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Summary Background Understanding the duration of protection and risk of reinfection after natural infection is crucial to planning COVID-19 vaccination for at-risk groups, including care home residents, particularly with the emergence of more transmissible variants. We report on the duration, neutralising activity, and protection against the alpha variant of previous SARS-CoV-2 infection in care home residents and staff infected more than 6 months previously. Methods We did this prospective observational cohort surveillance in 13 care homes in Greater London, England. All staff and residents were included. Staff and residents had regular nose and throat screening for SARS-CoV-2 by RT-PCR according to national guidelines, with ad hoc testing of symptomatic individuals. From January, 2021, antigen lateral flow devices were also used, but positive tests still required RT-PCR confirmation. Staff members took the swab samples for themselves and the residents. The primary outcome was SARS-CoV-2 RT-PCR positive primary infection or reinfection in previously infected individuals, as determined by previous serological testing and screening or diagnostic RT-PCR results. Poisson regression and Cox proportional hazards models were used to estimate protective effectiveness of previous exposure. SARS-CoV-2 spike, nucleoprotein, and neutralising antibodies were assessed at multiple timepoints as part of the longitudinal follow-up. Findings Between April 10 and Aug 3, 2020, we recruited and tested 1625 individuals (933 staff and 692 residents). 248 participants were lost to follow-up (123 staff and 125 residents) and 1377 participants were included in the follow-up period to Jan 31, 2021 (810 staff and 567 residents). There were 23 reinfections (ten confirmed, eight probable, five possible) in 656 previously infected individuals (366 staff and 290 residents), compared with 165 primary infections in 721 susceptible individuals (444 staff and 277 residents). Those with confirmed reinfections had no or low neutralising antibody concentration before reinfection, with boosting of titres after reinfection. Kinetics of binding and neutralising antibodies were similar in older residents and younger staff. Interpretation SARS-CoV-2 reinfections were rare in older residents and younger staff. Protection from SARS-CoV-2 was sustained for longer than 9 months, including against the alpha variant. Reinfection was associated with no or low neutralising antibody before reinfection, but significant boosting occurred on reinfection. Funding Public Health England.

Relapsed or refractory primary central nervous system lymphoma (rrPCNSL) confers a poor prognosis with no accepted standard of care. Very few prospective studies have been conducted in this patient group. This study was a multicenter phase 1/2 study that investigated thiotepa in combination with ifosfamide, etoposide, and rituximab (TIER) for the treatment of PCNSL relapsed or refractory to high-dose methotrexate-based chemotherapy. A 3 + 3 design investigated the recommended phase 2 dose of thiotepa for a single-stage phase 2 cohort by assessing the activity of 2 cycles of TIER against rrPCNSL. The primary outcome was overall response rate. The dose-finding study demonstrated that 50 mg/m2 of thiotepa could be safely delivered within the TIER regimen. No dose-limiting toxicities were encountered in phase 1, and TIER was well-tolerated by the 27 patients treated in phase 2. The most common grade 3 to 4 toxicities were neutropenia (56% of patients) and thrombocytopenia (39%). An overall response was confirmed in 14 patients (52%), which met the prespecified threshold for clinically relevant activity. The median progression-free survival was 3 months (95% confidence interval [CI], 2 to 6 months) and overall survival 5 months (95% CI, 3 to 9 months). Exploratory analyses suggest a greater benefit for thiotepa-naïve patients. Six patients successfully completed autologous stem cell transplantation (ASCT) consolidation, with 4 experiencing durable remissions after a median follow-up of 50 months. The TIER regimen can be delivered safely and is active against rrPCNSL. When it is followed by ASCT, it can provide durable remission and long-term survival. However, for the majority of patients, prognosis remains poor, and novel treatment strategies are urgently needed. This trial was registered at https://www.clinicaltrialsregister.eu/ctr-search/search as EudraCT 2014-000227-24 and ISRCTN 12857473.

To understand SARS-Co-V-2 infection and transmission in UK nursing homes in order to develop preventive strategies for protecting the frail elderly residents.An outbreak investigation involving 394 residents and 70 staff, was carried out in 4 nursing homes affected by COVID-19 outbreaks in central London. Two point-prevalence surveys were performed one week apart where residents underwent SARS-CoV-2 testing and had relevant symptoms documented. Asymptomatic staff from three of the four homes were also offered SARS-CoV-2 testing.Overall, 26% (95% CI 22-31) of residents died over the two-month period. All-cause mortality increased by 203% (95% CI 70-336) compared with previous years. Systematic testing identified 40% (95% CI 35-46) of residents as positive for SARS-CoV-2, and of these 43% (95% CI 34-52) were asymptomatic and 18% (95% CI 11-24) had only atypical symptoms; 4% (95% CI -1 to 9) of asymptomatic staff also tested positive.The SARS-CoV-2 outbreak in four UK nursing homes was associated with very high infection and mortality rates. Many residents developed either atypical or had no discernible symptoms. A number of asymptomatic staff members also tested positive, suggesting a role for regular screening of both residents and staff in mitigating future outbreaks.

A number of recent authors, most notably Joseph Heath, have persausively defended a market‐centered account of corporate responsibility that grounds standards of business conduct upon the normative presuppositions of the market. They have us focus on two important items: first, the value of welfare, or Pareto efficient outcomes, which underwrites the legitimacy of market arrangements; and second, the behavioral requirements needed to assure that corporations conduct business in a manner consistent with this value. This article critically examines the aspirations of this literature by embracing its basic method but questioning how well it understands the aim of the market. It puts forth a limited case for corporate responsibility anchored in other dimensions of the public good, distinct from the value of efficiency, and argues that a plausible understanding of corporate responsibility arises from the notion that market arrangements are sites of delegated social authority to provision other aspects of the common good.

IntroductionSARS-CoV-2 serological studies have so far focused mainly on adults. Public Health England initiated prospective, longitudinal SARS-CoV-2 sero-surveillance in schools across England after the first national lockdown, which allowed comparison of child and adult responses to SARS-CoV-2 infection over time.MethodsStaff and students had venepuncture for SARS-CoV-2 antibodies in school during June, July and December 2020. Blood samples were tested for nucleocapsid (Abbott) and receptor binding domain (RBD) antibodies (in-house assay), and student samples were additionally assessed for live virus neutralising activity.ResultsIn June 2020, 1,344 staff and 835 students were tested. Overall, 11.5% (95% CI: 9.4-13.9) and 11.3% (95% CI: 9.2-13.6; p=0.88) of students had nucleoprotein and RBD antibodies, compared to 15.6% (95% CI: 13.7-17.6) and 15.3% (95% CI: 13.4-17.3; p=0.83) of staff. Live virus neutralising activity was detected in 79.8% (n=71/89) of nucleocapsid and 85.5% (71/83) of RBD antibody positive children. RBD antibodies correlated more strongly with neutralising antibodies (rs=0.7527; ps=0.3698; pConclusionRBD antibodies correlated more strongly with live virus neutralising activity. Most seropositive students and staff retained RBD antibodies for >6 months after SARS-CoV-2 infection.

Citizen science aims to bridge the gap between science and society by engaging people in understanding the process of science. This is needed to foster informed democratic involvement of critical, environmentally informed citizens. Can these aspirations be facilitated by school-based citizen science that offers opportunity to engage scientifically with environmental issues at a scale with local relevance? This is tested through application of Marine Metre Squared (Mm2), a citizen science initiative for long-term monitoring of the New Zealand intertidal zone. Through direct observation and “hands-on” engagement, participants are involved in place-based learning that connects them with nature. Strong interest from teachers and uptake into school programmes has been key to its success in collecting long term biodiversity data. Through facilitated delivery, the project also has the capacity to meet school curriculum goals and develop the environmental science citizenship capabilities of participants. Assessing the use of Mm2 as a citizen science intervention within schools, we found that it affected science learning, skill development and environmental attitudes. Our findings further demonstrate the effect of extended involvement in a citizen science project, the value of a local issue-focused project for student learning outside the classroom, and how school science education can be enriched through citizen science to also grow civic responsibility for the environment (environmental citizenship).

Memory B cells (MBC) can provide a recall response able to supplement waning antibodies with an affinity-matured response better able to neutralise variant viruses. We studied a cohort of vulnerable elderly care home residents and younger staff, a high proportion of whom had lost neutralising antibodies (nAb), to investigate their reserve immunity from SARS-CoV-2-specific MBC. Class-switched spike and RBD-tetramer-binding MBC with a classical phenotype persisted five months post-mild/asymptomatic SARS-CoV-2 infection, irrespective of age. Spike/RBD-specific MBC remained detectable in the majority who had lost nAb, although at lower frequencies and with a reduced IgG/IgA isotype ratio. Functional spike/S1/RBD-specific recall was also detectable by ELISpot in some who had lost nAb, but was significantly impaired in the elderly, particularly to RBD. Our findings demonstrate persistence of SARS-CoV-2-specific MBC beyond loss of nAb, but highlight the need for careful monitoring of functional defects in RBD-specific B cell immunity in the elderly.One sentence summaryCirculating class-switched spike and RBD-specific memory B cells can outlast detectable neutralising antibodies but are functionally constrained in the elderly.

Background: Secondary CNS lymphoma is a rare but potentially lethal event in patients with diffuse large B-cell lymphoma. We aimed to assess the activity and safety of an intensive, CNS-directed chemoimmunotherapy consolidated by autologous haematopoietic stem-cell transplantation (HSCT) in patients with secondary CNS lymphoma. Methods: This international, single-arm, phase 2 trial was done in 24 hospitals in Italy, the UK, the Netherlands, and Switzerland. Adults (aged 18–70 years) with histologically diagnosed diffuse large B-cell lymphoma and CNS involvement at the time of primary diagnosis or at relapse and Eastern Cooperative Oncology Group Performance Status of 3 or less were enrolled and received three courses of MATRix (rituximab 375 mg/m2, intravenous infusion, day 0; methotrexate 3·5 g/m2, the first 0·5 g/m2 in 15 min followed by 3 g/m2 in a 3 h intravenous infusion, day 1; cytarabine 2 g/m2 every 12 h, in 1 h intravenous infusions, days 2 and 3; thiotepa 30 mg/m2, 30 min intravenous infusion, day 4) followed by three courses of RICE (rituximab 375 mg/m2, day 1; etoposide 100 mg/m2 per day in 500–1000 mL over a 60 min intravenous infusion, days 1, 2, and 3; ifosfamide 5 g/m2 in 1000 mL in a 24 h intravenous infusion with mesna support, day 2; carboplatin area under the curve of 5 in 500 mL in a 1 h intravenous infusion, day 2) and carmustine–thiotepa and autologous HSCT (carmustine 400 mg/m2 in 500 mL glucose 5% solution in a 1–2 h infusion, day −6; thiotepa 5 mg/kg in saline solution in a 2 h infusion every 12 h, days −5 and −4). The primary endpoint was progression-free survival at 1 year. Overall and complete response rates before autologous HSCT, duration of response, overall survival, and safety were the secondary endpoints. Analyses were in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02329080. The trial ended after accrual completion; the database lock was Dec 31, 2019. Findings: Between March 30, 2015, and Aug 3, 2018, 79 patients were enrolled. 75 patients were assessable. 319 (71%) of the 450 planned courses were delivered. At 1 year from enrolment the primary endpoint was met, 42 patients were progression free (progression-free survival 58%; 95% CI 55–61). 49 patients (65%; 95% CI 54–76) had an objective response after MATRix–RICE, 29 (39%) of whom had a complete response. 37 patients who responded had autologous HSCT. At the end of the programme, 46 patients (61%; 95% CI 51–71) had an objective response, with a median duration of objective response of 26 months (IQR 16–37). At a median follow-up of 29 months (IQR 20–40), 35 patients were progression-free and 33 were alive, with a 2-year overall survival of 46% (95% CI 39–53). Grade 3–4 toxicity was most commonly haematological: neutropenia in 46 (61%) of 75 patients, thrombocytopenia in 45 (60%), and anaemia in 26 (35%). 79 serious adverse events were recorded in 42 (56%) patients; four (5%) of those 79 were lethal due to sepsis caused by Gram-negative bacteria (treatment-related mortality 5%; 95% CI 0·07–9·93). Interpretation: MATRix–RICE plus autologous HSCT was active in this population of patients with very poor prognosis, and had an acceptable toxicity profile. Funding: Stand Up To Cancer Campaign for Cancer Research UK, the Swiss Cancer Research foundation, and the Swiss Cancer League.

Background: Care homes have been disproportionately affected by the COVID-19 pandemic. We investigated the potential role of asymptomatic infection and silent transmission in London care homes that reported no cases of COVID-19 during the first wave of the pandemic. Methods: Five care homes with no cases and two care homes reporting a single case of COVID-19 (non-outbreak homes) were investigated with nasal swabbing for SARS-CoV-2 RT-PCR and serology for SARS-CoV-2 antibodies five weeks later. Whole genome sequencing (WGS) was performed on RT-PCR positive samples. Serology results were compared with those of six care homes with recognised outbreaks. Findings: Across seven non-outbreak homes, 718 (387 staff, 331 residents) individuals had a nasal swab and 651 (386 staff, 265 residents) had follow-up serology. Sixteen individuals (13 residents, 3 staff) in five care homes with no reported cases were RT-PCR positive (care home positivity rates, 0 to 7.6%) compared to 13 individuals (3.0 and 10.8% positivity) in two homes reporting a single case.Seropositivity across these seven homes varied between 10.7-56.5%, with four exceeding community seroprevalence in London (14.8%). Seropositivity rates for staff and residents correlated significantly (rs 0.84, [95% CI 0.51-0.95] p

Two London care homes experienced a second COVID-19 outbreak, with 29/209 (13.9%) SARS-CoV-2 RT-PCR-positive cases (16/103 residents, 13/106 staff). In those with prior SARS-CoV-2 exposure, 1/88 (1.1%) individuals (antibody positive: 87; RT-PCR-positive: 1) became PCR-positive compared with 22/73 (30.1%) with confirmed seronegative status. After four months protection offered by prior infection against re-infection was 96.2% (95% confidence interval (CI): 72.7–99.5%) using risk ratios from comparison of proportions and 96.1% (95% CI: 78.8–99.3%) using a penalised logistic regression model.

BackgroundWe investigated six London care homes experiencing a COVID-19 outbreak and found very high rates of SARS-CoV-2 infection among residents and staff. Here we report follow-up serological analysis in these care homes five weeks later.MethodsResidents and staff had a convalescent blood sample for SARS-CoV-2 antibody levels and neutralising antibodies by SARS-COV-2 RT-PCR five weeks after the primary COVID-19 outbreak investigation.ResultsOf the 518 residents and staff in the initial investigation, 208/241 (86.3%) surviving residents and 186/254 (73.2%) staff underwent serological testing. Almost all SARS-CoV-2 RT-PCR positive residents and staff were antibody positive five weeks later, whether symptomatic (residents 35/35, 100%; staff, 22/22, 100%) or asymptomatic (residents 32/33, 97.0%; staff 21/22, 95.1%). Symptomatic but SARS-CoV-2 RT-PCR negative residents and staff also had high seropositivity rates (residents 23/27, 85.2%; staff 18/21, 85.7%), as did asymptomatic RT-PCR negative individuals (residents 62/92, 67.3%; staff 95/143, 66.4%). Neutralising antibody was present in 118/132 (89.4%) seropositive individuals and was not associated with age or symptoms. Ten residents (10/108, 9.3%) remained RT-PCR positive, but with lower RT-PCR cycle threshold values; all 7 tested were seropositive. New infections were detected in three residents and one staff member.ConclusionsRT-PCR testing for SARS-CoV-2 significantly underestimates the true extent of an outbreak in institutional settings. Elderly frail residents and younger healthier staff were equally able to mount robust and neutralizing antibody responses to SARS-CoV-2. More than two-thirds of residents and staff members had detectable antibodies against SARS-CoV-2 irrespective of their nasal swab RT-PCR positivity or symptoms status.

High-dose methotrexate (HD-MTX) is increasingly used as prophylaxis for patients with diffuse large B-cell lymphoma (DLBCL) at high risk of central nervous system (CNS) relapse. However, there is limited evidence to guide whether to intercalate HD-MTX (i-HD-MTX) between R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone given at 21-day intervals) or to give it at the end of treatment (EOT) with R-CHOP-21. We conducted a retrospective, multicenter analysis of 334 patients with DLBCL who received CNS prophylaxis with i-HD-MTX (n = 204) or EOT HD-MTX (n = 130). Primary end points were R-CHOP delay rates and HD-MTX toxicity. Secondary end points were CNS relapse rate, progression-free survival, and overall survival. The EOT group had more patients with a high CNS international prognostic index (58% vs 39%; P < .001) and more concurrent intrathecal prophylaxis (56% vs 34%; P < .001). Of the 409 cycles of i-HD-MTX given, 82 (20%) were associated with a delay of next R-CHOP (median, 7 days). Delays were significantly increased when i-HD-MTX was given after day 9 post–R-CHOP (26% vs 16%; P = .01). On multivariable analysis, i-HD-MTX was independently associated with increased R-CHOP delays. Increased mucositis, febrile neutropenia, and longer median inpatient stay were recorded with i-HD-MTX delivery. Three-year cumulative CNS relapse incidence was 5.9%, with no differences between groups. There was no difference in survival between groups. We report increased toxicity and R-CHOP delay with i-HD-MTX compared with EOT delivery but no difference in CNS relapse or survival. Decisions on HD-MTX timing should be individualized and, where i-HD-MTX is favored, we recommend scheduling before day 10 of R-CHOP cycles.

Scope: This guideline is aimed at providing healthcare professionals with clear guidance on the diagnosis and management of primary central nervous system lymphoma (PCNSL), defined as diffuse large B‐cell lymphoma (DLBCL) solely confined to the central nervous system (CNS): brain, spinal cord, cranial nerves, eyes and meninges. Secondary CNS lymphoma, immunodeficiency‐associated lymphoma and rare forms of non‐DLBCL CNS lymphoma are outside the scope of this guideline. It is not the intention of this guideline to provide treatment recommendations for all situations and clinicians are advised to take individual patient circumstances into account when making management decisions.

The MATRix chemoimmunotherapy regimen is highly effective in patients with newly diagnosed primary diffuse large B-cell lymphoma of the central nervous system (PCNSL). However, nothing is known about its feasibility and efficacy in everyday practice, where patients are more often older/frailer than those enrolled in clinical trials. We conducted a retrospective study addressing tolerability/efficacy of MATRix in 156 consecutive patients with newly diagnosed PCNSL treated outside a clinical trial. Median age and ECOG Performance Status of considered patients were 62 years (range 28–78) and 2 (range 0–4). The overall response rate after MATRix was 79%. Nine (6%) treatment-related deaths were recorded. After a median follow-up of 27.4 months (95% confidence interval [CI] 24.4–31.9%), the two-year progression-free and overall survival were 56% (95% CI 48.4–64.9%) and 64.1% (95% CI 56.7–72.5%) respectively. Patients not eligible for the IELSG32 trial were treated with lower dose intensity and had substantially worse outcomes than those fulfilling inclusion criteria. This is the largest series of PCNSL patients treated with MATRix outside a trial and recapitulates the IELSG32 trial outcomes in the non-trial setting for patients who fit the trial criteria. These data underscore the feasibility and efficacy of MATRix as induction treatment for fit patients in routine practice.

Background: We investigated six London care homes experiencing a COVID-19 outbreak and found very high rates of SARS-CoV-2 infection among residents and staff. Here we report follow-up investigations including antibody testing in the same care homes five weeks later. Methods: Residents and staff involved in the initial investigation had a repeat nasal swab for SARS-CoV-2 RT-PCR and a blood test for SARS CoV-2 antibodies using ELISA based on SARS-CoV-2 native viral antigens derived from infected cells and virus neutralisation. Findings: Of the 518 residents and staff in the initial investigation, 208/241 (86.3%) surviving residents and 186/254 (73.2%) staff underwent repeat testing. Almost all SARS-CoV-2 RT-PCR positive residents and staff were also antibody positive five weeks later, whether symptomatic (residents 35/35, 100%; staff, 22/22, 100%) or asymptomatic (residents 32/33, 97.0%; staff 21/22, 95.1%). Symptomatic but SARS-CoV-2 RT-PCR negative residents and staff also had high seropositivity rates (residents 23/27, 85.2%; staff 18/21, 85.7%) as did asymptomatic RT-PCR negative individuals (residents 62/92, 67.3%; staff 95/143, 66.4%). Neutralising antibody was present in 118/132 (89.4%) seropositive individuals and was not associated with age or symptoms. Ten residents (10/108, 9.3%) remained RT-PCR positive but with lower RT-PCR cycle threshold values; all 7 tested were seropositive. New infections were detected in three residents and one staff. Interpretation: RT PCR provides a point prevalence of SARS-CoV-2 infection but significantly underestimates total exposure in outbreak settings. In care homes experiencing large COVID-19 outbreaks, most residents and staff had neutralising SARS-CoV-2 antibodies, which was not associated with age or symptoms. Funding: None Declaration of Interests: None. Ethics Approval Statement: The research protocol was approved by the PHE Research Ethics and Governance Group (REGG Ref: NR0204, 07 May 2020).

In the majority of UK laboratories initial testing for HIV is now performed using a fourth generation test, which is a combination test for antibody to HIV and p24 antigen. These tests should be able to detect antibody to both HIV-1 and HIV-2. In addition, due to the heterogeneity of the virus they should be able to reliably detect antibody to the main circulating subtypes of HIV-1, i.e. group M (Major), O (Outlier), and N (non-M, non-O). The p24 antigen is an HIV capsid protein which is produced in large quantities during initial infection, prior to seroconversion. The sensitivity and specificity of fourth generation tests is typically > 99%. However, all positive results need further confirmation tests, as discussed below. Third generation laboratory assays only test for the presence of antibody to HIV. Though it includes the detection of IgM (which is not included in second generation assays), they do not detect early infection with isolated HIV antigen prior to seroconversion. Point-of-care testing for HIV is performed in the clinic or at bedside. Like laboratory based assays these tests can be either third or fourth generation. The sensitivity and specificity of point-of-care tests is considered lower than that of laboratory tests, and all positive results require confirmation with a laboratory assay. The window period is the length of time following infection with HIV until the appearance of laboratory markers of HIV infection in the blood. This period varies depending on which marker, i.e. antibody or antigen, is being tested for. The window period for fourth-generation tests is between eleven days and one month. Patients being counselled prior to this testing should be advised that a negative result does not cover risk exposures in the preceding month. These patients should be advised to have repeat testing if they have any further exposure risks in the preceding month prior to testing. For third-generation tests the window period is up to three months, correlating with the amount of time it may take for antibodies to HIV to develop.

Electronic health records (EHRs) have become ubiquitous tools and represent the standard of care for 96% of hospitals and 86% of ambulatory physicians in the United States. With adoption of EHRs came the promise of improved efficiency, higher-quality care, and lower costs. Unfortunately, some clinicians are now spending twice as much time on documentation as they spend seeing patients, and the documentation paradigm of problem-oriented medical records is contributing to this imbalance. It is time to consider new innovations. The collaborative wiki format offers many opportunities to ease the burden of documentation as well as to increase the usefulness of the recorded clinical data. Wikis support multiple authorship, have built-in features to track edits and changes, allow for contextual linkages (e.g., linking medical problems to their treatment), and support new technologies such as application programming interfaces, which allow for safe and secure exchange of information. In this Perspective, the authors describe the rationale for considering this approach to clinical documentation and propose a pilot to learn about its effectiveness. They believe wiki-based documentation will become increasingly attractive, especially as new legislation and directives from policymakers seek to reduce the crushing documentation burden and as the U.S. health care system transitions from an episode-based payment structure to a value-based, outcomes-focused system.

Introduction Primary CNS lymphoma (PCNSL) requires a biopsy for diagnosis but can be inconclusive when steroids are administered. Without treatment median survival is 1.5–3.3 months, improving to 10–20 months with oncological treatment. This study aimed to compare outcomes of PCNSL treated under haematology to those of clinical oncologists. Methods Retrospective casenote review of patients with PCNSL treated under oncologists (2006–2010) and haematologists (2011–2016). Results 121 cases were identified (median age 63 years; range 19–84). Median WHO performance status (PS) was 1. 11.6% required repeat biopsy. 10 patients were managed palliatively due to poor PS. 67 cases were managed under haematology. Median symptom duration was 28 days (range 2–540). Median time from MRI to diagnosis was 18 days (range 6–232). 66 patients received chemotherapy, 1 received radiotherapy. Median overall survival (OS) was 8 months (95%CI: 0.7–15.3), 5-year OS was 22.4%. 44 cases were managed under oncology. Median symptom duration was 28 days (range 2–365). Median time from MRI to diagnosis was 16 days (range 6–309). 34 patients received radiotherapy first-line, 10 received chemotherapy. Median OS was 7 months (95%CI: 0–21.5), 5-year OS was 15.9%. Multivariate analysis demonstrated PS (HR 2.02 (95%CI: 1.08–3.76)) and symptom duration (HR 0.63 (95%CI: 0.41–0.96)) to be significant prognostic indicators for OS. Discussion PCNSL carries poor prognosis and outcomes from the ‘haematology era’ are similar to those achieved by clinical oncologists. Delay in diagnosis leads to worse outcomes and highlights the ongoing need to streamline current clinical services to improve outcomes.

Introduction: Secondary CNS dissemination (SCNSL) is a rare but lethal event in pts with diffuse large B-cell lymphoma (DLBCL). It can occur both at presentation, in pts with systemic disease, or at relapse, during or after primary therapy. Following the experience from primary CNS lymphoma, pts with SCNSL are currently treated with high-dose-methotrexate-based chemo and autologous transplant (ASCT). However, this strategy is associated with poor control of extra-CNS disease, and only 1/3 of pts proceed to ASCT and recover from this event. Thus, we designed a multicenter phase II trial addressing an intensified chemoimmunotherapy consolidated by ASCT in HIV-neg pts with SCNSL (NCT02329080). Methods: Inclusion criteria were: histologically confirmed DLBCL; CNS involvement at presentation (concomitant to systemic disease) or relapse (isolated or concomitant to systemic lymphoma); age 18-70 ys; ECOG-PS ≤3; no prior treatment with high-dose methotrexate. Registered pts received 3 courses of MATRIX followed by 3 courses of RICE combined with intrathecal chemo and consolidated by BCNU-thiotepa/ASCT. The primary endpoint was 1-yr PFS. The Fleming design was used; to detect a difference in 1-yr PFS from 50% (P0) to 65% (P1), 69 pts were required (one-sided, type I error 5%, power 80%), with a dropout of 10%, 76 pts were needed. If ≥41 pts were progression-free at 1 yr, the strategy would be considered effective. Results: Between 3/2015 and 8/2018, 79 pts were enrolled at 24 centers in 4 countries; 75 pts (median age 58, range 23-70; 38 males) were assessable. CNS involvement was recorded at presentation in 32 (43%) pts and at relapse in 43 (isolated site in 15, concomitant to systemic relapse in 28). CNS sites were brain parenchyma in 34 (45%) pts, brain + eyes in 10 (13%), brain + CSF in 13 (17%), brain + CSF + eyes in 6 (8%), CSF/meninges in 8 (11%), spinal cord in 2 (3%), and eyes in 2 (3%). Median time to CNS involvement was 5 months (range 1-61) in the 43 pts registered at relapse; 20 (47%) of them had refractory disease. 320 (71%) of the 450 planned chemo courses were delivered; 64 (85%) pts received intrathecal chemo. 78 SAEs were recorded in 42 pts, mostly due to FN and infections (64) or bleeding (5); 74 (95%) SAEs were followed by recovery. The 4 lethal SAEs (TRM= 5%) and the 5 transient interruptions occurred during MATRIX. Dose reductions were indicated in 33 (10%) courses. Most common g4 toxicities were thrombocytopenia in 118 (37%) courses, neutropenia in 113 (35%) and infections in 9 (3%). Stem cells collection was successful (median of 6.75M/kg; range: 2.4 - 45) in 42 (88%) of the 48 pts referred for leukapheresis. 55 (73%; 95%CI 63-83%) pts achieved a response after 2 courses of MATRIX; 19 (95%) of the 20 pts who had a CR after 2 MATRIX maintained the response after RICE; 9 (26%) of the 35 pts who had a PR after 2 MATRIX achieved a CR after RICE. Conversely, only 3 of 16 pts with PD/SD after 2 MATRIX achieved a response from RICE. 49 pts (65%; 95%CI 54-76%) achieved a response after MATRIX-RICE induction, and 36 responders received ASCT; 13 responders did not receive ASCT due to insufficient mobilization (n=4), PD due to treatment delay (5), frailty (2), neurological decline (1), and consent withdrawal (1). 45 pts (60%; 95%CI 50-70%) had responsive disease after the whole treatment. At 1 year from registration, 41 pts were progression free (efficacy threshold ≥41). At a median follow-up of 25 (12-47) months, 31 pts are progression free, with a 2-yr PFS of 42 ± 6% for the whole series and 75 ± 7% for the 36 transplanted pts (Fig. A & B). Sites of relapse/progression were CNS in 10 pts, extra-CNS organs in 9 and both in 18. Overall, 33 pts are alive, with a 2-yr OS of 42 ± 6% for the whole series and 82 ± 7% for transplanted pts. Causes of death were lymphoma (35) and toxicity (4); 3 pts died without evidence of disease due to neurological decline, PTE and sudden death. Pts with CNS disease at presentation had the best outcome (Fig. C), whereas CSF/meningeal disease (Fig. D) and age >60 ys were independently associated with poor outcome. Conclusions: MATRIX-RICE followed by ASCT achieved the primary endpoint in this very-poor-prognosis population, without major safety concerns. Survival figures of transplanted pts seem a little better than reported in prior trials, whereas pts with MATRIX-refractory disease had no benefit from crossing to RICE. The best survival figures were recorded in chemo-naïve pts treated at presentation and in pts without CSF/meningeal disease. Figure Disclosures Ferreri: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding. Doorduijn:Roche: Honoraria, Research Funding. Nassi:Merck: Consultancy; Takeda: Consultancy; Janssen: Consultancy. McKay:Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Davies:ADCT Therapeutics: Honoraria, Research Funding; Karyopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; MorphoSys AG: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Janssen: Honoraria, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Research Funding. Fox:Celgene: Consultancy; Gilead: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; Sunesis: Consultancy; Takeda Pharmaceuticals: Consultancy; Atara Biotherapeutics: Consultancy; Adienne: Other: Travel Support. Osborne:Gilead: Membership on an entity's Board of Directors or advisory committees; NIL: Employment; NIL: Other: leadership; NIL: Other: Stock & other ownership interests; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees. Liberati:Incyte: Consultancy; Novartis: Other: Clinical trial support; Janssen: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Roche: Other: Clinical trial support; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Celgene: Honoraria, Other: Clinical trial support; Bristol-Myers Squibb: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zambello:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Zucca:Celltrion Helathcare: Membership on an entity's Board of Directors or advisory committees; AstraZenaca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Merck: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding; Kite, A Gilead Company: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other: Travel Grant. Cwynarski:Adienne: Consultancy; Takeda: Consultancy, Other: conference and travel support , Speakers Bureau; Roche,: Consultancy, Other: conference and travel support, Speakers Bureau; Autolus: Consultancy; KITE: Consultancy; Gilead: Consultancy, Other: conference and travel support, Speakers Bureau; Celgene: Consultancy; Atara: Consultancy; Janssen: Other: conference and travel support, Speakers Bureau.

BACKGROUND Outcomes for patients (pts) with primary CNS diffuse large B cell lymphoma (PCNSL) have improved over recent years, largely through optimisation of first-line methotrexate (MTX)-containing protocols and dose-intensive chemotherapy consolidation. However, 30-50% of pts experience refractory or relapsed (r/r) disease, which confers very poor outcomes and short survival. By contrast to systemic DLCBL, there is no accepted standard approach for r/r PCNSL. Thiotepa is an alkylating agent highly efficient at crossing the BBB and widely incorporated within high-dose therapy and autologous stem cell transplantation (HDT-ASCT) protocols for PCNSL, but has not undergone dose-finding studies nor been incorporated within salvage regimens for PCNSL. The TIER study investigates the safety and efficacy of adding thiotepa, in a dose-escalation design, to the Rituximab, Ifosphamide and Etoposide (R-IE) salvage regimen1. METHODS TIER is an open label, phase I/II UK NCRI TAP study for pts with r/r PCNSL, previously treated with a high-dose MTX-based regimen. In phase I, the RP2D of thiotepa within the TIER combination was established using a 3+3 design, with dose escalations of 30, 40 and 50mg/m2 (dose level 2 (n=4), 3 (n=5) and 4 (n=27) respectively), given on day 5 of R-IE cycle1. The Phase II primary endpoint was overall response rate (ORR) after cycle 2 of TIER (C2) by centrally reviewed contrast-enhanced MRI2, on an intention-to-treat (ITT) basis. Further treatment and consolidation after the primary endpoint MRI was at the discretion of investigators. Key secondary end-points were 2-year PFS, EFS and OS. RESULTS Thirty-six pts were recruited from Jun 2015-Apr 2019 at 13 centres (characteristics: Table 1). The median number of prior lines was 2 (range 1-4) with 44% of patients deemed refractory to their previous line of therapy. During phase I (n=10) no dose limiting toxicities (DLTs) were observed up to and including 50mg/m2 thiotepa, constituting the RP2D (n=27). 56 cycles of TIER were administered across both phases; 5 pts had >1 dose reductions. Median time between C1D1 and C2D1 was 24.7 days (range 22-38). Relative mean dose intensity of thiotepa, ifosphamide and etoposide was 71.8 (SD 44.9), 76.4 (SD 41.6), and 76.8 (SD 41.8) respectively. Further therapy after 2 cycles of TIER was delivered to 41.7% of pts (16.7% ASCT, 22.2% TIE, and 2.8% WBRT). The most common grade 3 / 4 adverse events were thrombocytopenia and neutropenia (47.2 and 55.6% occurring in 15 and 18 pts respectively). 17 serious adverse events (SAEs) were reported in 12 pts, of which 4 were haematological. Of these, 13 were considered related to TIER. Commonly occurring non-haematological SAEs were respiratory tract infections (23.5%) and seizures (11.8%). At data lock, 10/27 pts had responded to treatment as assessed by local investigators (ORR 37%, CR rate 15%). 13 pts were non-evaluable (7 progressed prior to C2 scan, 2 withdrew consent, and 4 awaiting scans) and classed as non-responders. Following data lock, responses were reported for 3 further pts (2 by local investigators and 1 by central review), resulting in a provisional ORR of 13/27 (48%). For the ITT population, median OS time was 3.52 months (95% CI 2.50, 14.17), and median PFS 2.86 months (95%CI 2.34, 6.05) (Figure 1). 6 pts underwent ASCT consolidation after TIER, of whom 2 have relapsed. CONCLUSIONS This is an early analysis of data from the phase I/II TIER study for a heavily pre-treated group of r/r PCNSL; the first such dose-escalation study for this patient group. Phase I determined a RP2D of 50mg/m2 of thiotepa incorporated in the R-IE regimen. There were no DLTs and toxicities, consistent with an intensive ifosphamide-based regimen. ORR was 10 pts (37%) with 3 further responses reported after data lock. If confirmed by central review, the primary endpoint of activity (ORR 40%) will have been reached. However, notwithstanding the response endpoint, most pts experienced very poor survival outcomes. These data describe the feasibility of TIER as a salvage regimen for r/r PCNSL but question the utility of this approach as a standard option, given the short PFS and OS times, except for the minority of pts who received ASCT. Biological and imaging sub studies are underway to identify predictors of outcome. In the modern era of effective first line immunochemotherapy approaches, pts with r/r PCNSL remain a major area of unmet need for whom novel experimental approaches are urgently required. Disclosures Fox: Gilead: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Sunesis: Consultancy; Takeda Pharmaceuticals: Consultancy; Atara Biotherapeutics: Consultancy; Adienne: Other: Travel Support. Martinez-Calle:ABBVIE: Other: Travel support. Collins:Gilead: Consultancy, Honoraria. Ferreri:Novartis: Consultancy; Celgene: Consultancy, Research Funding; Roche: Research Funding; Kite: Consultancy. Davies:BioInvent: Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Karyopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Bayer: Research Funding; ADCT Therapeutics: Honoraria, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; MorphoSys AG: Honoraria, Membership on an entity's Board of Directors or advisory committees. Johnson:Roche: Consultancy, Honoraria, Speakers Bureau; Takeda: Other: Travel, accomodations, expenses. Cwynarski:Adienne: Consultancy; Takeda: Consultancy, Other: conference and travel support , Speakers Bureau; Roche,: Consultancy, Other: conference and travel support, Speakers Bureau; Autolus: Consultancy; KITE: Consultancy; Gilead: Consultancy, Other: conference and travel support, Speakers Bureau; Celgene: Consultancy; Atara: Consultancy; Janssen: Other: conference and travel support, Speakers Bureau.

Background The International Extranodal Lymphoma Study Group-32 (IELSG32) trial is an international randomised phase 2 study that addresses two key clinical questions in the treatment of patients with newly diagnosed primary CNS lymphoma. Results of the first randomisation have demonstrated that methotrexate, cytarabine, thiotepa, and rituximab (called the MATRix regimen) is the induction combination associated with significantly better outcome compared with the other induction combinations tested. Here, we report the results of the second randomisation that addresses the efficacy of myeloablative chemotherapy supported by autologous stem-cell transplantation (ASCT), as an alternative to whole-brain radiotherapy (WBRT), as consolidation after high-dose-methotrexate-based chemoimmunotherapy. Methods HIV-negative patients (aged 18–70 years) with newly diagnosed primary CNS lymphoma and an Eastern Cooperative Oncology Group performance status of 0–3 were randomly assigned to receive four courses of methotrexate 3·5 g/m2 on day 1 plus cytarabine 2 g/m2 twice daily on days 2 and 3 (group A); or the same combination plus two doses of rituximab 375 mg/m2 on days −5 and 0 (group B); or the same methotrexate–cytarabine–rituximab combination plus thiotepa 30 mg/m2 on day 4 (group C), with the three groups repeating treatment every 3 weeks. Patients with responsive or stable disease after induction treatment, with adequate autologous peripheral blood stem-cell collection, and without persistent iatrogenic side-effects, were eligible for the second randomisation between WBRT (photons of 4–10 MeV; five fractions per week; fraction size 180 cGy; started within 4 weeks from the last induction course; group D) and carmustine–thiotepa conditioned ASCT (carmustine 400 mg/m2 on day −6, and thiotepa 5 mg/kg every 12 h on days −5 and −4, followed by reinfusion of autologous peripheral blood stem cells; group E). A permuted block randomised design was adopted for both randomisations, and a computer-generated randomisation list was used within each stratum. No masking after assignment to intervention was adopted. The primary endpoint was 2-year progression-free survival, with induction group and response to induction chemotherapy as stratification parameters. Analyses were done on a modified intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT01011920. Findings Between Feb 19, 2010, and Aug 27, 2014, 227 patients were recruited from 53 centres in five countries. 219 of 227 enrolled patients were assessable. Of the 122 patients eligible for the second randomisation, 118 patients were randomly assigned to WBRT or ASCT (59 patients per group) and constitute the study population. WBRT and ASCT were both effective, and achieved the predetermined efficacy threshold of at least 40 progression-free survivors at 2 years among the first 52 patients in both groups D and E. There were no significant differences in 2-year progression-free survival between WBRT and ASCT: 80% (95% CI 70–90) in group D and 69% (59–79) in group E (hazard ratio 1·50, 95% CI 0·83–2·71; p=0·17). Both consolidation therapies were well tolerated. Grade 4 non-haematological toxicity was uncommon; as expected, haematological toxicity was more common in patients treated with ASCT than in those who received WBRT. Two toxic deaths (infections) were recorded, both in patients who received ASCT. Interpretation WBRT and ASCT are both feasible and effective as consolidation therapies after high-dose methotrexate-based chemoimmunotherapy in patients aged 70 years or younger with primary CNS lymphoma. The risks and implications of cognitive impairment after WBRT should be considered at the time of therapeutic decision. Funding Agenzia Italiana del Farmaco, Cancer Research UK, Oncosuisse, and Swiss National Science Foundation.

The context of safety and empathic connection inherent in a well-maintained therapeutic relationship provides the disconfirmation of danger necessary for emotional healing. The process involves a two-way information exchange identical to that between a mother and a toddler who has fallen. In mindfulness meditation, it appears that healing takes place without the presence of a witness, but a closer examination suggests that the mental state achieved by the meditator may actually put the individual in a context of connection with an internalized presence. When the goal is behavior change, a context of connection is a regular and important part of the coaching role of the therapist as the patient traverses the stages of change.

A 77 year old Bangladeshi man presented with jaundice, abdomnal discomfort and reduced appetite for 3–4 weeks. He had no ecent foreign travel, did not use recreational drugs and was not mmunosuppressed. He had a background of atrial fibrillation, type diabetes mellitus, hypertension and congestive cardiac failure. His liver function tests were deranged with total bilirubin: 85 mol/L (normal

It is strange that contemporary discussions of "corporate social responsibil ity" rarely take the term "responsibility" seriously. Deference is shown to praiseworthy corporate behavior without focusing on the underlying philo sophical issue of whether there are any obligations to reinvest in communi ties, orient operations toward long term development, or protect the envi ronment. It is for this reason that I find it valuable that Denis Arnold and Keith Bustos focus their remarks on a rather basic question: should we place moral responsibility for environmental degradation on businesses even when they have lawfully participated in the marketplace? They answer this question in the affirmative for two central reasons. First, they argue that there are few political, i.e., legislative and administrative, avenues available to correct for corporate activity that adversely impacts key public goods such as air, water and health. Second, the benefits that have accrued to corporations during the last five to six decades have come at a high price, namely, the environ mental health of the planet and thereby the well-being of current and future generations. Justice demands that the benefits one receives should be proportionate to the costs imposed on others through the realization of these benefits. Corporations, thus, have duties to adjust their practices to mini mize these social costs and compensate communities for past harm.

As gas turbine (GT) temperatures have increased, thermal barrier coatings (TBCs) have become a critically important element in hot section component durability. Ceramic TBCs permit significantly increased gas temperatures, reduced cooling requirements, and improve engine fuel efficiency and reliability. TBCs are in use throughout the GT hot section with turbine blades, vanes, and combustion hardware, now being designed with TBCs or upgraded with TBCs during component refurbishment (Miller, 1987, “Current Status of Thermal Barrier Coatings,” Surf. Coat. Technol., 30(1), pp. 1–11; Clarke et al., 2012, “Thermal-Barrier Coatings for More Efficient Gas-Turbine Engines,” MRS Bull., 37(10), pp. 891–898). While the industry standard 6–9 wt. % yttria stabilized zirconia (7YSZ) has been the preferred ceramic composition for the past 30+ yr, efforts have been underway to develop improved TBCs (Stecura, 1986, “Optimization of the Ni–Cr–Al–Y/ZrO2–Y2O3 Thermal Barrier System,” Adv. Ceram. Mater., 1(1), pp. 68–76; Stecura, 1986, “Optimization of the Ni–Cr–Al–Y/ZrO2–Y2O3 Thermal Barrier System,” NASA Technical Memorandum No. 86905). The principal development goals have been to lower thermal conductivity, increase the sintering resistance, and have a more stable crystalline phase structure allowing to use above 1200 °C (2192 °F) (Levi, 2004, “Emerging Materials and Processes for Thermal Barrier Systems,” Curr. Opin. Solid State Mater. Sci., 8(1), pp. 77–91; Clarke, 2003, “Materials Selection Guidelines for Low Thermal Conductivity Thermal Barrier Coatings,” Surf. Coat. Technol., 163–164, pp. 67–74). National Aeronautics and Space Administration (NASA) has developed a series of advanced low conductivity, phase stable and sinter resistant TBC coatings utilizing multiple rare earth dopant oxides (Zhu and Miller, 2004, “Low Conductivity and Sintering-Resistant Thermal Barrier Coatings,” U.S. Patent No. 6,812,176 B1). One of the coating systems NASA developed is based on Ytterbia, Gadolinia, and Yttria additions to ZrO2 (YbGd-YSZ). This advanced low conductivity (low k) TBC is designed specifically for combustion hardware applications. In addition to lower thermal conductivity than 7YSZ, it has demonstrated thermal stability and sintering resistance to 1650 °C (3000 °F). The Electric Power Research Institute (EPRI) and cincinnati thermal spray (CTS) have teamed together in a joint program to commercialize the YbGd-YSZ TBC coating system for GT combustion hardware. The program consists of validation of coating properties, establishment of production coating specifications, and demonstration of coating performance through component engine testing of the YbGd-YSZ TBC coating system. Among the critical to quality coating characteristics that have been established are (a) coating microstructure, (b) TBC tensile bond strength, (c) erosion resistance, (d) thermal conductivity and sintering resistance, and (e) thermal cycle performance. This paper will discuss the coating property validation results comparing the YbGd-YSZ TBC to baseline production combustor coatings and the status of coating commercialization efforts currently underway.

Introduction: IELSG32 is an international randomized phase II trial with 2 key clinical questions in pts with PCNSL. The first question focused on optimal induction therapy, and results of the 1st randomization have demonstrated that MATRix combination (methotrexate (MTX), cytarabine (ARAC), thiotepa, rituximab (R)) is associated with significantly better outcome [Ferreri AJ, et al. Lancet Haematol 2016]. The second question addresses the efficacy and neurotolerability of ASCT, as an alternative to WBRT as consolidation. Herein, we report the results of the 2nd randomization (NCT01011920). Methods: HIV-neg pts 18-70 ys and ECOG PS ≤3 with new histology-proven PCNSL and measurable disease were randomly assigned to receive 4 courses of MTX-ARAC (arm A); or R-MTX-ARAC (arm B); or MATRix (arm C). ASC were collected after 2nd c. Pts with responsive or stable disease were further randomized between WBRT 36 ± 9 Gy (arm D) and BCNU-thiotepa conditioned/ASCT (arm E). Stratification parameters were induction arm and response . Primary endpoint of the 2ndrandomization was 2-year PFS. To demonstrate a 2-yr PFS improvement from 65% (P0) to 85% (P1), 52 pts/arm (one-sided; α 5%; β 95%) were required. Consolidation arm would be considered effective if ≥40 pts were progression-free survivors at 2 ys. Analyses were performed on an intention-to-treat (ITT) basis. Effects of consolidation treatments on neurocognitive functions and quality of life (QoL) were assessed with the IPCG tests panel and EORTC-QLQ at baseline, after treatment and every 6 months afterwards. Results: 227 pts were enrolled in 52 centers of 5 countries; 219 assessable pts were referred to 1st randomization (arm A 75; B 69; C 75). 167 pts had responsive or stable disease after induction: 49 pts were excluded from 2nd randomization (poor mobilization, poor condition or patients' refusal); 118 pts were thus randomized (59 pts/arm) and constitute the study population (median age 58 ys; range 18-70). 15 (13%) pts had high IELSG risk, 3 pts had ocular disease and 20 pts had meningeal disease; with the exception of a higher male prevalence in arm D, there were no differences in clinical presentation between two arms; There were 6 protocol violations: 4 pts randomly allocated to arm D were treated with ASCT and 2 pts randomly allocated to arm E were treated with WBRT; 5 pts (D 2; E 3) refused consolidation. Therefore, per-protocol (PP) groups consisted of 55 pts treated with WBRT and 58 with ASCT. Both consolidation therapies were well tolerated. Grade 4 toxicity was uncommon (≤5% of pts); as expected, hematological toxicity was more common in arm E (neutropenia 5% vs. 71%; p=0.00001 - thrombocytopenia 2% vs. 72%; p=0.00001). There were 2 toxic deaths (infections), both in arm E. Neuropsychological tests showed a significant impairment of attention/executive functions and a non-significant trend to impaired memory among pts treated with WBRT, whereas pts treated with ASCT exhibited improved functions. Both consolidation therapies were associated with significant improvement in language and QoL. Both WBRT and ASCT were active and resulted in significant improvement in CR rate: from 54% after induction to 95% (95%CI: 90-100) after consolidation in arm D, and from 53% to 93% (95%CI: 87-99) in arm E. After a median follow-up of 40 months (range 24-76), there were 20 events (16 relapses, 2 PDs, 2 off-therapy deaths) in arm D, and 25 events (18 relapses, 2 PDs, 2 toxic deaths, 3 off-therapy deaths) in arm E. Importantly, WBRT and ASCT were both effective, with a number of progression-free survivors at 2 ys equal to the pre-determined efficacy threshold: 40 among both the first 52 arm-D and 52 arm-E pts. There were no significant differences in PFS between WBRT and ASCT; on ITT basis, the 2-yr PFS was 80 ± 5% after WBRT and 70 ± 6% after ASCT; per protocol, the 2-yr PFS was 76 ± 6% and 75 ± 6%, respectively. In multivariate analysis, IELSG risk group, number of lesions and induction arm were independently associated with PFS; gender, CSF cytology status and consolidation arm were not. Forty-two pts randomized to arm D and 37 randomized to arm E are alive, with 2-year OS of 85 ± 5% and 71 ± 6% (p=0.12), respectively. Conclusions: WBRT and ASCT are both feasible, active and effective as consolidation therapies after high-dose-MTX-based chemoimmunotherapy in pts ≤70 ys with PCNSL. Potential impairment of specific neurocognitive functions after WBRT should be considered at the time of therapeutic decision. Disclosures Ferreri: Sandoz: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Research Funding, Speakers Bureau; Italfarmaco: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adienne: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees. Fox:Adienne: Honoraria, Research Funding; Takeda: Honoraria, Other: travel funding; Gilead: Honoraria, Other: travel funding; Janssen: Honoraria, Other: travel funding; AbbVie: Consultancy. Röth:Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria. Johnson:Celldex Therapeutics: Research Funding. Linton:Takeda: Research Funding. Hess:Roche: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Roche, CTI, Pfizer, Celgene: Research Funding; Celgene: Honoraria; Pfizer: Honoraria. Stilgenbauer:Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau. Rummel:Roche Pharma AG: Other: Personal fees, Research Funding; Mundipharma GmbH: Other: Personal fees, Research Funding. Illerhaus:Riemser: Honoraria; Amgen: Honoraria.

Objectives An unlinked anonymous seroprevalence study was conducted to estimate the prevalence of hepatitis C virus (HCV) infection in samples derived from antenatal clinic attendees at 2 East London Hospitals. An unexpectedly high HCV seroprevalence of 2.6% (1.2% viraemic) had been revealed during an unlinked study of the emergency department at 1 of these hospitals. Design 1000 stored residual samples were tested for HCV antibody (anti-HCV) and reactive samples were further tested for HCV RNA. The study was reviewed by the East Midland NRES ethics committee project ID 181154, approval number 15/WS/0125. Results The anti-HCV reactivity rate was 0.5% (5/1000) with 0.1% (1/1000) confirmed viraemic. Prevalence for the other blood-borne viruses was higher: 1% (10/1000) were hepatitis B surface antigen positive and 0.3% were HIV antigen/antibody positive (3/1000). There were no co-infections. Conclusions More data to establish the prevalence of HCV in the antenatal population is needed. The addition of anti-HCV testing to the well-established antenatal screening programme provides a unique opportunity to impact on the health of pregnant women, their children, partners and future pregnancies in this new era of treatment for hepatitis C.

This report describes the value of a voluntary error reporting system and the impact of a series of quality assurance (QA) measures including checklists and timeouts on reported error rates in patients receiving radiation therapy.A voluntary error reporting system was instituted with the goal of recording errors, analyzing their clinical impact, and guiding the implementation of targeted QA measures. In response to errors committed in relation to treatment of the wrong patient, wrong treatment site, and wrong dose, a novel initiative involving the use of checklists and timeouts for all staff was implemented. The impact of these and other QA initiatives was analyzed.From 2001 to 2011, a total of 256 errors in 139 patients after 284,810 external radiation treatments (0.09% per treatment) were recorded in our voluntary error database. The incidence of errors related to patient/tumor site, treatment planning/data transfer, and patient setup/treatment delivery was 9%, 40.2%, and 50.8%, respectively. The compliance rate for the checklists and timeouts initiative was 97% (P.001). These and other QA measures resulted in a significant reduction in many categories of errors. The introduction of checklists and timeouts has been successful in eliminating errors related to wrong patient, wrong site, and wrong dose.A comprehensive QA program that regularly monitors staff compliance together with a robust voluntary error reporting system can reduce or eliminate errors that could result in serious patient injury. We recommend the adoption of these relatively simple QA initiatives including the use of checklists and timeouts for all staff to improve the safety of patients undergoing radiation therapy in the modern era.

The purpose of these studies was to evaluate the effect of lerisetron (1-phenyl-methyl-2-piperazinyl-1H-benzimidazole hydrochloride, CAS 143257-98-1, F- 0930-RS2), a new 5-HT 3 receptor antagonist, on ipecacuanha-induced nausea and vomiting. The ipecacuanha model of emesis has been used to test the anti-emetic activity of several different 5-HT 3 antagonists and the anti-emetic doses that were effective in the ipecacuanha model have been found to correlate well with the clinically effective doses. Study 1 investigated oral doses of lerisetron from 4 mg to 40 mg. Study 2 evaluated the duration of effect of a single dose of 20 mg oral lerisetron. Study 3 evaluated intravenous doses of 18 mg and 12 mg lerisetron. In Study 1, the 40 mg dose of oral lerisetron inhibited emesis in all test subjects. The percentage of subjects who experienced an emetic episode increased as the dose of lerisetron decreased. At the lowest dose level tested five of six subjects had an emetic episode compared with four out of five in the placebo group. In Study 2, 20 mg oral lerisetron was effective up to 12 h after administration. When ipecacuanha was administered at 18 h post-dose three of seven subjects had an emetic episode and at 24 h post-dose the incidence of emesis was similar to the placebo treatment groups in the previous study. Study 3 demonstrated the effectiveness of intravenous doses of lerisetron. The 18 mg intravenous dose reduced the number of patients experiencing emetic episodes by 75 % compared with placebo, doses below 12 mg i.v. were not evaluated because of the reduced efficacy of the compound at this dose level. In conclusion, lerisetron has been shown to be effective in the treatment of ipecacuanha-induced nausea and vomiting at intravenous doses of 18 mg and at oral doses of 20 mg for up to 12 hours.

Adriamycin used in combination with vitamin E (Tocopherol) was evaluated in the treatment of Nb rat prostate adenocarcinoma. Vitamin E has been shown to enhance the growth-inhibitory effects of adriamycin on human prostatic carcinoma cells in vitro. The adriamycin-vitamin E treatment groups had the lowest average final tumor volume, but the mortality rate was 57% (17/30). These results suggest that vitamin E may play a role in enhancing the cytotoxic effects of adriamycin, but may not have any protective effect on normal cells as previously suggested through in vitro methods.