Craig D. Higgins

Risk of cancer in patients treated with human pituitary growth hormone in the UK, 1959–85: a cohort study

BACKGROUND Growth hormone raises serum concentrations of insulin-like growth factor IGF-I, which is mitogenic and antiapoptotic. There is evidence that raised endogenous levels of growth hormone and IGF-I might be associated with increased risk of certain solid cancers, but there have been no data on long-term risks of solid cancers after growth hormone treatment. METHODS We did a cohort study to investigate cancer incidence and mortality in 1848 patients in the UK who were treated during childhood and early adulthood with human pituitary growth hormone during the period from 1959 to 1985. Patients were followed up for cancer incidence to December, 1995 and for mortality to December, 2000. Risk of cancer in the cohort was compared with that in the general population, controlling for age, sex, and calendar period. FINDINGS Patients treated with human pituitary growth hormone had significantly raised risks of mortality from cancer overall (standardised mortality ratio 2.8, 95% CI 1.3-5.1; ten cases), colorectal cancer (10.8, 1.3-38.8; two cases), and Hodgkins disease (11.4, 1.4-41.3; two cases). Incidence of colorectal cancer was also greatly raised (7.9, 1.0-28.7). After exclusion of patients whose original diagnosis rendered them at high risk of cancer, the significance and size of the risks of colorectal cancer incidence and mortality, and of Hodgkins disease mortality were increased. INTERPRETATION Although based on small numbers, the risk of colorectal cancer is of some concern and further investigation in other cohorts is needed. We have no evidence as to whether growth hormone in modern dosage regimens is associated with an increased risk of colorectal cancer.

Mortality in Women with Turner Syndrome in Great Britain: A National Cohort Study

CONTEXT Turner syndrome is characterized by complete or partial X chromosome monosomy. It is associated with substantial morbidity, but mortality risks and causes of death are not well described. OBJECTIVES Our objective was to investigate mortality and causes of death in women with Turner syndrome. DESIGN AND SETTING We constructed a cohort of women diagnosed with Turner syndrome at almost all cytogenetic centers in Great Britain and followed them for mortality. PATIENTS A total of 3,439 women diagnosed between 1959-2002 were followed to the end of 2006. OUTCOME MEASURES Standardized mortality ratios (SMRs) and absolute excess risks were evaluated. RESULTS In total, 296 deaths occurred. Mortality was significantly raised overall [SMR = 3.0; 95% confidence interval (CI) = 2.7-3.4] and was raised for nearly all major causes of death. Circulatory disease accounted for 41% of excess mortality, with greatest SMRs for aortic aneurysm (SMR = 23.6; 95% CI = 13.8-37.8) and aortic valve disease (SMR = 17.9; 95% CI = 4.9-46.0), but SMRs were also raised for other circulatory conditions. Other major contributors to raised mortality included congenital cardiac anomalies, diabetes, epilepsy, liver disease, noninfectious enteritis and colitis, renal and ureteric disease, and pneumonia. Absolute excess risks of death were considerably greater at older than younger ages. CONCLUSIONS Mortality in women with Turner syndrome is 3-fold higher than in the general population, is raised for almost all major causes of death, and is raised at all ages, with the greatest excess mortality in older adulthood. These risks need consideration in follow-up and counseling of patients and add to reasons for continued follow-up and preventive measures in adult, not just pediatric, care.

Risk of Second Malignancy After Non-Hodgkin's Lymphoma: A British Cohort Study

PURPOSE To assess long-term site-specific risks of second malignancy following non-Hodgkins lymphoma (NHL) in relation to treatment and demographic factors. PATIENTS AND METHODS A cohort of 2,456 patients with NHL who were first treated from 1973 to 2000 and were younger than 60 years from centers in the British National Lymphoma Investigation were observed, and occurrences of second malignancy was compared with expectations based on general population cancer rates in England and Wales. RESULTS In total, 123 second malignancies occurred. Relative risks (RRs) were significantly elevated for all malignancies combined (RR = 1.3; 95% CI, 1.1 to 1.6) and for leukemia (RR = 8.8; 95% CI, 5.1 to 14.1) and lung cancer (RR = 1.6; 95% CI, 1.1 to 2.3). RRs of malignancy overall diminished significantly with increasing age at first treatment. Leukemia risk was significantly increased after chemotherapy (RR = 10.5; 95% CI, 5.0 to 19.3) and mixed-modality treatment (RR = 13.0; 95% CI, 5.2 to 26.7). Relative risks of lung (RR = 1.9; 95% CI, 1.1 to 3.1) and colorectal (RR = 2.1; 95% CI, 1.1 to 3.6) cancers were significantly raised following chemotherapy. CONCLUSION NHL patients are at elevated risk of developing second malignancy, particularly leukemia and lung cancer. The relative risk is greater with patients who are younger at first treatment. Chemotherapy predisposes patients toan increased risk of leukemia, and possibly lung and colorectal cancers. The role of specific drug treatments in the etiology of solid cancers after NHL deserves further investigation.

The immune response to primary EBV infection: a role for natural killer cells

The role of antigen‐specific CD3+CD8+ cytotoxic T cells in the control of primary Epstein–Barr Virus (EBV) infection is well established. However, time is required for the antigen‐specific immune response to develop and expand. In contrast, innate immune responses, such as natural killer (NK) cells, are considered vital early in the infection process. We analysed the scale, phenotype and function of the NK cell response during symptomatic primary EBV infection, infectious mononucleosis (IM) and showed that NK cell numbers were significantly elevated both at diagnosis of IM and in the first month following diagnosis. There were also significant changes in cell phenotype and function, an increase in the proportion of CD56bright cells at diagnosis, and freshly isolated cells showing an enhanced ability to kill EBV‐infected cell lines. Moreover, in our cohort of IM patients higher NK cell counts were associated with significantly lower viral load in peripheral blood. Our results suggest NK cells have an important role in the control of primary EBV infection by eliminating infected B cells and augmenting the antigen‐specific T cell response via release of immunomodulatory cytokines. The magnitude of the NK cell response may ultimately determine whether primary EBV infection has a clinical outcome.

Cancer incidence in women with Turner syndrome in Great Britain: a national cohort study

BACKGROUND Turner syndrome, one of the most common cytogenetic abnormalities, is characterised by complete or partial X-chromosome monosomy. Cancer risks in women with Turner syndrome have not been clearly established. We aimed to compare the risk of cancer in women with this syndrome with that of the general population. METHODS We formed a national cohort of 3425 women who were cytogenetically diagnosed with Turner syndrome in Great Britain between 1959 and 2002. Identifying information for these patients was sent to the National Health Service Central Register (NHSCR) for England and Wales and to the NHSCR for Scotland. Individuals who were identified on this register were followed-up for cancer incidence. Standardised incidence ratios (SIRs) and 95% CIs were calculated on the basis of the number of cancers observed compared with that expected based on national incidence rates. Cumulative risk estimates were obtained by use of the Kaplan-Meier method. FINDINGS A total of 58,299 person-years were accrued during the study, with a mean of 17.0 years (SD 8.6) follow-up per patient. 73 malignancies other than non-melanoma skin cancer occurred (SIR 0.9 [95% CI 0.7-1.2]). Risks were significantly increased for tumours of the CNS (n=13; 4.3 [2.3-7.4]), especially for meningioma (n=7; 12.0 [4.8-24.8]) and childhood brain tumours (n=3; 10.3 [2.1-30.1]), and for cancers of the bladder and urethra (n=5; 4.0 [1.3-9.2]) and eye (n=2; 10.5 [1.3-37.9]), compared with the general population. However, the risk of breast cancer was significantly decreased (n=10; 0.3 [0.2-0.6]). The SIR for cutaneous melanoma was 2.2 (95% CI 1.0-4.4; n=8), and one of the ocular cancers was a melanoma. The risk of corpus uteri cancer was significantly increased at ages 15-44 years (n=3; 8.0 [1.6-23.2]). During follow-up, five women, all with a Y-chromosome lineage, developed gonadoblastoma of the ovary, corresponding to a cumulative risk of 7.9% (95% CI 3.1-19.0) by age 25 years in this group. INTERPRETATION This study shows that, in addition to having an increased risk of gonadoblastoma, women with Turner syndrome seem to be at increased risk for meningioma and childhood brain tumours, and possibly bladder cancer, melanoma, and corpus uteri cancer, but are at a decreased risk for breast cancer. Reasons for these risks might relate to genetic and hormonal factors or to the effects of hormonal treatments given to women with Turner syndrome.

Second Cancer Risk After Chemotherapy for Hodgkin's Lymphoma: A Collaborative British Cohort Study

PURPOSE We investigated the long-term risk of second primary malignancy after chemotherapy for Hodgkins lymphoma (HL) in a much larger cohort than any yet published, to our knowledge. PATIENTS AND METHODS We followed 5,798 patients with HL treated with chemotherapy in Britain from 1963 to 2001--of whom 3,432 also received radiotherapy--to assess second primary malignancy risks compared with general population-based expectations. RESULTS Second malignancies occurred in 459 cohort members. Relative risk (RR) of second cancer was raised after chemotherapy alone (RR, 2.0; 95% CI, 1.7 to 2.4) but was much lower than after combined modalities (RR, 3.9; 95% CI, 3.5 to 4.4). After chemotherapy alone, there were significantly raised risks of lung cancer, non-HL, and leukemia, each contributing approximately equal absolute excess risk. After combined modalities, there were raised risks of these and several other cancers. Second cancer risk peaked 5 to 9 years after chemotherapy alone, but it remained raised for 25 years and longer after combined modalities. Risk was raised after each common chemotherapy regimen except, based on limited numbers and follow-up, adriamycin, bleomycin, vinblastine, and dacarbazine. The age and time-course relations of lung cancer differed between chemotherapy alone and combined modalities. CONCLUSION Although chemotherapy alone leads to raised risk of second malignancy, this risk is lower and affects fewer anatomic sites than that after combined modalities, and it is slight if at all after 15 years follow-up. The mechanism of lung cancer etiology may differ between chemotherapy and radiotherapy.

HLA class I polymorphisms are associated with development of infectious mononucleosis upon primary EBV infection

Infectious mononucleosis (IM) is an immunopathological disease caused by EBV that occurs in young adults and is a risk factor for Hodgkin lymphoma (HL). An association between EBV-positive HL and genetic markers in the HLA class I locus has been identified, indicating that genetic differences in the HLA class I locus may alter disease phenotypes associated with EBV infection. To further determine whether HLA class I alleles may affect development of EBV-associated diseases, we analyzed 2 microsatellite markers and 2 SNPs located near the HLA class I locus in patients with acute IM and in asymptomatic EBV-seropositive and -seronegative individuals. Alleles of both microsatellite markers were significantly associated with development of IM. Specific alleles of the 2 SNPs were also significantly more frequent in patients with IM than in EBV-seronegative individuals. IM patients possessing the associated microsatellite allele had fewer lymphocytes and increased neutrophils relative to IM patients lacking the allele. These patients also displayed higher EBV titers and milder IM symptoms. The results of this study indicate that HLA class I polymorphisms may predispose patients to development of IM upon primary EBV infection, suggesting that genetic variation in T cell responses can influence the nature of primary EBV infection and the level of viral persistence.

Sexual History and Epstein-Barr Virus Infection

To determine the role of sexual contact in transmission of Epstein-Barr virus (EBV) and occurrence of infectious mononucleosis (IM), a cross-sectional study was undertaken of EBV serologic testing and histories of IM and sexual behavior among 1006 new students at Edinburgh University. Prevalence of EBV seropositivity was significantly greater among women (79.2%) than among men (67.4%; P<.001) and among those who had ever been sexually active (82.7%) than among those who had not (63.7%; P<.001). Having a greater number of sex partners was a highly significant risk factor for EBV seropositivity. Two thirds of IM cases, but only a tenth of asymptomatic primary EBV infections, were statistically attributable to sexual intercourse. The findings suggest that EBV transmission occurs during sexual intercourse or closely associated behaviors. Transmission in this way appears to account for most cases of IM but for only a minority of cases of asymptomatic EBV infection, which mainly occur at younger ages.

Combined Analysis of Mortality in Three United Kingdom Nuclear Industry Workforces, 1946-1988

Mortality during 1946-1988 has been analyzed in 75,006 employees of the United Kingdom Atomic Energy Authority, the Atomic Weapons Establishment and the Sellafield plant of British Nuclear Fuels. All-cause mortality was 19% lower than national rates among workers monitored for external radiation exposure and 18% lower among nonmonitored workers. Cancer mortality was also lower than national rates and was similar in the two groups of workers [rate ratio (RR) = 0.96]. Of 29 specific cancer sites examined, only for cancers of the pleura and uterus were there statistically significant excesses of mortality in monitored workers relative to nonmonitored workers [RR = 7.08, two-sided P (2P) = 0.008 and RR = 3.02, 2P = 0.003, respectively]. There was little association between cumulative external radiation and risk of death from all cancers combined 10 or more years after exposure [z for trend = +0.11, one-sided P (1P) = 0.5]. A positive association was observed for leukemia (assuming a 2-year lag between external radiation and increasing risk of death) (1P = 0.009) but not for other cancers associated with external radiation in previous analyses (lung, uterus, prostate and multiple myeloma, all 1P > or = 0.1). Positive associations (1P < or = 0.05) were also observed for melanoma and other skin cancers (1P = 0.03) and ill-defined and secondary cancers (1P = 0.04), but these results are difficult to interpret and, given the number of associations examined, may be chance findings. Estimates of excess relative risk per sievert were -0.02 (95% CI = -0.5-+0.6) for all cancers except leukemia and +4.18 for leukemia (95% CI = +0.4-+13.4). The positive estimates for leukemia contrast with negative values found for workers in the United States, although the confidence intervals obtained in the two studies overlap. While our estimates of risk are compatible with those derived from studies of A-bomb survivors, the statistical uncertainty associated with them is such that the data are consistent with risks ranging from no additional risk to twice the risk for cancers other than leukemia and, for leukemia, from one-fifth to three times the risk in A-bomb survivors.

Analysis of Immune Activation and Clinical Events in Acute Infectious Mononucleosis

The symptoms of infectious mononucleosis (IM) are thought to be caused by T cell activation and cytokine production. Surface lymphocyte activation marker (SLAM)-associated protein (SAP) regulates lymphocyte activation via signals from cell-surface CD244 (2B4) and SLAM (CD150). We followed T cell activation via this SAP/SLAM/CD244 pathway in IM and analyzed whether the results were associated with clinical severity. At diagnosis, SAP, SLAM, and CD244 were significantly up-regulated on CD4 and CD8 T cells; expression decreased during IM, but CD244 and SLAM levels remained higher on CD8 cells 40 days later. There were significantly more lymphocytes expressing CD8 and CD244/CD8 in patients with severe sore throat. The expression of CD8 alone and CD244 on CD8 cells correlated with increased virus load. We suggest that T cells expressing CD244 and SLAM are responsible for the clinical features of IM but that the control of activation is maintained by parallel increased expression of SAP.