples (95% confidence interval [CI], 33 to 38%) had titers that were ≥ 8. Only in cohorts eligible for catch-up vaccination did the majority of individuals have protective antibody levels. Antibody levels were higher in children eligible for vaccination at primary and secondary school ages, compared to those eligible below the age of 5 years. In those eligible for completed vaccination under the current schedule, protective levels were very modest and there was no evidence of superiority to cohorts that were eligible for the previous schedule. This supports a need for older childhood or adolescent booster vaccination in those previously eligible for vaccination during the infant, toddler, or preschool periods, to maintain direct protection and potentially enhance population immunity.

Melatonin affects the temporal pattern of vocal signatures in birds

In humans and other animals, melatonin is involved in the control of circadian biological rhythms. Here, we show that melatonin affects the temporal pattern of behavioral sequences in a noncircadian manner. The zebra finch (Taeniopygia guttata) song and the crow of the Japanese quail (Coturnix japonica) are courtship vocalizations composed of a stereotyped sequence of syllables. The zebra finch song is learned from conspecifics during infancy, whereas the Japanese quail crow develops normally without auditory input. We recorded and analyzed the complete vocal activity of adult birds of both species kept in social isolation for several weeks. In both species, we observed a shortening of signal duration following the transfer from a light-dark (LD) cycle to constant light (LL), a condition known to abolish melatonin production and to disrupt circadian rhythmicity. This effect was reversible because signal duration increased when the photoperiod was returned to the previous LD schedule. We then tested whether this effect was directly related to melatonin by removal of the pineal gland, which is the main production site of circulating melatonin. A shortening of the song duration was observed following pinealectomy in LD. Likewise, melatonin treatment induced changes in the temporal structure of the song. In a song learning experiment, young pinealectomized finches and young finches raised in LL failed to copy the temporal pattern of their tutor's song. Taken together, these results suggest that melatonin is involved in the control of motor timing of noncircadian behavioral sequences through an evolutionary conserved neuroendocrine pathway.

Editorial

TOPLAS will have four issues per year from now on! The goal is to have each of the four issues contain 5--6 articles, instead of the previous schedule of six issues that each typically contained 3--4 articles. Historically, TOPLAS had four issues per volume from 1980 to 1992, and all but three of those issues contained 5 or more articles. I hope that the TOPLAS readers will enjoy the fewer, thicker issues of TOPLAS. I thank the associate editors who continue to serve TOPLAS, and I also thank Wei Li and Aaron Stump who in the Winter of 2012 reached the end of their terms and stepped down as associate editors. Welcome to Michael Hicks who is a new associate editor.

An Automatic Course Scheduling Approach Using Instructors' Preferences

University Courses Timetabling problem has been extensively researched in the last decade. Therefore, numerous approaches were proposed to solve UCT problem. This paper proposes a new approach to process a sequence of meetings between instructors, rooms, and students in predefined periods of time with satisfying a set of constraints divided in variety of types. In addition, this paper proposes new representation for courses timetabling and conflict-free for each time slot by mining instructor preferences from previous schedules to avoid undesirable times for instructors. Experiments on different real data showed the approach achieved increased satisfaction degree for each instructor and gives feasible schedule with satisfying all hard constraints in construction operation. The generated schedules have high satisfaction degrees comparing with schedules created manually. The research conducts experiments on collected data gathered from the computer science department and other related departments in Jordan University of Science and Technology- Jordan.

Horizontal inequity under a dual income tax system: principles and measurement

Tax systems with separate taxation of wage and capital income, also called dual income tax systems, have gained relevance through the Mirrlees Review. Obviously, such tax systems are exposed to horizontal equity (HE) failures, or horizontal inequity (HI). HE and HI have a firm grip on assessment of fair tax policies, both from an academic point of view and in general public debate. The dual income tax system of Norway was modified by the tax reform of 2006 precisely because the previous schedule failed to deliver equal tax treatment of equals. This paper discusses the meaning and measurement of HI effects of dual income tax systems, and evaluates the development of HI for Norway over the time period 2000–2008 using microdata. A copula-based identification strategy efficiently establishes a framework for evaluations of HI over time. The dual income tax system and the early announcement of its impending revision during the period under examination created measurement problems which we had to account for by defining a new income concept for the empirical strategy. As expected, we find less HI in Norway after the reform of 2006.

Tolerability of Human Immunoglobulin 10% Administered Subcutaneously Following Administration of Recombinant Human Hyaluronidase (rHuPH20) in Primary Immunodeficiency Disease (PIDD) Patients

Tolerability of Human Immunoglobulin 10% Administered Subcutaneously Following Administration of Recombinant Human Hyaluronidase (rHuPH20) in Primary Immunodeficiency Disease (PIDD) Patients

FDG-PET probe-guided surgery for recurrent retroperitoneal testicular tumor recurrences

Aim Tumor marker based recurrences of previously treated testicular cancer are generally detected with CT scan. They sometimes cannot be visualized with conventional morphologic imaging. FDG-PET has the ability to detect these recurrences. PET probe-guided surgery, may facilitate the extent of surgery and optimize the surgical resection. Methods Three patients with resectable 2nd or 3rd recurrent testicular cancer based on elevated tumor markers after previous various chemotherapy schedules and resections of residual retroperitoneal tumor masses were included in this study. A diagnostic FDG-PET was performed and a hotspot in previously operated area of the retroperitoneal space in all three patients was visualized. PET probe-guided surgery was performed using a high-energy gamma probe 3 h post-injection of 500 MBq FDG. Results All patients showed extended adhesions and scar tissue in the retroperitoneal area due to the previous surgeries. Pre-operative PET/CT scan showed a good correlation with intra-operative PET probe-guided detection of recurrent lesions. There was a high target to background ratio (TGB) of 5:1 during the procedure. In one patient, a 2 cm large lesion, which did not show on pre-operative FDG-PET scan, was detected with the PET probe. Histopathologic tissue evaluation demonstrated recurrent vital tumor in all PET probe positive lesions. Conclusions PET probe-guided surgery seems to be a promising tool to localize FDG-PET positive lesion in recurrent testicular cancer in hardly accessible surgical locations. PET probe-guided surgery might be a useful technique in surgical oncology for recurrent testicular cancer and has the potential to be applied in surgery of other malignant diseases.

A Phase 2 Dose Regimen Optimization Study of Three Schedules of Voreloxin as Single Agent Therapy for Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia.

Abstract 1037Poster Board I-59 Background:Voreloxin is a first-in-class anticancer quinolone derivative (AQD) that intercalates DNA and inhibits topoisomerase II, inducing apoptosis. Interim results of REVEAL-1, a Phase 2 (Ph 2) dose regimen optimization study of 3 schedules (sch) of single agent voreloxin in newly diagnosed elderly acute myeloid leukemia (AML) patients (pts), are reported. The initial dose regimen, voreloxin 72 mg/m2 qw x 3, was established in a Ph 1 dose-escalation study in relapsed/refractory leukemia pts (Lancet J et al., Proc ASH 2007). Overall remission rate (ORR = CR+CRp) was high (41%), but this regimen was less well tolerated in the frontline elderly population. The protocol explored 2 alternative voreloxin sch: 72 mg/m2 voreloxin qw x 2 and days 1 and 4 (d 1,4). A final cohort of pts is enrolling to the d 1,4 sch at 90 mg/m2. Dose escalation was based on safety data from the 72 mg/m2 cohort and from an ongoing Ph 1b/2 study of 90 mg/m2 voreloxin d 1,4 in combination with 1g/m2/d cytarabine x 5d (Lancet J, et al, ASCO 2009). Methods:Ph 2 study of 3 voreloxin sch (30 pts/sch): A 72 mg/m2 qw x 3 or B 72 mg/m2 qw x 2 or C 72 mg/m2 on d 1,4. C at 90 mg/m2 voreloxin is now enrolling to 20 pts. Eligibility: newly diagnosed AML (de novo or secondary AML), pts age ≥ 60 with ≥ 1 additional adverse risk factor (age ≥ 70, secondary AML, intermediate or unfavorable cytogenetics, or PS 2). PK were evaluated in a pt subset in cycle 1. Patient bone marrow aspirates (BMA) taken prior to dosing were tested ex vivo for extreme drug resistance (EDR®) to voreloxin. Results:To date, 105 pts have been treated. Preliminary safety and ORR are available for A, B and C at 72 mg/m2 voreloxin. Twelve pts in C at 90 mg/m2 are too early to evaluate (TETE).DemographicsSchedule (72 mg/m2)A d 1, 8, 15B d 1, 8C d 1, 4AllN29352993Median Age (range)74(60,89)74(63,86)70(60,83)73(60,89)ECOG 0-186%89%72%83%ECOG 214%11%28%17%AHD38%29%28%31%≥ 7076%77%52%69%Cytogenetics SWOGFavorable0%6%7%4%Unfavorable41%46%48%45%Intermediate48%31%31%37%Unknown/not available10%17%13%14%Grade 3 or Higher Infections and MucositisSchedule (72 mg/m2)A d 1, 8, 15B d 1, 8C d 1, 4N293529Febrile Neutropenia38%63%48%Pneumonia31%34%24%Sepsis/bacteremia55%26%10%Infections59%26%28%Upper GI mucositis31%14%21%Lower GI mucositis10%6%0%OutcomeSchedule (72 mg/m2)A d 1, 8, 15B d 1, 8C d 1, 4N293529CR + CRp %41%29%38%Reinduction (CR) No.4(2)8(3)10(5)Consolidation 1 No.997Consolidation 2 No.18430-day all-cause mortality17%9%7%60-day all-cause mortality38%)37%14%Median OS days (95% CI)261d (44, NR)147d (55, NR)TETEMedian OS months8.74.9TETENR not yet reachedCharacteristics of RespondersSchedule (72 mg/m2)A d 1, 8, 15B d 1, 8C d 1, 4AllCR/CRpCR/CRpCR/CRpCR/CRpN(%)12(41%)10(29%)11(38%)33(35%)Age % Response in Category≥ 7036%33%33%33%<7057%13%43%38%PS % Response in CategoryECOG 250%25%38%38%ECOG 0-140%29%38%35%Presence of AHD % Response in CategoryAHD yes45%20%9%28%AHD no38%32%48%39%Cytogenetics % Response in CategoryIntermediate/Unfavorable35%33%26%32%Intermediate43%45%33%41%Unfavorable25%25%21%24%FavorableNA0%100%50%Risk Factors % Response in Category166%29%80%55%244%29%14%30%325%25%20%33%4NA50%NA50%NA not applicableOverall incidence of infections and mucositis were reduced in B and C, sch with 2 voreloxin doses, relative to A which had 3 voreloxin doses. Voreloxin PK were similar to those in an earlier Ph 1 study in relapsed/refractory AML (Lancet J, et al., Proc ASH 2007). Pts whose BMA were inhibited < 48% by 1 μM voreloxin had a greater chance of treatment failure (p = 0.043) than those whose BMA were inhibited by ≥ 48%. Conclusions:In REVEAL-1, voreloxin demonstrates clinical activity with 3 dosing sch in previously untreated elderly (age ≥ 60) AML pts who are unlikely to benefit from standard chemotherapy. ORR across 3 sch was 35%; the majority (76%) were CR. Responses were seen in each risk factor category and with multiple risk factors. Of reinduced pts, 45% achieved CR(p). Durable remissions exceeding 6 months were observed in 50% (A) and 63% (B) thus far. C d 1,4 was selected for further development based on ORR (38%), 30 and 60 day all-cause mortality (7% and 14%, respectively) and an improved safety profile with lower rates of infection compared to previous schedules. Further accrual to C 90 mg/m2voreloxin d 1,4 is ongoing. Disclosures:Ravandi:Sunesis: sunesis study steering committee. Cripe:Sunesis: Research Funding. Chen:sunesis: Employment. Mahadocon:sunesis: Employment. Fox:Sunesis: Employment. Berman:Sunesis: Employment. Michelson:sunesis: Employment. Stuart:sunesis: sunesis study steering committee.

VAMP/ThaCyDex: Velcade® (Bortezomib), Adriamycin, Melphalan and Prednisone Alternating with Thalidomide, Cyclophosphamide and Dexametasone as a Salvage Regimen in Relapsed Multiple Myeloma Patients

Background: Bortezomib and Thalidomide have demonstrated to be effective in relapsed and refractory Multiple Myeloma (MM) patients, including those with adverse cytogenetics (CG). Moreover, Bortezomib and thalidomide-based combinations result attractive to improve efficacy, but toxicity could be increased. Based on this background, we have tested if an alternating regimen consisting on two highly effective schedules could overcome MM drug resistance without an increase in toxicity in relapsed/refractory MM patients.Patients and Methods: Treatment schedule consisted on 6 alternating cycles of VAMP (Bortezomib 1,3mg/msq IV days 1,4,8 and 11; Melphalan, 9mg/msq po, days 1–4; Prednisone 60mg/msq po, days 1–4; and conventional or liposomal Adriamycin 40 or 30mg/msq respectively on day 1 of a 28 day cycle) alternating with ThaCyDex (Thalidomide 200mg/d po day 1–28; Cyclophosphamide 50mg/d po, days 1–28; and Dexametasone 40mg/d po, days 1–4). After 6 cycles, responding patients, received the previous schedule, every other month as consolidation therapy.Results: From June 2007 until August 2008, 20 patients have been included, with a median age of 63 years (Range 48–81); 15 patients (75%) had previously received autologous stem cell transplantation. 6 patients (30%) had previously received Bortezomib-based therapy, and one patient (5%) had previously received IMID-based therapy. Efficacy and toxicity were evaluated on an intent-to-treat basis. After a median of 6 cycles, 20 patients were evaluable for response, 9 patients (42%) achieved immunofixation negative Complete Response (CR), 3 patients (16%) nCR, 9 patients (47%) partial response, which makes an ORR of 94,7%. In addition, 1 patient (5%) remained in stable disease and one patient died during induction therapy due to septic shock. Seven patients presented high risk cytogenetic abnormalities [t(4;14) and/or delRB], and CR was obtained in 3 of them (42%) plus one additional nCR in 1 patient (14%). Moreover, allogeneic stem cell transplantation was performed in two of these high risk patients, as they were effectively rescued by this salvage regimen. Two patients progressed during the consolidation treatment. Toxicity was manageable, being haematologic events the most frequently reported. 6 patients (30%) developed ≥G3 thrombocytopenia and 6 patients (30%) neutropenia. Infection ≥G3 occurred in 3 patients (16%). Despite the combination of two drugs with potential neurologic toxicity, the use of them in alternated schedule resulted in that only 3 patients (15%) developed Peripheral Polyneuropathy, none of them >G2.Conclusion: Preliminary results show that alternating VAMP/ThaCyDex is a highly effective salvage regimen in relapsed/refractory MM patients, including high risk subgroup with adverse cytogenetic abnomalities. Haematologic toxicity was the most frequent adverse event, while the incidence of Peripheral Polyneuropathy was low, despite the use of two neurotoxic drugs. This results indicate that the alternating approach allows the exposure to a large number of active drugs without increase in the toxicity. A second analysis will be performed in December 2008 and results will be updated.