EBV-associated primary CNS lymphoma occurring after immunosuppression is a distinct immunobiological entity.

Primary central nervous system lymphoma (PCNSL) is confined to the brain, eyes, and cerebrospinal fluid without evidence of systemic spread. Rarely, PCNSL occurs in the context of immunosuppression (eg, posttransplant lymphoproliferative disorders or HIV [AIDS-related PCNSL]). These cases are poorly characterized, have dismal outcome, and are typically Epstein-Barr virus (EBV)-associated (ie, tissue-positive). We used targeted sequencing and digital multiplex gene expression to compare the genetic landscape and tumor microenvironment (TME) of 91 PCNSL tissues all with diffuse large B-cell lymphoma histology. Forty-seven were EBV tissue-negative: 45 EBV- HIV- PCNSL and 2 EBV- HIV+ PCNSL; and 44 were EBV tissue-positive: 23 EBV+ HIV+ PCNSL and 21 EBV+ HIV- PCNSL. As with prior studies, EBV- HIV- PCNSL had frequent MYD88, CD79B, and PIM1 mutations, and enrichment for the activated B-cell (ABC) cell-of-origin subtype. In contrast, these mutations were absent in all EBV tissue-positive cases and ABC frequency was low. Furthermore, copy number loss in HLA class I/II and antigen-presenting/processing genes were rarely observed, indicating retained antigen presentation. To counter this, EBV+ HIV- PCNSL had a tolerogenic TME with elevated macrophage and immune-checkpoint gene expression, whereas AIDS-related PCNSL had low CD4 gene counts. EBV-associated PCNSL in the immunosuppressed is immunobiologically distinct from EBV- HIV- PCNSL, and, despite expressing an immunogenic virus, retains the ability to present EBV antigens. Results provide a framework for targeted treatment.

The association of adolescents' smoking with the physical activity levels of their friends.

BACKGROUND: Smoking is inversely related to people's Physical Activity Level (PAL). As the behavior of friends may affect the choices and behavior of adolescents, having friends with a high PAL may potentially protect against adolescent smoking. This study aims to assess whether adolescents' smoking is associated with the PAL of their friends. METHODS: SILNE-R survey data of 11.918 adolescents from 55 different schools in 7 European cities was used to determine weekly smoking, individual PAL, PAL of friends, school PAL, and smoking of friends. Multilevel, multivariable logistic regression analysis were used to assess the association between the PAL of friends and weekly smoking. Several socio-demographic variables were included as covariates in the analysis. RESULTS: Our results indicated that 10.8% of the respondents was smoking weekly. Weekly smoking was most common among adolescents whose friends had a PAL of 0-42.0 min per day (14.5%). Respondents were significantly more likely to be smoking weekly if their friends were on average 0-42 min vs. 80-180 min physically active (OR 1.27 [95% CI 1.04-1.55]). This association existed independently of the individual PAL of respondents. Stratification for smoking of friends yielded equal results, although the association appeared to be somewhat stronger for those with smoking friends (OR 1.38 [95% CI 1.06-1.82]). CONCLUSION: Adolescents are less likely to smoke weekly if they associate with friends who spend >80 min per day on physical activity. Initiatives aimed at the prevention of smoking among adolescents may benefit from organizing group-based physical activity programs.

Smoking Behaviour Among People Living with HIV and AIDS: A Sub-Group Comparison.

Recent advancements in the treatment of HIV have significantly improved long-term health outcomes and life expectancy among people living with HIV/AIDS. As such, healthcare professionals have begun to focus more seriously on health protective behaviour changes that could further reduce mortality including smoking and tobacco dependence. A cross-sectional survey was conducted with 438 people living with HIV/AIDS (PLWHA) attending a clinic in an urban area to measure current smoking behaviours. After removing missing data, the final sample was 402 service users. Among those surveyed 141 (35.0%) were current smokers with 35 (8.2%) ex-smokers. Rates among key sub-groups were higher. Comparatively, smoking prevalence was very low among African migrants (8, 7.2%), particularly African born women (1, 1.3%). In line with international studies, smoking prevalence among PLWHA was nearly double that of the general population. These findings come at a time when smoking in the general population in Ireland is at an all-time low, making the need to address tobacco dependence among PLWHA all the more vital.

Adoptive T cell immunotherapy for treatment of ganciclovir-resistant cytomegalovirus disease in a renal transplant recipient.

Cytomegalovirus (CMV) is a significant cause of morbidity, mortality and graft loss in solid organ transplantation (SOT). Treatment options for ganciclovir-resistant CMV are limited. We describe a case of ganciclovir-resistant CMV disease in a renal transplant recipient manifested by thrombotic microangiopathy-associated glomerulopathy. Adoptive T cell immunotherapy using CMV-specific T cells from a donor bank was used as salvage therapy. This report is a proof-of-concept of the clinical and logistical feasibility of this therapy in SOT recipients.

Second-hand smoke exposure levels and tobacco consumption patterns among a lesbian, gay, bisexual and transgender community in Ireland.

OBJECTIVES: To estimate and identify characteristics of tobacco use, including use of roll-your-own (RYO) cigarettes and second-hand smoke (SHS) exposure, among a self-identified lesbian, gay, bisexual and transgender (LGBT) community in Ireland. STUDY DESIGN: Web-based self-administered questionnaire survey using a cross-sectional study design. METHODS: A convenience sample of 661 self-identified LGBT respondents was recruited through a well-advertised web-based survey tool method between March and May 2012. Prevalence rates were adjusted for age, sexual orientation, social class and nationality. Multivariable logistic regression was performed to characterize tobacco use profile and SHS exposure levels for estimating adjusted odds ratios (AOR) with 95% confidence intervals (CI). RESULTS: Of the 661 respondents, 45.3% (95% CI 44.9-45.7) reported current use of tobacco and 15.6% reported current use of RYO cigarettes (results were significantly higher for lesbians in both categories). In addition, 40.3% (95% CI 39.9-40.6) of respondents reported SHS exposure at home (significantly higher in gays), and 50.1% (95% CI 49.3-50.8) reported SHS exposure in cars (significantly higher in lesbians); these two groups were not mutually exclusive. The oldest individuals and non-Irish nationals were more than twice as likely to report SHS exposure in cars compared with the youngest individuals and Irish nationals, and the least-educated individuals were more than twice as likely to report current use of RYO cigarettes compared with the most-educated individuals (AOR 2.26; 95% CI 1.06-4.79). Non-tobacco users were less likely to report SHS exposure at home compared with current tobacco users (AOR 0.31; 95% CI 0.21-0.46). DISCUSSION: Despite inherent methodological limitations associated with identification of such a study sample, the adjusted rates indicate that tobacco use is very high among the LGBT community in Ireland compared with the general Irish population (smoking rate 29%). High levels of SHS exposure at home and in cars further underscore the significance of smoke-free private vehicle and 100% smoke-free home policies. A targeted tobacco control strategy should be explored for this vulnerable population.

Particulate matter in aerosols produced by two last generation electronic cigarettes: a comparison in a real-world environment.

The design of e-cigarettes (e-cigs) is constantly evolving and the latest models can aerosolize using high-power sub-ohm resistance and hence may produce specific particle concentrations. The aim of this study was to evaluate the aerosol characteristics generated by two different types of electronic cigarette in real-world conditions, such as a sitting room or a small office, in number of particles (particles/cm3). We compared the real time and time-integrated measurements of the aerosol generated by the e-cigarette types Just Fog and JUUL. Real time (10s average) number of particles (particles/cm3) in 8 different aerodynamic sizes was measured using an optical particle counter (OPC) model Profiler 212-2. Tests were conducted with and without a Heating, Ventilating Air Conditioning System (HVACS) in operation, in order to evaluate the efficiency of air filtration. During the vaping sessions the OPC recorded quite significant increases in number of particles/cm3. The JUUL e-cig produced significantly lower emissions than Just Fog with and without the HVACS in operation. The study demonstrates the rapid volatility or change from liquid or semi-liquid to gaseous status of the e-cig aerosols, with half-life in the order of a few seconds (min. 4.6, max 23.9), even without the HVACS in operation. The e-cig aerosol generated by the JUUL proved significantly lower than that generated by the Just Fog, but this reduction may not be sufficient to eliminate or consistently reduce the health risk for vulnerable non e-cig users exposed to it.

Immunogenicity and Safety of a 3-Antigen Hepatitis B Vaccine vs a Single-Antigen Hepatitis B Vaccine: A Phase 3 Randomized Clinical Trial.

Importance: There is a need for improved immunogenicity of hepatitis B virus (HBV) vaccines among young adults with risk of infection. Objectives: To demonstrate manufacturing equivalence of a 3-antigen (3A) HBV vaccine, evaluate noninferiority of seroprotection rate (SPR) of 3A-HBV vs single-antigen (1A) HBV after 2 and 3 vaccine doses, and compare safety and reactogenicity between 3A-HBV and 1A-HBV vaccines. Design, Setting, and Participants: This phase 3, double-blinded, randomized clinical trial included healthy adults aged 18 to 45 years randomized to 1 of three 3A-HBV groups or 1 control group receiving 1A-HBV. The trial was conducted at 37 community clinics and academic hospitals in Canada, Europe, the United Kingdom, and the United States between December 2017 and October 2019. Participants were followed up for 48 weeks after the first vaccination. Interventions: Intramuscular administration of 3A-HBV (10 µg) or 1A-HBV (20 µg) on days 0, 28, and 168. Main Outcomes and Measures: Geometric mean concentration (GMC) of serum hepatitis B surface antibodies (anti-HBs) and proportion of participants achieving seroprotection. Results: Of 2838 participants, 1638 (57.8%) were women, 2595 (91.5%) were White, and 161 (5.7%) were Black or African American. A total of 712 participants (25.1%) were randomized to the 1A-HBV group and 2126 (74.9%) to 3A-HBV. The mean (SD) age at informed consent was 33.5 (8.0) years. The study demonstrated 3A-HBV lot-to-lot consistency, as the 2-sided 95% CIs for each pairwise comparison for the anti-HBs GMC ratios were within 0.67 and 1.50 (eg, adjusted GMC ratio, lot A vs lot B: 0.82; 95% CI, 0.67-1.00; lot A vs lot C: 0.95; 95% CI, 0.78-1.15; lot B vs lot C: 1.16; 95% CI, 0.95-1.41). The SPR of the pooled 3A-HBV was noninferior to 1A-HBV and higher than 1A-HBV after 2 vaccinations at day 168 (90.4% [95% CI, 89.0%-91.8%] vs 51.6% [95% CI, 47.5%-55.6%]) and 3 vaccinations at day 196 (99.3% [95% CI, 98.7%-99.6%] vs 94.8% [95% CI, 92.7%-96.4%]). The mean GMC of anti-HBs with 3A-HBV was 7.9 times higher after 2 vaccinations at day 168 and 3.5 times higher after 3 vaccinations at day 196 compared with 1A-HBV (after 2 vaccinations, 3A-HBV: GMC, 118.7 mIU/mL; 95% CI, 108.0-129.0 mIU/mL; SE, 1.0 mIU/mL; 1A-HBV: GMC, 15.0 mIU/mL; 95% CI, 12.9-17.5 mIU/mL; SE, 1.0 mIU/mL; after 3 vaccinations, 3A-HBV: GMC, 5442.4 mIU/mL; 95% CI, 4967.0-5963.0 mIU/mL; SE, 1.0 mIU/mL; 1A-HBV: 1567.2 mIU/mL; 95% CI, 1338.0-1834.0 mIU/mL; SE, 1.0 mIU/mL). Rates of local and systemic reactogenicities were higher with 3A-HBV compared with 1A-HBV (local: 1805 of 2124 [85.0%] vs 469 of 712 [65.9%]; systemic: 1445 [68.0%] vs 428 [60.1%]). Vaccine discontinuation due to adverse events (AE) was uncommon, and serious AEs were infrequent, reported in 42 participants (2.0%) and 3 participants (0.4%) in the 3A-HBV and 1A-HBV groups, respectively. Conclusions and Relevance: In this study, consistently higher antibody concentrations and SPRs were found with 3A-HBV after 2 and 3 doses vs 1A-HBV in adults aged 18 to 45 years old. The safety and efficacy of 3A-HBV shows its usefulness for the prevention of hepatitis B in young healthy adults. Trial Registration: Clinicaltrials.gov Identifier: NCT03408730; EU Clinical Trials Number: 2017-001820-22.

Second-hand smoke exposure in cars and respiratory health effects in children.

We examined potential associations of ever asthma, and symptoms of wheeze (past 12 months), hay fever, eczema and bronchitis (cough with phlegm) among school children exposed to second-hand smoke (SHS) in cars, using a modified Irish International Study of Asthma and Allergies in Childhood (ISAAC) protocol. 2,809 children of 13-14 yrs old and who selected randomly from post-primary schools throughout Ireland completed the 2007 ISAAC self-administered questionnaire. Adjusted OR (adjusted for sex, active smoking status of children interviewed and their SHS exposure at home) were estimated for the associations studied, using multivariable logistic regression techniques. Overall, 14.8% (13.9% in young males, 15.4% in young females) of Irish children aged 13-14 yrs old were exposed to SHS in cars. Although there was a tendency towards increased likelihood of both respiratory and allergic symptoms with SHS exposure in cars, wheeze and hay fever symptoms were significantly higher (adjusted OR 1.35 (95% CI 1.08-1.70) and 1.30 (1.01-1.67), respectively), while bronchitis symptoms and asthma were not significant (1.33 (0.92-1.95) and 1.07 (0.81-1.42), respectively). Approximately one in seven Irish schoolchildren are exposed to SHS in cars and could have adverse respiratory health effects. Further studies are imperative to explore such associations across different population settings.

Crystal structure of Cd,Zn metallothionein.

The anomalous scattering data from five Cd in the native protein were used to determine the crystal structure of cadmium, zinc (Cd,Zn) metallothionein isoform II from rat liver. The structure of a 4-Cd cluster was solved by direct methods. A 2.3 A resolution electron density map was calculated by iterative single-wavelength anomalous scattering. The structure is folded into two domains. The amino terminal domain (beta) of residues 1 to 29 enfolds a three-metal cluster of one Cd and two Zn atoms coordinated by six terminal cysteine thiolate ligands and three bridging cysteine thiolates. The carboxyl terminal domain (alpha) of residues 30 to 61 enfolds a 4-Cd cluster coordinated by six terminal and five bridging cysteine thiolates. All seven metal sites have tetrahedral coordination geometry. The domains are roughly spherical, and the diameter is 15 to 20 A; there is limited contact between domains. The folding of alpha and beta is topologically similar but with opposite chirality. Redundant, short cysteine-containing sequences have similar roles in cluster formation in both alpha and beta.

Low birthweight and preterm birth rates 1 year before and after the Irish workplace smoking ban.

OBJECTIVE: It is well-established that maternal smoking has adverse birth outcomes (low birthweight, LBW, and preterm births). The comprehensive Irish workplace smoking ban was successfully introduced in March 2004. We examined LBW and preterm birth rates 1 year before and after the workplace smoking ban in Dublin. DESIGN: A cross-sectional observational study analysing routinely collected data using the Euroking K2 maternity system. SETTING: Coombe University Maternal Hospital. POPULATION: Only singleton live births were included for analyses (7593 and 7648, in 2003 and 2005, respectively). METHODS: Detailed gestational and clinical characteristics were collected and analysed using multivariable logistic regression analyses and subgroup analyses. MAIN OUTCOME MEASURES: Maternal smoking rates, mean birthweights, and adjusted odds ratios (ORs) of LBW and preterm births in 2005 versus 2003. RESULTS: There was a 25% decreased risk of preterm births (OR, 0.75; 95% CI, 0.59-0.96), a 43% increased risk of LBW (OR, 1.43; 95% CI, 1.10-1.85), and a 12% fall in maternal smoking rates (from 23.4 to 20.6%) in 2005 relative to 2003. Such patterns were significantly maintained when specific subgroups were also analysed. Mean birthweights decreased in 2005, but were not significant (P=0.99). There was a marginal increase in smoking cessation before pregnancy in 2005 (P=0.047). CONCLUSIONS: Significant declines in preterm births and in maternal smoking rates after the smoking ban are welcome signs. However, the increased LBW birth risks might reflect a secular trend, as observed in many industrialised nations, and merits further investigations.

Lung cancer and urban air-pollution in Dublin: a temporal association?

In 1990, the sale, marketing and distribution of bituminous coal, primarily used for domestic heating, were banned across Dublin. This study exploits the potential of a 'natural experiment' to assess a temporal association between adjusted annual lung cancer death rates and the changing annual mean urban air-pollution concentrations in Dublin from 1981 to 2000. Annual mean 'black smoke' (BS) concentration was used as an indicator variable for the urban air-pollution mixture. Log-linear Poisson regression model (with an offset) was used to estimate adjusted rate ratios of lung cancer death rates between two periods (1981-1990 and 1991-2000) relative to the year 1990. A significant (p<0.0001) two-third decline in BS concentration (28.2 microg/m(3)) was seen between the two periods [pre-ban (46.4 microg/m(3)) vs. post-ban (18.2 microg/m(3))]. Relative to 1990 (rate ratio= 1 ), a slightly greater decline (2%) in death rates was achieved in the pre-ban period (1981-1990) when mean annual BS concentrations were very high, but a lower decline (1%) was seen in the post-ban period (1991-2000) corresponding to very low mean annual BS concentrations. In other words, a further fall in adjusted rates in lung cancer was achievable both in the pre-ban and the post-ban periods when simultaneously controlling for BS and smoking. A temporal association thus observed between lung cancer death rates and the changing BS concentrations suggests that control of particulate air-pollution could further reduce lung cancer rates, irrespective of smoking patterns.

Rising prevalence of asthma but declining wheeze in teenagers (1995-2003): ISAAC protocol.

The results of the initial International Study of Asthma and Allergies in Childhood (ISAAC) undertaken in the mid 1990s demonstrated a substantial increase in asthma and wheeze symptoms prevalence in Irish teenagers aged 13-14 years from the 1980s. International research suggests that asthma has increased further in some countries and this study was undertaken to determine whether an upward trend in childhood asthma prevalence has continued in the Republic of Ireland in recent years. We therefore conducted two further national cross sectional studies in the same previously surveyed childhood population throughout the Republic of Ireland, one in 1998 (n=2580) and the other in 2002-3 (n=3089). We report here on rising prevalence trends of asthma (42.1% relative increase) but falling wheeze (10.4% relative reduction) prevalence in these teenage children in 2002-3.

Reductions in tobacco smoke pollution and increases in support for smoke-free public places following the implementation of comprehensive smoke-free workplace legislation in the Republic of Ireland: findings from the ITC Ireland/UK Survey.

OBJECTIVE: To evaluate the psychosocial and behavioural impact of the first ever national level comprehensive workplace smoke-free law, implemented in Ireland in March 2004. DESIGN: Quasi-experimental prospective cohort survey: parallel cohort telephone surveys of national representative samples of adult smokers in Ireland (n = 769) and the UK (n = 416), surveyed before the law (December 2003 to January 2004) and 8-9 months after the law (December 2004 to January 2005). MAIN OUTCOME MEASURES: Respondents' reports of smoking in key public venues, support for total bans in those key venues, and behavioural changes due to the law. RESULTS: The Irish law led to dramatic declines in reported smoking in all venues, including workplaces (62% to 14%), restaurants (85% to 3%), and bars/pubs (98% to 5%). Support for total bans among Irish smokers increased in all venues, including workplaces (43% to 67%), restaurants (45% to 77%), and bars/pubs (13% to 46%). Overall, 83% of Irish smokers reported that the smoke-free law was a "good" or "very good" thing. The proportion of Irish homes with smoking bans also increased. Approximately 46% of Irish smokers reported that the law had made them more likely to quit. Among Irish smokers who had quit at post-legislation, 80% reported that the law had helped them quit and 88% reported that the law helped them stay quit. CONCLUSION: The Ireland smoke-free law stands as a positive example of how a population-level policy intervention can achieve its public health goals while achieving a high level of acceptance among smokers. These findings support initiatives in many countries toward implementing smoke-free legislation, particularly those who have ratified the Framework Convention on Tobacco Control, which calls for legislation to reduce tobacco smoke pollution.

Smoking, occupancy and staffing levels in a selection of Dublin pubs pre and post a national smoking ban, lessons for all.

BACKGROUND: On the 29th March 2004 the Irish government introduced a comprehensive workplace smoking ban to protect the health of workers. This study evaluates the impact the ban had on staffing levels, customer numbers and smoking rates in a sample of 38 public houses in Dublin. METHODS: A total of 38 public houses were visited prior to the introduction of the ban, each visit lasted at least three hours, and the number of staff, customers and the number of people smoking was recorded each hour. Follow-up visits were conducted exactly one year later, on the same day of the week and at the same time of day, allowing controlling for seasonal and weekday effects. RESULTS: There was a decrease (8.82%) in average staff levels while customer numbers increased by 11% and there was a dramatic reduction in numbers smoking on a visit to a pub (77.8%). CONCLUSIONS: The hospitality industry predicted major job losses as a consequence of the introduction of the smoking ban; this work has shown that there was no significant decrease in the number of staff employed or in customer numbers. There was full compliance, with no customers smoking inside the public houses following the introduction of the ban. The ban has been good for the industry, staff, and customers.

Smoking profile of non-consultant hospital doctors.

BACKGROUND: In 1994 Doll and colleagues published smoking mortality figures for British doctors over 40 years. AIMS: To assess smoking prevalence among junior doctors in a major Dublin teaching hospital. METHODS: One hundred and fourteen non-consultant doctors (NCHDs) at St James's Hospital received a confidential smoking questionnaire. RESULTS: One hundred and six NCHDs responded (93%). Three refused, five were not available. Ninety per cent were aged 24-35 years. Twenty-six per cent of the doctors had smoked for 10 to 15 years. Seventy-five per cent were smoking more than 10 cigarettes daily. Ninety-seven per cent (20) of smokers wanted to stop smoking. Seventy-four per cent (17) had unsuccessfully attempted to quit. The smoking cessation method most commonly used was'cold turkey' in 60%. Others included nicotine replacement, bupropion and hypnotherapy. CONCLUSION: A significant per centage of NCHDs (22%) continue to smoke, despite overwhelming evidence that this causes health problems. The prevalence in our study is lower than the national figure of 29%.

Lifestyle-related cancer death rates in Ireland: decreasing or increasing?

We examined death patterns of tobacco-related cancers (lung, oesophagus, larynx, and pharynx) and of non-tobacco related cancers (breast and prostate) from 1972 to 2001 in Ireland, utilizing the WHO Cancer Mortality Database. Estimated-annual-percent-changes (EAPC) in age-adjusted cancer death rates (standardised to world standard population) were calculated by age (10-year groups), period (10-year intervals) and sex. Overall, EAPCs of all the cancer sites studied showed a declining trend in the most recent period (1992-2001), with male oesophageal cancer rates showing a deceleration between 1992 and 2001. In 1992-2001, the youngest age-group studied (45-54 year-olds) showed a statistically significant declining annual rate particularly for lung cancer (males), breast and laryngeal cancer (females); prostate cancer death rates have slowed down in the youngest adults (45-54 year-olds); and the oldest age-groups studied (75-84 year-olds) are also showing an annual deceleration in some cancer sites, with a significant declining annual rate for breast cancer. In conclusion, the current and the future cancer death rates of some common life-style related cancers in Ireland are encouraging.

Effects of granulocyte-macrophage colony-stimulating factor and dose intensification of V-ICE chemotherapy in small-cell lung cancer: a prospective randomized study of 300 patients.

PURPOSE: To assess whether granulocyte-macrophage colony-stimulating factor (GM-CSF) reduces the toxicity of chemotherapy and alters delivered dose-intensity. To assess the feasibility of dose-intensification of chemotherapy in small-cell lung cancer (SCLC) and determine whether it has an impact on outcome. MATERIALS AND METHODS: Patients with good- or intermediate-prognosis SCLC entered a prospective multicenter study that involved a 2 x 2 factorial design with randomization to six cycles of chemotherapy with ifosfamide 5 g/m2, carboplatin 300 mg/m2, etoposide 120 mg/m2 intravenously (I.V.) on days 1 and 2 and 240 mg/m2 orally on day 3, and vincristine 0.5 mg/m2 I.V. on day 15 (V-ICE) every 3 weeks (intensified arm) or every 4 weeks (standard arm). A second double-blind randomization to subcutaneous GM-CSF (250 microg/m2/d) or placebo for 14 days between chemotherapy cycles was made. RESULTS: Three hundred patients were entered. Myelosuppression was the main toxicity, with no significant difference in the incidence or grade between treatment groups. The incidence of febrile neutropenia and bacteriologically confirmed sepsis was unaffected by chemotherapy schedule or use of GM-CSF. Twenty-six percent greater dose-intensity was delivered in the intensified arm, with a trend for greater dose-intensity for those who received GM-CSF. Eighty-three percent of patients achieved a response (51% complete response [CR] rate), with no significant difference in response rates between treatment groups. Survival was significantly increased in the intensified compared with the standard arm (P = .0014); median survival rates were 443 versus 351 days and 2-year survival rates were 33% versus 18%, respectively. CONCLUSION: GM-CSF does not reduce the incidence of complications from myelosuppression of aggressive chemotherapy. Dose intensification of V-ICE to a 3-week schedule in SCLC is not associated with increased toxicity, but appears to improve survival significantly. Future studies should aim to deliver chemotherapy in maximal-tolerated dose-intensities.