High diversity of non-human leukocyte antigens in transplant-associated coronary artery disease

BACKGROUND: Antibodies to endothelial derived non-human leukocyte antigens (HLA) have been associated with transplant (Tx)-associated coronary artery disease (CAD) after cardiac transplantation; however, few have been identified. The aim of this study was to screen a human coronary artery endothelial cell cDNA library with patient sera to establish the diversity and nature of the target antigens. METHODS: A human coronary artery endothelial cell cDNA library was screened with sera from seven long-term cardiac transplant patients with angiographically diagnosed TxCAD and sera from five healthy volunteers. RESULTS: Of the seven patients' sera, five showed reactivity, as did sera from two of the five normal subjects. Eighteen positive cDNA clones were isolated by TxCAD sera; DNA sequence analysis and DNA database searching identified all but one clone; 16 were nuclear or cytoplasmic proteins and 1 of them was the cell surface protein neuropilin 2. Five clones were targeted by normal sera. A different spectrum of reactive clones was identified by the sera of each patient where reactive clones were evident. CONCLUSIONS: A high diversity of non-HLA antigens, probably autoantigens, are involved in the pathogenesis of TxCAD.     

HPV infection and number of lifetime sexual partners are strong predictors for 'natural' regression of CIN 2 and 3

The aim of this paper was to evaluate the factors that predict regression of untreated CIN 2 and 3. A total of 93 patients with colposcopic persistent CIN 2 and 3 lesions after biopsy were followed for 6 months. Human papillomavirus (HPV) types were determined by polymerase chain reaction at enrolment. We analysed the biologic and demographic predictors of natural regression using univariate and multivariate methods. The overall regression rate was 52% (48 out of 93), including 58% (22 out of 38) of CIN 2 and 47% (26 out of 55) of CIN 3 lesions (P=0.31 for difference). Human papillomavirus was detected in 84% (78 out of 93) of patients. In univariate analysis, 80% (12 out of 15) of lesions without HPV regressed compared to 46% (36 out of 78) of lesions with HPV infection (P=0.016). Women without HPV and those who had a resolution of HPV had a four-fold higher chance of regression than those with persistent HPV (relative odds=3.5, 95% CI=1.4-8.6). Women with five or fewer lifetime sexual partners had higher rates of regression than women with more than five partners (P=0.003). In multivariate analysis, HPV status and number of sexual partners remained as significant independent predictors of regression. In conclusion, HPV status and number of lifetime sexual partners were strongly predictive of regression of untreated CIN 2 and 3.     

Human papillomavirus positivity predicts favourable outcome for squamous carcinoma of the tonsil

Mutations in the p53 and retinoblastoma (pRb) pathways associated with the use of tobacco and alcohol are common in squamous cell carcinoma (SCC) of the head and neck. Cell cycle proteins are also affected by human papillomavirus (HPV), which may also have an aetiological role in cancers at particular sites, most notably the tonsil. Attempts to identify prognostic molecular markers in head and neck cancers have met with conflicting results, but few studies have been undertaken with tumours of known HPV status at a single anatomic site. In our study 86 tonsil cancers were analysed for HPV status by sequence analysis of polymerase chain reaction products and for the expression of cell cycle proteins (p53, p21(CIP1/WAF1), pRb, p16(INK4A), cyclin D1 and p27(KIP1)) by immunohistochemistry. The HPV status could be established in 67 of the tumours. Thirty-one (46%) of these were HPV-positive, predominantly (28/31) for HPV16. Findings were related to tumour recurrence and patient survival. None of the cell cycle proteins independently predicted recurrence or survival. Patients with HPV-positive tumours, however, were significantly less likely (p < 0.05) to have recurrence or to die of disease than those with HPV-negative tumours, after adjusting for the effects of the cell cycle proteins, clinical stage, pathological node status, tumour grade, age, gender and treatment. These findings support the concept that HPV-positive tonsil cancers may be a distinct biological group with less aggressive characteristics. Screening of tonsil cancers for HPV DNA may help optimise treatment and provide more accurate prognostic information.     

Prognostic factors in Waldenstrom's macroglobulinemia: description of the complications during the evolution-preliminary results on 101 patients

Data on clinical features observed in patients with Waldenstrom's macroglobulinemia (WM) during follow-up remain limited. Therefore, we evaluated 860 follow-up procedures in 101 patients. Median age was 66 years and 5-year overall survival 72%, with a median follow-up of 36 months in surviving patients. Sixteen patients presented at diagnosis with two or three cytopenias lasting for at least 3 months (multiple cytopenias [MC]), and MC improved after treatment in eight patients, 4 to 18 months later. MC was observed during at least 6 consecutive months in 23 other patients, 2 to 73 months (median, 24) after diagnosis. MC occurred off-therapy in 12 patients, and on-therapy in 11. Regression occurred in three of the former patients, and in seven of the latter (6 to 24 months after completion of treatment; median, 7). Finally, the 4-year estimated cause-specific cumulative incidence was 40% in the 101 patients. A second malignancy was observed in 11 patients, histological transformation in three, and rapid rise of M-component in only six patients. In conclusion, the present analysis pointed out a high incidence of long lasting MC during the evolution of WM, and a low frequency of rapid rise of M component.     

Survival and functional outcome of children with hypothalamic/chiasmatic tumors

BACKGROUND: The management of children with hypothalamic (H) and/or chiasmatic (C) tumors remains controversial. We evaluated the impact of clinical and neuroimaging parameters and primary therapy on overall (OS) and progression-free (PFS) survival and on neuroendocrine and neurocognitive outcome in children with H and/or C tumors. METHODS: Records were reviewed for 73 children with H and/or C tumors treated at St. Jude Children's Research Hospital between October 1981 and December 1999. RESULTS: Thirty-six patients received irradiation or chemotherapy immediately postdiagnosis and 37 were observed. The 6-year OS and PFS rates were 86 +/- 5%; and 36 +/- 7%, respectively. The 6-year PFS rates for the irradiation, chemotherapy, and observation groups were 69 +/- 16%, 12 +/- 11%, and 37 +/- 9%, respectively. In multivariate analysis, intracranial NF1 lesions (P = 0.015) and initial irradiation (P = 0.056) led to better PFS rates. There was no difference in OS between those initially treated or observed. Mean serial intelligence quotient (IQ) scores were 86 and 86 at diagnosis and at 6 years later, respectively. Patients younger than 5 years old had a lower mean IQ score at diagnosis (79.1) than older patients (96.3; P = 0.003). Patients who were irradiated at diagnosis had a significantly higher cumulative incidence of endocrinopathy at 3 years (P = 0.008). CONCLUSIONS: Overall survival for children with H and/or C tumors is excellent. Initial treatment with radiation and the presence of intracranial NF1 lesions were positive predictors of PFS. Mean IQ is significantly compromised at diagnosis, but does not change over time or with irradiation. Overall survival is not affected by initial observation. We recommend observation in asymptomatic patients, platinum-based chemotherapy in younger patients, and irradiation in older symptomatic patients.     

An open randomised trial of second-line endocrine therapy in advanced breast cancer. comparison of the aromatase inhibitors letrozole and anastrozole

It was previously shown that letrozole (Femara) was significantly more potent than anastrozole (Arimidex) in inhibiting aromatase activity in vitro and in inhibiting total body aromatisation in patients with breast cancer. The objective of this study was to compare letrozole (2.5 mg per day) and anastrozole (1 mg per day) as endocrine therapy in postmenopausal women with advanced breast cancer previously treated with an anti-oestrogen. This randomised, multicentre and multinational open-label phase IIIb/IV study enrolled 713 patients. Treatment was for advanced breast cancer that had progressed either during anti-oestrogen therapy or within 12 months of completing that therapy. Patients had tumours that were either positive for oestrogen and/or progesterone receptors (48%) or of unknown receptor status (52%). The primary efficacy endpoint was time to progression (TTP). Secondary endpoints included objective response, duration of response, rate and duration of overall clinical benefit (responses and long-term stable disease), time to treatment failure, and overall survival, as well as general safety. There was no difference between the treatment arms in TTP; median times were the same for both treatments. Letrozole was significantly superior to anastrozole in the overall response rate (ORR) (19.1% versus 12.3%, P=0.013), including in predefined subgroups (receptor status-unknown, and soft-tissue- and viscera-dominant site of disease). There were no significant differences between the treatment arms in the rate of clinical benefit, median duration of response, duration of clinical benefit, time to treatment failure or overall survival. Both agents were well tolerated and there were no significant differences in safety. These results support previous data documenting the greater aromatase-inhibiting activity of letrozole and indicate that advanced breast cancer is more responsive to letrozole than to anastrozole as second-line endocrine therapy.     

Caring for the underserved: current practice of alumni of the National Health Service Corps

The objective of this study was to examine the number and characteristics of National Health Service Corps (NHSC) alumni who currently practice with an underserved population. The study design was a cross-sectional survey mailed in 1998 to a sample of 2,160 alumni. The response rate was 58.9 percent; overall, 52.5 percent of respondents reported currently working with the underserved. In bivariate analyses, retention in practice with the underserved was associated with several clinician and service experience variables. In a logistic regression model, higher initial desire to work with the underserved, older age, job satisfaction, and higher salary were associated with current service. The authors conclude that more than half of the NHSC alumni responding to the survey reported working with an underserved population in 1998. Associations between clinician and service experience characteristics and retention in practice with the underserved can inform policy and research to improve retention.     

Seasonal patterns of invasive pneumococcal disease

Pneumococcal infections increase each winter, a phenomenon that has not been well explained. We conducted population-based active surveillance for all cases of invasive pneumococcal disease in seven states; plotted annualized weekly rates by geographic location, age, and latitude; and assessed correlations by time-series analysis. In all geographic areas, invasive pneumococcal disease exhibited a distinct winter seasonality, including an increase among children in the fall preceding that for adults and a sharp spike in incidence among adults each year between December 24 and January 7. Pneumococcal disease correlated inversely with temperature (r -0.82 with a 1-week lag; p<0.0001), but paradoxically the coldest states had the lowest rates, and no threshold temperature could be identified. The pattern of disease correlated directly with the sinusoidal variations in photoperiod (r +0.85 with a 5-week lag; p<0.0001). Seemingly unrelated seasonal phenomena were also somewhat correlated. The reproducible seasonal patterns in varied geographic locations are consistent with the hypothesis that nationwide seasonal changes such as photoperiod-dependent variation in host susceptibility may underlie pneumococcal seasonality, but caution is indicated in assigning causality as a result of such correlations.