Infant vaccinations and risk of childhood acute lymphoblastic leukaemia in the USA Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of bladder carcinoma Critical windows of exposure to household pesticides and risk of childhood leukemia. Th2-Associated Local Reactions to the Acellular Diphtheria-Tetanus-Pertussis Vaccine in 4- to 6-Year-Old Children Long-Lasting Effects of BCG Vaccination on Both Heterologous Th1/Th17 Responses and Innate Trained Immunity Risk indicators in childhood malignancies Efficacy of BCG vaccination in prevention of cancer: an update. Interleukin-6, C-Reactive Protein, and Abnormal Cardiorespiratory Responses to Immunization in Premature Infants Risk of childhood leukemia associated with vaccination, infection, and medication use in childhood: the Cross-Canada Childhood Leukemia Study. Vaccination and the risk of childhood acute leukaemia: the ESCALE study (SFCE). Risk of lymphoma and leukaemia after bacille Calmette-Guérin and smallpox vaccination: a Danish case-cohort study. BCG vaccination and the subsequent development of cancer in humans. BCG and vole bacillus vaccination in adolescence and mortality from leukaemia. Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of bladder carcinoma.
Summary Previous studies have suggested that infant vaccinations may reduce the risk of subsequent childhood leukaemia .  Vaccination histories were compared in 439 children ( ages 0–14 ) diagnosed with acute lymphoblastic leukaemia ( ALL ) in nine Midwestern and Mid-Atlantic states ( USA ) between 1 January 1989 and 30 June 1993 and 439 controls selected by r and om-digit dialing and individually matched to cases on age , race and telephone exchange . Among matched pairs , similar proportions of cases and controls had received at least one dose of oral poliovirus ( 98 % ) , diphtheria – tetanus – pertussis ( 97 % ) , and measles – mumps – rubella ( 90 % ) vaccines . Only 47 % of cases and 53 % of controls had received any  Haemophilus influenzae type b ( Hib ) vaccine  ( relative risk ( RR ) = 0.73 ; 95 % confidence interval ( CI ) 0.50–1.06 ) . Although similar proportions of cases ( 12 % ) and controls ( 11 % ) received the polysaccharide Hib vaccine ( RR = 1.13 ; 95 % CI 0.64–1.98 ) , more controls ( 41 % ) than cases ( 35 % ) received the conjugate Hib vaccine ( RR = 0.57 ; 95 % CI 0.36–0.89 ) . Although we found no relationship between most infant vaccinations and subsequent risk of childhood ALL , our findings suggest that infants receiving the conjugate Hib vaccine may be at reduced risk of subsequent childhood acute lymphoblastic leukemia . Further studies are needed to confirm this association and , if confirmed , to eluci date the underlying mechanism The st and ard of care for most patients with non-muscle-invasive bladder cancer ( NMIBC ) is immunotherapy with intravesical Bacillus Calmette-Guérin ( BCG ) , which activates the immune system to recognize and destroy malignant cells and has demonstrated durable clinical benefit . Urologic best- practice guidelines and consensus reports have been developed and strengthened based on data on the timing , dose , and duration of therapy from r and omized clinical trials , as well as by critical evaluation of criteria for progression . However , these reports have not penetrated the community , and many patients do not receive appropriate therapy . Additionally , several immune checkpoint inhibitors have recently been approved for treatment of metastatic disease . The approval of immune checkpoint blockade for patients with platinum-resistant or -ineligible metastatic bladder cancer has led to considerations of exp and ed use for both advanced and , potentially , localized disease . To address these issues and others surrounding the appropriate use of immunotherapy for the treatment of bladder cancer , the Society for Immunotherapy of Cancer ( SITC ) convened a Task Force of experts , including physicians , patient advocates , and nurses , to address issues related to patient selection , toxicity management , clinical endpoints , as well as the combination and sequencing of therapies . Following the st and ard approach established by the Society for other cancers , a systematic literature review and analysis of data , combined with consensus voting was used to generate guidelines . Here , we provide a consensus statement for the use of immunotherapy in patients with bladder cancer , with plans to up date these recommendations as the field progresses The potential etiologic role of household pesticide exposures was examined in the Northern California Childhood Leukemia Study . A total of 162 patients ( 0 - 14 years old ) with newly diagnosed leukemia were rapidly ascertained during 1995 - 1999 , and 162 matched control subjects were r and omly selected from the birth registry . The use of professional pest control services at any time from 1 year before birth to 3 years after was associated with a significantly increased risk of childhood leukemia [ odds ratio ( OR ) = 2.8 ; 95 % confidence interval ( CI ) , 1.4 - 5.7 ] , and the exposure during year 2 was associated with the highest risk ( OR = 3.6 ; 95 % CI , 1.6 - 8.3 ) . The ORs for exposure to insecticides during the 3 months before pregnancy , pregnancy , and years 1 , 2 , and 3 were 1.8 ( 95 % CI , 1.1 - 3.1 ) , 2.1 ( 95 % CI , 1.3 - 3.5 ) , 1.7 ( 95 % CI , 1.0 - 2.9 ) , 1.6 ( 95 % CI , 1.0 - 2.7 ) , and 1.2 ( 95 % CI , 0.7 - 2.1 ) , respectively . Insecticide exposures early in life appear to be more significant than later exposures , and the highest risk was observed for exposure during pregnancy . Additionally , more frequent exposure to insecticides was associated with a higher risk . In contrast to insecticides , the association between herbicides and leukemia was weak and nonsignificant . Pesticides were also grouped based on where they were applied . Exposure to indoor pesticides was associated with an increased risk , whereas no significant association was observed for exposure to outdoor pesticides . The findings suggest that exposure to household pesticides is associated with an elevated risk of childhood leukemia and further indicate the importance of the timing and location of exposure ABSTRACT Acellular vaccines against diphtheria-tetanus-pertussis ( acellular pertussis ) ( DTaP ) are being progressively introduced into vaccination programs worldwide , with the aim of reducing T-helper 1 (Th1)-associated reactogenicity associated with the cellular diphtheria-tetanus-pertussis ( whole-cell pertussis ) ( DTwP ) vaccine . The DTaP vaccine has an improved safety profile in infants , but little information is available concerning the nature of the ensuing immunological memory in older children and how this may affect the reactogenicity of DTaP booster doses . We have addressed this question in the present study by assessing polyclonal and vaccine antigen-specific humoral and cellular immune responses to boosting with DTaP in 4- to 6-year-old children primed during infancy with DTaP ( n = 30 ) or DTwP ( n = 16 ) and by correlating these parameters , in particular cytokine responses , with expression of local side effects at the injection site . Large local reactions ( ≥50-mm diameter ) 24 to 72 h after receiving the DTaP booster occurred in 43 % of exclusively DTaP-primed children , in contrast to 6 % of children primed with DTwP. These reactions were associated with vigorous T helper 2 (Th2)-polarized memory responses to vaccine antigen exemplified by interleukin 5 ( IL-5 ) , IL-6 , and IL-13 production and log-scale boosting of tetanus-specific immunoglobulin E and occurred most frequently among children who are intrinsically “ high Th2 responders ” as detected by in vitro responsiveness to polyclonal mitogen . Our findings suggest that priming during infancy with DTaP  promotes stable , boostable Th2-polarized immunity against vaccine antigens , which in a significant subset of children is subsequently associated with local reactions at the booster site . The time course of these reactions suggests that the underlying mechanism involves reactivation of Th2-polarized cellular immune memory We have recently shown that BCG ( Bacillus Calmette-Guérin ) vaccination  in healthy volunteers induces epigenetic reprogramming of monocytes , leading to increased cytokine production in response to nonrelated pathogens for up to 3 months after vaccination . This phenomenon was named ‘ trained immunity ' . In the present study we assessed whether BCG was able to induce long-lasting effects on both trained immunity and heterologous T helper 1 ( Th1 ) and Th17 immune responses 1 year after vaccination . The production of TNFα and IL-1β to mycobacteria or unrelated pathogens was higher after 2 weeks and 3 months postvaccination , but these effects were less pronounced 1 year after vaccination . However , monocytes recovered 1 year after vaccination had an increased expression of pattern recognition receptors such as CD14 , Toll-like receptor 4 ( TLR4 ) and mannose receptor , and this correlated with an increase in proinflammatory cytokine production after stimulation with the TLR4 lig and lipopolysaccharide . The heterologous production of Th1 ( IFN-γ ) and Th17 ( IL-17 and IL-22 ) immune responses to nonmycobacterial stimulation remained strongly elevated even 1 year after BCG vaccination . In conclusion , BCG induces sustained changes in the immune system associated with a nonspecific response to infections both at the level of innate trained immunity and at the level of heterologous Th1/Th17 responses A series of 972 childhood malignancies was compared with a control series of healthy children matched for date and place of birth . Several variables were tested for possible aetiological significance . The information was obtained from the Finnish Cancer Registry and from the antenatal records of the mothers . No significant associations were found between the various types of malignancies and the variables studied . In the group consisting of all malignancies , a risk ratio of 2.0 could be significantly excluded for most variables . In the leukaemia group , both pelvic X‐ray and polio vaccination were associated with slightly elevated risk ratios , but the differences between this group and the matched controls were not statistically significant . BCG vaccination was performed during the perinatal period in 90 % of the children , but the proportion was the same in the study and control groups , and hence the hypothesis that this vaccination confers protection was not supported . The information is considered prospect i ve and relatively reliable , and the authors suggest that these data may be useful when more extensive series are compiled from various sources From 1949 to 1951 , a controlled trial of BCG vaccinations was conducted in Puerto Rico . The 191,827 children , 1 - 18 years of age , initially enrolled in the study were skin-tested with tuberculin to determine their eligibility for vaccination . A total of 82,269 children were classified as reactors and not vaccinated . Of the 109 , 558 nonreactors , 31,586 refused vaccination  , 50,634 were vaccinated with BCG  , and 27,338 were left unvaccinated as controls . We ascertained the incidence of cancer over an average follow-up period of 23.3 years in the latter two groups using the Puerto Rico Central Cancer Registry . By the end of December 1973 , a total of 77 cancers had been diagnosed among the controls and 150 among the vaccinees . The overall incidence of cancer among the two groups was similar . Although a number of differences existed between the vaccinee group and the controls in regard to the incidence of cancer at various " sites " , none of these differences was statistically significant . However , when cases of lymphosarcoma and Hodgkin 's disease were combined for analysis , a statistically significant excess of cases occurred among the vaccinees . We concluded that BCG vaccination had no protective effect on the subsequent development of cancer in this population . The slight excess of cases of lymphosarcoma and Hodgkin 's disease among the vaccinees raised the possibility that BCG may have had an adverse effect Objective . We report our experience with routine immunization of 89 premature infants in the neonatal intensive care unit because 1 ) a substantial number of them developed abnormal clinical signs , and 2 ) all but one of those who received diphtheria , tetanus , and whole-cell pertussis ( DTwP ) vaccine  responded with elevations of interleukin-6 ( IL-6 ) and C-reactive protein ( CRP ) concentrations that are otherwise characteristic of bacterial disease . Methodology . We hypothesized that the elevated IL-6 and CRP levels were solely a response to immunization and that treatment with antibiotics was not necessary . We performed this study in two consecutive parts . In part 1 , we prospect ively evaluated 79 consecutive premature infants who were immunized with DTwP , Haemophilusb conjugate vaccine , hepatitis B vaccine , and inactivated polio vaccine , ( Hib , HBV , and IPV ) .  IL-6 and CRP were determined before immunization and every 12 hours on three occasions after immunization . In part 2 , we studied an additional 10 infants who received acellular pertussis vaccine ( DTaP ) and who , 2 days later ,  received Hib , HBV , and IPV immunization simultaneously .  We followed the same schedule of IL-6 and CRP determinations as in part 1 . Results . In part 1 , 24 infants ( 30 % ) developed abnormal cardiorespiratory signs within 24 hours after immunization . CRP and IL-6 values rose to abnormal levels after immunization in all but one infant ; that infant was later shown to have a T-cell abnormality . In part 2 , 3 infants had abnormal cardiorespiratory signs after simultaneous immunization with Hib , HBV , and IPV , but not after DTaP. IL-6 and CRP levels remained normal in all 10 infants . Conclusions . Part 1 demonstrates clearly the temporal relationship between IL-6 and CRP increments after DTwP , Hib , HBV , and IPV vaccines . In part 2 ( DTaP was substituted for DTwP ) , there were no elevations of IL-6 or CRP , thus indicating that whole-cell pertussis component of DTwP was responsible for IL-6 and CRP elevations . Abnormal cardiorespiratory signs occurred frequently after immunizations in part 1 , but they were unrelated to the magnitude of IL-6 and CRP elevations . The frequency of cardiorespiratory difficulty and its occasional severity suggest a need to monitor premature infants for ∼48 hours after routine immunization Current hypotheses consonant with the peak in leukemia incidence in early childhood point to an infectious etiology . The authors examined the effect of postnatal exposures predicted to affect early immune functioning , including childhood vaccinations , illness , medication use , and breastfeeding patterns . Children 0 - 15 years of age diagnosed with leukemia from 1990 to 1994 and resident within principal cities across Canada were eligible for inclusion . Through pediatric oncology centers and population -based cancer registries , 399 cases were ascertained at the time of diagnosis . For each participating case , an age- , gender- , and area-matched control was r and omly selected from government health insurance rolls . Risk factor information was obtained through personal interviews with each child 's parents or guardians . Conditional logistic regression was used to calculate odds ratios , with adjustment for potential confounders . Use of immunosuppressant medication by the index child led to a deficit of risk ( odds ratio = 0.37 , 95 % confidence interval : 0.16 , 0.84 ) , while vitamin intake was positively associated with leukemia ( odds ratio = 1.66 , 95 % confidence interval : 1.18 , 2.33 ) . Breastfeeding for more than 6 months was also protective ( p < 0.05 ) . Results persisted for cases diagnosed with acute lymphoblastic leukemia and for children diagnosed at 1 - 5 years of age . These findings suggest a role for early immunologic challenge in the expression of childhood leukemia BACKGROUND In 2002 , a poster alerted the French health authorities to the possibility that the risk of childhood leukaemia might be increased by hepatitis B vaccination . Elucidating the role of vaccination in the aetiology of childhood acute leukaemia ( AL ) was therefore included in the objectives of an ongoing national study . METHODS The ESCALE study was a French national population -based case-control study conducted in France in 2003 and 2004 in order to investigate the role of infectious , environmental and genetic factors in four childhood neoplastic diseases ( leukaemia , lymphoma , neuroblastoma and brain tumour ) . The controls were r and omly selected from the French population and age and gender frequency matched with the cases . A total of 776 cases of AL ( 91 % of the eligible cases ) and 1681 controls ( 71 % of the eligible controls ) were included . In a specific st and ardized telephone interview , which was the same for both the cases and controls , each mother was asked to read out her child 's complete vaccination record . RESULTS No association between vaccination and the risk of childhood AL : acute lymphoblastic leukaemia or acute myeloblastic leukaemia was observed . No relationship between the risk of leukaemia and the type of vaccine , number of doses of each vaccine , total number of injections , total number of vaccine doses or number of early vaccinations was evidence d. No confounding factor was observed . CONCLUSION The study did not show any evidence of a role of vaccination in the aetiology of childhood leukaemia Vaccines may have non-specific effects as suggested mainly in mortality studies from low-income countries . The objective was to examine the effects of BCG and smallpox vaccinations on subsequent risk of lymphoma and leukaemia in a Danish population experiencing rapid out-phasing of these vaccines . In a background cohort ( N=47,622 ) from the Copenhagen School Health Records Register , cases of leukaemia ( N=20 ) and lymphoma ( N=51 ) were identified through the Danish Cancer Registry . The vaccination status of the cases was compared with the vaccination status of a 5 % r and om sample ( N=2073 ) of the background cohort and analysed in a case-cohort design . BCG vaccination reduced the risk of lymphomas ( HR=0.49 ( 95 % CI : 0.26 - 0.93 ) ) , whereas smallpox vaccination did not ( HR=1.32 ( 0.56 - 3.08 ) ) . With the small number of leukaemia cases , the analysis of leukaemia had limited power ( BCG vaccination HR=0.81 ( 0.31 - 2.16 ) ; smallpox vaccination HR=1.32 ( 0.49 - 3.53 ) ) . The present study with very reliable vaccine history information indicates a beneficial effect of BCG vaccination on the risk of lymphomas In 1950 approximately one-half of the population of Muscogee County , Georgia , and Russell County , Alabama , who were over the age of 5 years took part in a tuberculosis survey that included a controlled trial of BCG vaccination .  A total of 16,913 persons were classed as vaccinees and 17,854 as controls .  By the end of 1977 , nearly 28 years later , 423 controls and 429 vaccinees were known to have developed cancer . Inasmuch as only 379 cancer cases were expected among vaccinees , there was no indication of any general protective effect of BCG vaccination against cancer . There were 18 sites with 5 or more cancers among controls and vaccinees and with observed/expected ratios greater than 1.49 or less than 0.68 . Fewer cancers among vaccinees than expected were found for only 6 of these 18 sites . Among the sites with excessive cases among vaccinees was the lymphoma-Hodgkin 's disease-leukemia group [ International Classification of Diseases ( Eighth Revision ) codes 200 - 202 , 204 - 207 ] , a group suspected from previous studies of occurring more frequently after BCG vaccination In total , 28 deaths from leukaemia are known to have occurred among the 54,239 participants in the Medical Research Council tuberculosis vaccines trial ( initially aged about 14 years ) , from its beginning in 1950 to the end of 1979 . There is evidence that this total is likely to be very nearly complete . During the entire period ( average 27.1 years ) the leukaemia mortality per million person-years was 25 in the BCG vaccinated group , 20 in the vole-bacillus vaccinated group , and 21 in the r and omly-allocated unvaccinated ( control ) group . Although there was neither a benefit nor a disadvantage from vaccination over the whole period , detailed figures suggested that there may have been a beneficial effect against leukaemia during the first 15 years after entry ( that is between age 15 and 30 years ) and a deleterious effect after longer intervals ( or above the age of 30 years ) . Alternatively this swing may simply represent an unusual chance fluctuation . There has been no sign in recent years of any substantial decrease in leukaemia mortality in Engl and and Wales at ages 15 - 29 years , although the proportion of children given  BCG vaccine  at about age 13 years has risen from less than 1 per cent ( for the cohort aged 15 - 19 years in 1951 - 1955 ) to more than 70 per cent 25 years later . It has therefore been provisionally concluded that chance is the explanation for the apparent swing from prevention to enhancement , and that BCG vaccination at age 13 - 14 years in Great Britain does not affect subsequent mortality from leukaemia The st and ard of care for most patients with non-muscle-invasive bladder cancer ( NMIBC ) is immunotherapy with intravesical Bacillus Calmette-Guérin ( BCG ) , which activates the immune system to recognize and destroy malignant cells and has demonstrated durable clinical benefit . Urologic best- practice guidelines and consensus reports have been developed and strengthened based on data on the timing , dose , and duration of therapy from r and omized clinical trials , as well as by critical evaluation of criteria for progression . However , these reports have not penetrated the community , and many patients do not receive appropriate therapy . Additionally , several immune checkpoint inhibitors have recently been approved for treatment of metastatic disease . The approval of immune checkpoint blockade for patients with platinum-resistant or -ineligible metastatic bladder cancer has led to considerations of exp and ed use for both advanced and , potentially , localized disease . To address these issues and others surrounding the appropriate use of immunotherapy for the treatment of bladder cancer , the Society for Immunotherapy of Cancer ( SITC ) convened a Task Force of experts , including physicians , patient advocates , and nurses , to address issues related to patient selection , toxicity management , clinical endpoints , as well as the combination and sequencing of therapies . Following the st and ard approach established by the Society for other cancers , a systematic literature review and analysis of data , combined with consensus voting was used to generate guidelines . Here , we provide a consensus statement for the use of immunotherapy in patients with bladder cancer , with plans to up date these recommendations as the field progresses
Leukemia is the most commonly diagnosed childhood cancer , although its etiology is still largely unknown .
Growing evidence supports a role for infection in the etiology of acute lymphocytic leukemia ( ALL ) , and the involvement of the immune system suggests that vaccination may also play a role .
However , the findings presented in the published literature are inconsistent .