ISA101 and nivolumab for HPV-16+ cancer: updated clinical efficacy and immune correlates of response.

BACKGROUND: The combination of ISA101, a human papilloma virus (HPV) 16 peptide vaccine, and nivolumab showed a promising response rate of 33% in patients with incurable HPV-16+ cancer. Here we report long-term clinical outcomes and immune correlates of response. METHODS: Patients with advanced HPV-16+ cancer and less than two prior regimens for recurrence were enrolled to receive ISA101 (100 µg/peptide) on days 1, 22, and 50 and nivolumab 3 mg/kg every 2 weeks beginning day 8 for up to 1 year. Baseline tumor samples were stained with multiplex immunofluorescence for programmed death-ligand 1 (PD-L1), programmed cell death protein-1 (PD-1), CD3, CD8, CD68, and pan-cytokeratin in a single panel and scanned with the Vectra 3.0 multispectral microscope. Whole transcriptome analysis of baseline tumors was performed with Affymetrix Clariom D arrays. Differential gene expression analysis was performed on responders versus non-responders. RESULTS: Twenty-four patients were followed for a median of 46.5 months (95% CI, 46.0 months to not reached (NR)). The median duration of response was 11.2 months (95% CI, 8.51 months to NR); three out of eight (38%) patients with objective response were without progression at 3 years. The median and 3-year overall survival were 15.3 months (95% CI, 10.6 months to 27.2 months) and 12.5% (95% CI, 4.3% to 36%), respectively. The scores for activated T cells ((CD3+PD-1+)+(CD3+CD8+PD-1+)), activated cytotoxic T cells (CD3+CD8+PD-1+), and total macrophage ((CD68+PD-L1-)+(CD68+PD-L1+)) in tumor were directly correlated with clinical response (p<0.05) and depth of response with the two complete response patients having the highest degree of CD8+ T cells. Gene expression analysis revealed differential regulation of 357 genes (≥1.25 fold) in non-responders versus responders (p<0.05). Higher expression of immune response, inflammatory response and interferon-signaling pathway genes were correlated with clinical response (p<0.05). CONCLUSIONS: Efficacy of ISA101 and nivolumab remains promising in long-term follow-up. Increased infiltration by PD-1+ T cells and macrophages was predictive of response. Enrichment in gene sets associated with interferon-γ response and immune infiltration strongly predicted response to therapy. A randomized trial is ongoing to test this strategy and to further explore correlates of immune response with combined nivolumab and ISA101, versus nivolumab alone. TRIAL REGISTRATION NUMBER: NCT02426892.

Qualitative dermatoglyphic traits in monozygotic and dizygotic twins of Albanian population in Kosovo.

Dermatoglyphs are polygenetically determined epidermal ridge configurations on the fingers, palms and soles. An analysis of the digito-palmar dermatoglyphics obtained from 69 pairs of same-sex twins (32 monozygotic and 37 dizygotic) was performed in the population of Kosovo. Qualitative traits on the fingers (whorls, arches, radial and ulnar loops) and palms (pattern frequencies in the thenar/I, II, III and IV interdigital areas and hypothenar, the frequencies of positions of axial triradius) of both hands were analysed. The homolateral and heterolateral concordance of dermatoglyphic patterns between twin pairs were calculated for the monozygotic and dizygotic twins separately. The estimates of heritability for qualitative dermatoglyphic traits and the impacts of twin's shared (c(2)) and non-shared (individual) environments (e(2)) were presented. According to our results, the heritability patterns sharply distinguish highly heritable dermatoglyphic traits (patterns on the thenar and I interdigital area, II interdigital area and all the digits) and the traits with weak genetic component (patterns on the III and IV interdigital area, the hypothenar and the axial triradius position). In addition, the concordance and the heritability estimates in twins correspond to the embryonic growth of fingers (from the first to the fifth finger) and palm patterns (the II interdigital area). Based on findings presented here, we expect that the noxious environmental factors (possibly causing diseases later in life) would leave traces on the dermatoglyphs, which could be recognized as the increased dissimilarity of the twins (and other relatives) in the III and IV interdigital area, hypothenar, and in axial triradius position.

Vaccines for older adults.

OBJECTIVE: To update senior care pharmacists with current recommendations on influenza, pneumococcal, zoster, and tetanus vaccines for older adults 65 years of age or older. DATA SOURCES: A search of immunization guidelines on influenza, pneumococcal, zoster, and tetanus infection was performed at various Web sites, including Immunization Action Coalition (www.immunize.org) and the Centers for Disease Control and Prevention (www.cdc.gov). MEDLINE (January 1966 to September 2008) and Pub-Med (January 1955-September 2008) databases and manual bibliographic searches were used to identify additional information. Search terms included influenza, herpes zoster, shingles, pneumococcal pneumonia, pneumovax, tetanus, and vaccine, used alone or in combination. STUDY SELECTION AND DATA EXTRACTION: Relevant English language articles identified from the data sources were evaluated. DATA SYNTHESIS: Trivalent influenza vaccine is recommended to high-risk groups and persons who are likely to transmit the infection, including selected health care staff and caretakers, adults 50 years of age or older, and those with comorbidities that increase the risk of influenza complications. Pneumococcal vaccine is recommended for all persons 65 years of age or older and those with certain medical conditions. One-time revaccination can be offered to the elderly who initially received the vaccine before they turned age 65 and at least five years passed since the initial vaccination. Zoster vaccine should be offered to all persons 60 years of age or older unless contraindications or precautions exist. Tetanus booster every 10 years should be considered in adults who have completed the primary series. Influenza and pneumococcal vaccines, as well as tetanus booster for post-exposure management, are covered under Medicare Part B. Zoster vaccine is covered under Medicare Part D. CONCLUSION: The Advisory Committee on Immunization Practices offers detailed recommendations for the prevention of influenza, invasive pneumococcal disease, zoster, and tetanus infection for target groups.

Human papillomavirus status and cervical abnormalities in women from public and private health care in Rio de Janeiro State, Brazil.

This article reports the HPV status and cervical cytological abnormalities in patients attended at public and private gynecological services from Rio de Janeiro State. It also comments the performance of each HPV DNA tests used. A set of 454 women from private health clinics was tested by routine Capture Hybrid II HPV DNA assay. Among these, 58.4% presented HPV and nearly 90% of them were infected by high risk HPV types. However, this group presented few premalignant cervical lesions and no invasive cervical cancer was registered. We also studied 220 women from low income class attended at public health system. They were HPV tested by polymerase chain reaction using My09/11 primers followed by HPV typing with E6 specific primers. The overall HPV prevalence was 77.3%. They also showed a high percentage of high squamous intraepithelial lesion-HSIL (26.3%), and invasive cervical carcinoma (16.3%). HPV infection was found in 93.1% and 94.4% of them, respectively. The mean ages in both groups were 31.5 and 38 years, respectively. In series 1, HPV prevalence declined with age, data consistent with viral transient infection. In series 2, HPV prevalence did not decline, independent of age interval, supporting not only the idea of viral persistence into this group, but also regional epidemiological variations in the same geographic area. Significant cytological differences were seen between both groups. Normal and benign cases were the most prevalent cytological findings in series 1 while pre-malignant lesions were the most common diagnosis in the series 2. HPV prevalence in normal cases were statistically higher than those from series 1 (p<0.001), indicating a higher exposure to HPV infection. Women from both samples were referred for previous abnormal cytology. However, socio-demographic evidence shows that women from series 1 have access to treatment more easily and faster than women from series 2 before the development of pre-malignant lesions. These data provides baseline support for the role of social inequalities linked to high risk HPV infection leading to cervical cancer. Broadly screening programs and the development of safe and effective vaccines against HPV would diminish the toll of this disease that affect mainly poor women.

Human papillomavirus status and cervical abnormalities in women from public and private health care in Rio de Janeiro State, Brazil / Papilomavírus humano e anormalidades cervicais em mulheres do sistema de saúde privado e público no Estado do Rio de Janeiro, Brasil

This article reports the HPV status and cervical cytological abnormalities in patients attended at public and private gynecological services from Rio de Janeiro State. It also comments the performance of each HPV DNA tests used. A set of 454 women from private health clinics was tested by routine Capture Hybrid II HPV DNA assay. Among these, 58.4 percent presented HPV and nearly 90 percent of them were infected by high risk HPV types. However, this group presented few premalignant cervical lesions and no invasive cervical cancer was registered. We also studied 220 women from low income class attended at public health system. They were HPV tested by polymerase chain reaction using My09/11 primers followed by HPV typing with E6 specific primers. The overall HPV prevalence was 77.3 percent. They also showed a high percentage of high squamous intraepithelial lesion-HSIL (26.3 percent), and invasive cervical carcinoma (16.3 percent). HPV infection was found in 93.1 percent and 94.4 percent of them, respectively. The mean ages in both groups were 31.5 and 38 years, respectively. In series 1, HPV prevalence declined with age, data consistent with viral transient infection. In series 2, HPV prevalence did not decline, independent of age interval, supporting not only the idea of viral persistence into this group, but also regional epidemiological variations in the same geographic area. Significant cytological differences were seen between both groups. Normal and benign cases were the most prevalent cytological findings in series 1 while pre-malignant lesions were the most common diagnosis in the series 2. HPV prevalence in normal cases were statistically higher than those from series 1 (p < 0.001), indicating a higher exposure to HPV infection. Women from both samples were referred for previous abnormal cytology. However, socio-demographic evidence shows that women from series 1 have access to treatment more easily and faster than women from series 2 before the development of pre-malignant lesions...

Este artigo analisa a infecção por HPV e anormalidades citológicas cervicais encontradas em pacientes atendidas em serviços ginecológicos dos sistemas de saúde público e privado do estado do Rio de Janeiro. O trabalho também avalia os testes utilizados para detecção de DNA do HPV em cada população estudada. Um grupo de 454 mulheres oriundas de serviços da rede privada de saúde foi testado por Captura do Híbrido II. Destas, 58,4 por cento apresentaram infecção por HPV e cerca de 90 por cento delas estavam infectadas por HPV de alto risco. Este grupo, entretanto, apresentava poucos casos de lesões cervicais pré-malígnas e nenhum caso de câncer. Estudamos, também, 220 mulheres de baixo nível econômico atendidas no serviço de saúde pública que foram testadas para HPV pela reação da polimerase em cadeia utilizando-se os oligonucleotídeos My09/My11. A identificação dos tipos foi efetuada por amplificação com oligonucleotídeos específicos para a região E6 do genoma viral. A prevalência de HPV nesta população foi de 77.3 por cento, observando-se uma alta porcentagem de casos de neoplasias intraepiteliais cervicais de alto grau (26,3 por cento) e de carcinoma cervical invasivo (16,3 por cento). A infecção por HPV foi achada em, respectivamente, 93,1 por cento e 94,4 por cento destes casos. A média de idade em ambos os grupos era de 31,5 e 38 anos, respectivamente. Na série 1, a prevalência da infecção por HPV decresce com a idade, enquanto na série 2 ela não desaparece, dando suporte não só à idéia de persistência viral neste grupo, mas também a variações epidemiológicas na mesma área geográfica. Diferenças significativas foram vistas nos dois grupos. Casos normais e benignos foram incidentes na série 1, enquanto as lesões malígnas predominaram na série 2. Ao contrário, casos normais infectados por HPV eram prevalentes na série 2 (p < 0.001), indicando maior exposição ao vírus. Embora as mulheres de ambos os grupos tenham sido incluídas no estudo por apresentarem citologia anormal, evidências sócio-demográficas demonstram que mulheres da série 1 tem acesso mais fácil e rápido ao tratamento do que as mulheres da série 2 antes que as lesões pré-malígnas se desenvolvam...

[Factors associated with smoking onset: 3-year cohort study of schoolchildren]. / Factores asociados con el inicio del tabaquismo: seguimiento a los 3 años de una cohorte de escolares.

OBJECTIVE: To analyze the predictors of smoking onset among schoolchildren. METHODS: A cohort study of 1056 children starting in first year secondary school at 44 schools in Barcelona was carried out. Participating children were invited to answer a lifestyle questionnaire every year for 4 years. Each questionnaire carried a personal code to allow the 4 questionnaires to be matched. Matching questionnaires were found for 729 children, 70% of the initial sample. RESULTS: Over the study period, the prevalence of regular smokers increased from 1.7% to 22% among boys and from 1.6% to 38.2% among girls. The predictors of smoking onset among boys were scoring high on the pro-smoking attitudes index (odds ratio [OR]=1.2; 95% confidence interval [CI], 1.1-1.3), intention to smoke in the future (OR=2.2; 95% CI, 1.0-4.9), low self-efficacy in resisting pressures to smoke (OR=0.98; 95% CI, 0.96-0.99), having siblings that smoke (OR=2.5; 95% CI, 1.2-5.4), and spending some free time in bars (OR=2.4; CI, 1.1-4.9). Among girls, the predictors were having low self-esteem (OR=0.94; 95% CI, 0.88-0.99), scoring low on the anti-tobacco attitudes index (OR=0.92; 95% CI, 0.88-0.97), having siblings who smoke (OR=2.5; 95% CI, 1.2-5.5), spending some free time in discotheques (OR=4.5; 95% CI, 1.9-11.8), and living in high socioeconomic-status neighborhoods (OR=3.1; 95% CI, 1.4-10.9). CONCLUSIONS: The results show the importance of cognitive variables as well as a variety of environmental variables, particularly the pattern of free time use and the influence of sibling models. Prevention programs must take into account smoking onset risk factors as a whole.

[Changes in tobacco use in the general population of Barcelona, 1983-2000]. / Cambios en el consumo de tabaco en la población general en Barcelona, 1983-2000.

OBJECTIVES: To analyze the prevalence trends for smoking and its determinants in the general population of Barcelona from 1983 to 2000. DESIGN: Time series study. SETTING: Health survey based on home interviews of a representative sample of the general population of Barcelona. PARTICIPANTS: In the years 1983, 1992, and 2000 we interviewed 3134, 5004, and 10,000 persons, respectively. MAIN OUTCOME MEASURES AND RESULTS: Between 1983 and 2000 daily tobacco use showed a steady tendency to decrease among men, with a prevalence that decreased from 54.6% to 38.3%, while in women, smoking increased between 1983 and 1992 (from 20.9% to 25.4%) but remained stable in 2000 (24.5%). The proportion of smokers who said they wanted to quit increased in both sexes from 1992 (54.2%) to 2000 (65.7%). During this period the proportion of smokers who said their doctor had advised them to quit increased from 36.1% to 48.1%. The trends for both sexes showed that consumption of tobacco products was greater among less privileged socioeconomic groups. CONCLUSIONS: The results of this study confirm the decrease in the prevalence of daily consumption of tobacco products and the increase in smokers who would like to quit, in parallel with the increase in advice from physicians to quit. However, the trends among younger groups remained stable, a finding that makes it necessary to intensify efforts aimed at this population group.

[Changing epidemiology of smoking: Barcelona, 2000-2001]. / La cambiante epidemiología del tabaquismo: Barcelona, 2000-2001.

CONTEXT: In recent years various initiatives of prevention and social changes have been carried out that should have an effect on epidemiology of smoking in our area. Their real effect is little known, however, because of methodological changes in the existing population surveys. In this work the data on smoking in the last city of Barcelona health survey (ESBA 2000-01) are analyzed, with reference to the cumulative information obtained along 18 years from the first survey in 1983. METHOD: ESBA 2000-01 is an interview health survey carried out on a weighted sample with 10,030 people. Data relative to tobacco use are showed for people 15-year-old or older included in the survey, stratified by age, sex, and class. Consumption context variables are also showed, and the tobacco consumption quitting among people who have smoked is analyzed. RESULTS: The proportion of daily smokers in the population over 14 years of age is 29 %, while that of former smokers is 21 % and 2.2 % in this population are occasional smokers. The prevalence is maximum in the 35-44 year-old group, and the prevalence is reduced drastically after this age. Stratified analysis by age, sex, and occupational category shows interesting differences among daily smokers. A strong gradient is observed according to occupational category in males. The situation is more complex in women. The typical smoker began when 17-year-old, and now consumes 16 cigarettes a day. Consumption is somewhat higher in males and is maximum in the 35-44 year-old group. Two-third of the smokers (65.7 %) want to quit smoking and more than one third (36 %) has attempted it along the last year. Almost half of smokers (48.1 %) have received advice to quit smoking from their physician. One of every four (24.9 %) smokers has been warned for smoking in some places. Almost half smokers are the only smoker in their home, and barely a third are the only smokers at work. The proportion of quitting increases with age in both sexes, and nowadays the differences in the probability of quitting smoking are few when the data are stratified by age groups. CONCLUSIONS: These results show the changing pattern of tobacco epidemiology in Barcelona: smoking is no longer the main behavior in no age and sex group, and the only social group in which more than half of its members smoke are 25-44 year-old not qualified worker males. This situation has occurred because of two processes: an important proportion of early quitting (demonstrated even in young adults) and a decrease in the beginning of the habit. Real differences are not observed between males and females with regard to the probability of quitting smoking. These data correct recent estimates that could be influenced by methodological changes in the instruments used.

[Trends in tobacco, alcohol and cannabis consumption among secondary school pupils in Barcelona, Spain (1987-1999)]. / Tendencias en el consumo de tabaco, alcohol y cannabis de los escolares de Barcelona (1987-1999).

OBJECTIVE: To describe trends in tobacco, alcohol, and cannabis consumption among secondary school pupils in Barcelona between 1987 and 1999. METHODS: Cross-sectional surveys administered to representative samples of pupils in the second year of secondary school between 1987 and 1999. The questionnaires were anonymous and self-completed. We present data from 5013 secondary school pupils from Barcelona who participated in one of the five surveys. RESULTS: Regular smoking (daily and weekly) showed a uniform decrease between 1987 and 1996. The results of the last survey (1999) showed an increase over those the 1996 survey, ranging from 13.4% for regular smoking to 38.7% for experimental smoking. Between 1987 and 1999, the percentage of schoolchildren who reported drinking at least half a glass of alcohol at some time showed an overall decrease of 14.0%. No differences in sex were found in problematic alcohol consumption, while a higher proportion of girls (14.0%) than boys (10.5%) reported getting drunk at some time. Whereas in 1996, 6.9% of the population studied had smoked cannabis at some time, in 1999 this proportion was 7.3%, with no differences between sexes. CONCLUSIONS: During the study period regular smoking increased, alcohol consumption decreased and cannabis consumption tended to level-off. Differences between boys and girls tended to disappear.

[Factors associated with smoking and the intention to smoke in secondary school pupils: results of the ESFA project in Barcelona, Spain]. / Factores asociados con la intención de fumar y el inicio del hábito tabáquico en escolares: resultados del estudio ESFA en Barcelona.

OBJECTIVE: To describe the factors asssociated with smoking and intention to smoke among a representative sample of first-grade pupils of secondary education (12-13 years old) in Barcelona. SUBJECTS AND METHODS: 37 secondary schools were randomly selected to evaluate the impact of a European-wide smoking prevention program (European Smoking prevention Frame Approach, ESFA project). In these schools, 1041 pupils of first grade of secondary education responded to a questionnaire designed at the University of Maastricht to study life-style attitudes and behaviours, mainly smoking. RESULTS: 9.8% of boys and 12.6% of girls declared to smoke either regulary or ocasionally. Among the no-smokers, 61.4% of the boys and 73.3% of the girls reported to have the intention to smoke in the future. Among the boys, factors associated with smoking included social norms (odds ratio [OR] = 2.5; 95% confidence interval [CI]: 1.2-5.2), smoking by siblings (OR = 2.4; 95% CI, 1.1-5.2), attitudes against smoking (OR = 0.3; 95% CI, 0.1-0.6), practicing some sports in the leisure time (OR = 0.3; 95% CI, 0.1-0.7) and having more available pocket money (OR = 3.2; 95% CI, 1.5-6.8). Intention to smoke was only related to attitudes (OR = 0.3; 95% CI, 0.2-0.5). Among girls, smoking was associated to perceived pressure to smoke (OR = 2.5; 95% CI, 1.2-5.0), consumption by friends (OR = 6.0; 95% CI, 2.4-15.4) and attitudes against smoking (OR = 0.2; 95% CI, 0.1-0.4), while intention was only associated to attitudes (OR = 0.4; 95% CI, 0.2-0.6) and hanging out in the street in the leisure time (OR = 2.2; 95% CI, 0.3-3.5). CONCLUSIONS: The results stress the need to deal simultaneoulsy with the different factors associated to smoking initiation and attitude shaping, including cognitive factors, environmental factors, and patterns of leisure time utilization.

Factores asociados con la intención de fumar y el inicio del hábito tabáquico en escolares: resultados del estudio ESFA en Barcelona / Factors associated with smoking and the intention to smoke in secondary school pupils: results of the ESFA project in Barcelona, Spain)

Objetivo: Describir los factores asociados con el consumo de tabaco y la intención de fumar en el futuro en una muestra representativa de escolares de primer curso de educación secundaria en Barcelona. Sujetos y métodos: Se seleccionaron 37 escuelas al azar para participar en la evaluación de un programa europeo de prevención del tabaquismo (European Smoking prevention Frame Approach, proyecto ESFA). En estas escuelas 1.041 alumnos de primer curso de Enseñanza Secundaria Obligatoria (ESO) contestaron a un cuestionario diseñado por la Universidad de Maastricht para estudiar las actitudes y conductas relacionadas con diversos comportamientos, incluyendo el consumo de tabaco. Resultados: El 9,8% de los chicos y el 12,6% de las chicas manifestaron fumar de forma regular u ocasional. Entre los no fumadores, un 61,4% de los chicos y un 73,3% de las chicas declararon tener intención de fumar en el futuro. En los chicos, los determinantes del consumo son la norma social (odds ratio [OR] = 2,5; intervalo de confianza [IC] del 95%, 1,2-5,2), el consumo de (..) (AU)

Objective: To describe the factors asssociated with smoking and intention to smoke among a representative sample of first-grade pupils of secondary education (12-13 years old) in Barcelona. Subjects and methods: 37 secondary schools were randomly selected to evaluate the impact of a European-wide smoking prevention program (European Smoking prevention Frame Approach, ESFA project). In these schools, 1041 pupils of first grade of secondary education responded to a questionnaire designed at the University of Maastricht to study life-style attitudes and behaviours, mainly smoking. Results: 9.8% of boys and 12.6% of girls declared to smoke either regulary or ocasionally. Among the no-smokers, 61.4% of the boys and 73.3% of the girls reported to have the intention to smoke in the future. Among the boys, factors associated with smoking (..) (AU)