Older women testing positive for HPV16/18 on cervical screening and risk of high-grade cervical abnormality

In Australia's HPV-based cervical screening program, we previously showed that risk of histological high-grade abnormality at 1 year post screening decreased with age in women with oncogenic HPV. In this study, we followed 878 HPV16/18 positive women aged 55 years and over for up to 3 years post screening test, to determine the proportion with histological high-grade abnormality (HGA, incorporating high-grade squamous intraepithelial abnormality (HSIL), adenocarcinoma in situ (AIS), squamous cell carcinoma (SCC) and adenocarcinoma) and to correlate risk of HGA with liquid-based cytology result and with prior screening history. HGA was detected in 7.8% at 1 year and 10.0% at 3 years, with no significant difference (P = .136), despite the number of women with follow-up information significantly increasing from 82.9% to 91.0% (P < .0001). The proportion of HPV16/18 positive women with HGA at 3 years was highest in those with an HSIL cytology result (79.0%) and lowest in those with negative cytology (6.2%). Women with an adequate screening history had fewer HGA than such women with inadequate prior screening (6.6% vs 16.0%, P = .001) or with a history of an abnormality (6.6% vs 14.4%, P = .001). HPV16/18 infection in women over 55 years may have a different natural history from that in younger women, in whom HGA are more common after HPV16/18 detection. In HPV-based cervical screening programs, management algorithms for screen-detected abnormalities based on risk stratification should include factors such as age, screening history and index cytology result, so that women receive appropriate investigation and follow-up.     

Detection of high-grade cervical disease among women referred directly to colposcopy after a positive HPV screening test varies with age and cytology findings

Australia's new HPV-based cervical screening program is based on an algorithm that incorporates reflex cytology to guide decisions about further follow-up with colposcopy and, if indicated, biopsy. We reviewed results for 2300 women referred directly for colposcopy after their first positive HPV screening test, to determine the proportion that had underlying histological high-grade abnormality (HGA). Overall, HGA was detected in 24.3% of women. Among HPV16/18 positive women, 18.0% had HGA, increasing from 6.6% among women with negative cytology to 79.7% among women with high-grade squamous lesion or worse, or any glandular lesion on cytology (HSIL+; P-trend < .001). For this latter group, the proportion with HGA was higher among HPV16/18 positive women than among those positive for other oncogenic types (68.8%; P = .029). Among women with ASC-H cytology, 51.8% had HGA, with no difference between HPV groups (P = .314). In analyses by age-groups, detection of HGA was highest, at 36.4%, among women younger than 35 years, then decreased significantly to 5.9%, among women aged 65 to 74 years (P-trend < .001). The relationship of decreasing HGA detection with increasing age was strong for women with negative cytology, and those with ASC-H cytology (P-trend < .001 for each). For women with HSIL+ cytology, detection of HGA was high and stable, regardless of age (P-trend = .211). This report describes the first follow-up colposcopy findings in Australia's new HPV-based cervical screening program. The results demonstrate the additional value of reflex cytology in managing HPV positive women and suggest that further refinement of the risk-based algorithm to account for age may be warranted.     

Cyclosporin nephrotoxicity in heart and lung transplant patients

Twenty-two patients with heart, lung or heart and lung transplants maintained on cyclosporin for periods ranging from 3 months to 10 years developed renal insufficiency which was investigated by renal biopsy. The histopathological changes were: (i) severe vascular and glomerular damage due to thrombotic microangiopathy (TM); (ii) a form of focal segmental glomerulosclerosis (FSGS); (iii) glomerular ischaemia. Rather than being separate entities, these changes appeared to represent a spectrum of pathology, some biopsies showing all three forms of glomerular injury. In all cases the glomerular changes were accompanied by arteriolar and arterial pathology, and we identified novel ultrastructural changes in the arteriolar endothelial basal lamina. Tubular atrophy was a consistent feature, the severity of which reflected the severity of the glomerular sclerosis, and which appeared to be a consequence of glomerular loss. Our findings are consistent with the nephrotoxic effects of cyclosporin being mediated chiefly via damage to preglomerular vessels and glomerular capillary endothelium. From an analysis of the clinical aspects of these cases, the effects of cyclosporin appear to be to some extent idiosyncratic, and therefore not entirely preventable, but strict monitoring of blood cyclosporin levels is essential to minimize the risk of permanent renal damage. Monitoring urinary protein in addition to plasma creatinine may detect the onset of FSGS, as proteinuria precedes creatinine elevation.      

Assessing the activity of cediranib, a VEGFR-2/3 tyrosine kinase inhibitor, against VEGFR-1 and members of the structurally related PDGFR family

Cediranib is a potent inhibitor of the VEGF receptor (VEGFR)-2 and VEGFR-3 tyrosine kinases. This study assessed the activity of cediranib against the VEGFR-1 tyrosine kinase and the platelet-derived growth factor receptor (PDGFR)-associated kinases c-Kit, PDGFR-α, and PDGFR-β. Cediranib inhibited VEGF-A-stimulated VEGFR-1 activation in AG1-G1-Flt1 cells (IC(50) = 1.2 nmol/L). VEGF-A induced greatest phosphorylation of VEGFR-1 at tyrosine residues Y1048 and Y1053; this was reversed by cediranib. Potency against VEGFR-1 was comparable with that previously observed versus VEGFR-2 and VEGFR-3. Cediranib also showed significant activity against wild-type c-Kit in cellular phosphorylation assays (IC(50) = 1-3 nmol/L) and in a stem cell factor-induced proliferation assay (IC(50) = 13 nmol/L). Furthermore, phosphorylation of wild-type c-Kit in NCI-H526 tumor xenografts was reduced markedly following oral administration of cediranib (≥1.5 mg/kg/d) to tumor-bearing nude mice. The activity of cediranib against PDGFR-β and PDGFR-α was studied in tumor cell lines, vascular smooth muscle cells (VSMC), and a fibroblast line using PDGF-AA and PDGF-BB ligands. Both receptor phosphorylation (IC(50) = 12-32 nmol/L) and PDGF-BB-stimulated cellular proliferation (IC(50) = 32 nmol/L in human VSMCs; 64 nmol/L in osteosarcoma cells) were inhibited. In vivo, ligand-induced PDGFR-β phosphorylation in murine lung tissue was inhibited by 55% following treatment with cediranib at 6 mg/kg but not at 3 mg/kg or less. In contrast, in C6 rat glial tumor xenografts in mice, ligand-induced phosphorylation of both PDGFR-α and PDGFR-β was reduced by 46% to 61% with 0.75 mg/kg cediranib. Additional selectivity was showed versus Flt-3, CSF-1R, EGFR, FGFR1, and FGFR4. Collectively, these data indicate that cediranib is a potent pan-VEGFR kinase inhibitor with similar activity against c-Kit but is significantly less potent than PDGFR-α and PDGFR-β.     

Longitudinal myocardial dysfunction in healthy older subjects as a manifestation of cardiac ageing

BACKGROUND: Abnormalities of longitudinal left ventricular (LV) contraction and relaxation may be early markers of cardiac disease. This study was designed to assess the relationship between long-axis LV function and age in healthy subjects. METHODS: 118 healthy individuals aged 57 +/-19 years (range 20-90 years) with no evidence of cardiovascular disease under-went echocardiography with Doppler examination of transmitral flow. To assess longitudinal LV function, systolic (S(m)), early diastolic (E(m)) and late diastolic (A(m)) mitral annular velocities were measured using colour-coded tissue Doppler imaging. RESULTS: The left atrium was enlarged (P<0.001) in subjects >/=60 years of age compared to those <60 years, but there were no differences in LV volumetric indices and ejection fraction. Peak E velocity was lower (P<0.001) and peak A velocity of transmitral flow was higher in older subjects (P<0.001) with a higher E/A ratio (P<0.001) and longer isovolumic relaxation time (P= 0.001) indicative of impaired ventricular relaxation. S m and E m mitral annular velocities decreased (P<0.001) and A m velocity increased (P=0.002) in the older group. E m velocity and E m /A m ratio showed a strong negative correlation with age (r= -0.80, P<0.001 and r=-0.78, P<0.001, respectively). CONCLUSIONS: Global LV systolic function is preserved but the velocity of long-axis systolic shortening is depressed in older individuals, indicating selective impairment of the longitudinal component of systolic contraction. The decline in the velocity of early diastolic long-axis LV lengthening and the changes in the pattern of transmitral flow suggest impaired ventricular relaxation. These measures of cardiac function may be a useful index of normal cardiac ageing.     

A proposed framework for addressing supervisee-supervisor value conflict

Value conflicts between supervisees and supervisors can adversely affect supervisee development, service provision, and the supervision relationship. However, the role of value conflicts in supervision has been minimally considered. Building on the Farnsworth and Callahan (2013) model for addressing client-clinician value conflict, we propose a supervision-specific framework to help supervisors and supervisees navigate value conflicts that emerge during supervision. The proposed framework consists of three steps: (a) detection of value conflict in supervision; (b) identification and articulation of value conflicts; and (c) determination of appropriate recommendations for supervisees. Neither punitive nor corrective in purpose, the model is eminently exploratory and educational in nature.     

Clonal evolution and lack of cytogenetic response are adverse prognostic factors for hematologic relapse of chronic phase CML patients treated with imatinib mesylate

We followed 141 patients treated with imatinib mesylate (> 300 mg) for chronicphase chronic myelogenous leukemia (CML) following failure of treatment with interferon. During 12 months from the start of imatinib mesylate treatment, 96.5% achieved a complete hematologic response, 47.0% achieved a major cytogenetic response, and 32.4% achieved a complete cytogenetic response. The proportion of patients with hematologic relapse was 10.9% at 12 months and 14.6% at 18 months. In a univariate Cox regression analysis, the only pretreatment characteristics that correlated with an increased risk of hematologic relapse were hemoglobin level less than 120 g/L (12 g/dL) (P =.02), increased bands in the peripheral blood (P =.01), and clonal evolution (P <.0001). In a multivariate analysis, an elevated platelet count (P =.03) and clonal evolution (P <.0001) were the only significant factors for hematologic relapse. During treatment, the absence of a major cytogenetic response within the first 6 months also significantly correlated with relapse (P =.03). Notably, patients failing to achieve a major cytogenetic response by 6 months had a significantly higher rate of hematologic relapse (27%) compared with those who achieved a major cytogenetic response by 6 months (3%), and patients with clonal evolution had a significantly higher risk of hematologic relapse (50%) than those without clonal evolution (9%).     

The nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse model of childhood acute lymphoblastic leukemia reveals intrinsic differences in biologic characteristics at diagnosis and relapse

Acute lymphoblastic leukemia cells from 19 children, including 7 who remain in first complete remission (CR1), were engrafted into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. High-level infiltration of bone marrow, spleen, and liver was observed, with variable infiltration of other organs. The immunophenotypes of xenografts were essentially unaltered compared with the original patient sample. In addition, sequencing of the entire p53 coding region revealed no mutations in 14 of 14 xenografts (10 from patients at diagnosis and 4 at relapse). Cells harvested from the spleens of engrafted mice readily transferred the leukemia to secondary and tertiary recipients. To correlate biologic characteristics of xenografts with clinical and prognostic features of the patients, the rates at which individual leukemia samples engrafted in NOD/SCID mice were analyzed. Differences in biologic correlates were encountered depending on stage of disease: a direct correlation was observed between the rate of engraftment and length of CR1 for samples harvested at relapse (r = 0.96; P =.002), but not diagnosis (r = 0.38; P =.40). In contrast, the in vivo responses of 6 xenografts to vincristine showed a direct correlation (r = 0.96; P =.002) between the length of CR1 and the rate at which the leukemia cell population recovered following vincristine treatment, regardless of whether the xenografts were derived from patients at diagnosis or relapse. This study supports previous findings that the NOD/SCID model of childhood ALL provides an accurate representation of the human disease and indicates that it may be of value to predict relapse and design alternative treatment strategies in a patient-specific manner.