Ulcerative cheilitis in a rhesus macaque.

A 2-year-old, female, simian immunodeficiency virus E543-infected rhesus macaque (Macaca mulatta) was presented for necropsy following euthanasia due to a history of diarrhea, weight loss, and a small, round ulcer along the left labial commissure. Histopathologic examination of the ulcer revealed infiltration by large numbers of degenerate and nondegenerate neutrophils and macrophages admixed with syncytial epithelial cells. Rare epithelial cells contained herpetic inclusion bodies. These cells stained positive for Human herpesvirus 1 via immunohistochemistry, and DNA sequencing confirmed the presence of closely related Macacine herpesvirus 1 (B virus).

Nonarteritic anterior ischaemic optic neuropathy in Addison's disease.

PURPOSE: To report three cases of Nonarteritic anterior ischaemic optic neuropathy (NAAION) in patients with Addison's disease. METHODS: We present a retrospective review of patients presenting with NAAION with underlying Addison's disease. RESULTS: Three eyes of two young patients presented with NAAION. Both patients had underlying Addison's disease with episodes of prolonged hypotension. CONCLUSION: To our knowledge, this is the first published report of NAAION associated with Addison's disease. As hypotension may be one of the few situations, in which NAAION may be treatable and the visual loss reversible, it is important to recognize and treat sustained episodes of hypotension in these individuals.

A randomised prospective double-masked exploratory study comparing combination photodynamic treatment and intravitreal ranibizumab vs intravitreal ranibizumab monotherapy in the treatment of neovascular age-related macular degeneration.

AIMS: The aim of this study is to evaluate the effect of standard-fluence verteporfin photodynamic therapy (PDT) delivered on the first day of a ranibizumab regimen for choroidal neovascularisation secondary to age-related macular degeneration compared with ranibizumab monotherapy. METHODS: Patients were randomised to sham or standard-fluence verteporfin PDT at baseline. The first of three monthly loading doses of ranibizumab was given on the same day, and thereafter patients received monthly treatment with ranibizumab as required. All patients underwent monthly visual acuity and OCT assessment and 3-monthly fluorescein angiography with follow-up to 1 year. RESULTS: In all, 18 patients were recruited. The PDT group gained a mean of 2.2 ETDRS letters at 1 year and the sham group gained a mean of 4.4 letters (P=0.47). Both groups required a mean of 1.3 injections of ranibizumab following the 3-month loading phase. Fluorescein angiography at 1 month demonstrated marked choroidal hypoperfusion in all patients treated with PDT with reduced choroidal perfusion persisting to month 12. This did not occur in the sham group. CONCLUSION: The addition of standard-fluence verteporfin PDT at baseline to a ranibizumab regimen conferred no benefit in terms of visual acuity or number of ranibizumab injections required at 1 year. The combination of these treatments resulted in persistent reduced choroidal perfusion, which raises potential safety concerns.

Ovarian pathology in rhesus macaques: a 12-year retrospective.

BACKGROUND: Ovarian pathology is an important cause of decreased fertility and reproductive capability and may impact multiple systems, particularly in aging rhesus macaques. METHODS: Retrospective histopathologic and immunohistochemical analysis of 458 female rhesus macaque necropsies over 12 years at the New England Primate Research Center in Southborough, MA. RESULTS: Degenerative and inflammatory changes in the ovaries included mineralization, infiltration by lymphocytes, macrophages and multinucleated giant cells, endometriosis, and arteriopathy. Cystic changes included follicular cysts, cystic rete, and mesonephric duct cysts with cystic rete the most common. Neoplasms included granulosa cell tumors, cystadenoma, cystadenocarcinoma, and teratoma. CONCLUSIONS: Ovarian lesions of the rhesus macaque are similar to those of cynomolgus macaques and humans. These lesions are frequently incidental findings but may impact metabolic and neurocognitive studies.

Growth characteristics, reproductive performance, and evaluation of their associative relationships in Brangus cattle managed in a Chihuahuan Desert production system1.

Balancing growth and reproductive performance in beef cattle managed in desert environments is challenging. Our objectives were to 1) evaluate trends in growth and reproductive traits, and 2) assess associative relationships between growth characteristics and reproductive performance in a Brangus herd managed in a Chihuahuan Desert production system from 1972 to 2006. Data were from bull (n = 597) and heifer calves (n = 585; 1988 to 2006) and cows (n = 525; repeated records of cows, n = 2,611; 1972 to 2006). Variables describing the growth curve of each cow were estimated using a nonlinear logistic function (each cow needed 6 yr of data). Mixed-effect models and logistic regression were used to analyze trends across years in growth and reproductive traits (both continuous and categorical). For continuous traits of calves, a slight cubic response (P < 0.01) described the dynamics of birth weight, 205-d BW, and 365-d BW across years. For categorical traits of females, positive linear trends (P < 0.05) across years were observed in percent pregnant as yearlings, calved at 2 yr of age, and first-calf heifer rebreeding (slopes ranged from 0.007 to 0.014%/yr). Autumn cow BW increased gradually until 1997 (509 kg +/- 8.8) and then decreased gradually by 0.6 kg/yr, whereas pregnancy percentage decreased gradually until 1995 (78.4% +/- 1.0) and then increased slightly by 0.2%/yr. A quadratic effect best described the dynamics of these 2 variables across years (P < 0.01) as well as estimates describing the growth curve of each cow. Specifically, asymptotic BW and age increased (P < 0.05) from 1972 to 1983 and 1990, respectively. Asymptotic age then decreased by 27% from 1983 to 1996 (P < 0.05). The maturing rate index was negatively correlated with age at first calving and calving interval (r = -0.42 and -0.18, P < 0.01), which suggested that early-maturing cows had enhanced fertility in this environment and production system. In summary, minimal changes were observed in measures of growth in bulls and heifers in a Brangus herd managed in the Chihuahuan Desert. Opposing relationships were observed among measures of cow size and fertility; as growth curves shifted toward earlier maturity, measures of reproductive performance suggested that fertility improved.

Primary postoperative chemotherapy without radiotherapy for treatment of brain tumours other than ependymoma in children under 3 years: results of the first UKCCSG/SIOP CNS 9204 trial.

BACKGROUND: Radiotherapy is an effective adjuvant treatment for brain tumours arising in very young children, but it has the potential to damage the child's developing nervous system at a crucial time - with a resultant reduction in IQ leading to cognitive impairment, associated endocrinopathy and risk of second malignancy. We aimed to assess the role of a primary chemotherapy strategy in avoiding or delaying radiotherapy in children younger than 3 years with malignant brain tumours other than ependymoma, the results of which have already been published. METHODS: Ninety-seven children were enrolled between March 1993 and July 2003 and, following diagnostic review, comprised: medulloblastoma (n=31), astrocytoma (26), choroid plexus carcinoma [CPC] (15), CNS PNET (11), atypical teratoid/rhabdoid tumours [AT/RT] (6) and ineligible (6). Following maximal surgical resection, chemotherapy was delivered every 14 d for 1 year or until disease progression. Radiotherapy was withheld in the absence of progression. FINDINGS: Over all diagnostic groups the cumulative progression rate was 80.9% at 5 years while the corresponding need-for-radiotherapy rate for progression was 54.6%, but both rates varied by tumour type. There was no clear relationship between chemotherapy dose intensity and outcome. Patients with medulloblastoma presented as a high-risk group, 83.9% having residual disease and/or metastases at diagnosis. For these patients, outcome was related to histology. The 5-year OS for desmoplastic/nodular medulloblastoma was 52.9% (95% confidence interval (CI): 27.6-73.0) and for classic medulloblastoma 33.3% (CI: 4.6-67.6); the 5-year EFS were 35.3% (CI: 14.5-57.0) and 33.3% (CI: 4.6-67.6), respectively. All children with large cell or anaplastic variants of medulloblastoma died within 2 years of diagnosis. The 5-year EFS for non-brainstem high-grade gliomas [HGGs] was 13.0% (CI: 2.2-33.4) and the OS was 30.9% (CI: 11.5-52.8). For CPC the 5-year OS was 26.67% (CI: 8.3-49.6) without RT. This treatment strategy was less effective for AT/RT with 3-year OS of 16.7% (CI: 0.8-51.7) and CNS PNET with 1-year OS of 9.1% (CI: 0.5-33.3). INTERPRETATION: The outcome for very young children with brain tumours is dictated by degree of surgical resection and histological tumour type and underlying biology as an indicator of treatment sensitivity. Overall, the median age at radiotherapy was 3 years and radiotherapy was avoided in 45% of patients. Desmoplastic/nodular sub-type of medulloblastoma has a better prognosis than classic histology, despite traditional adverse clinical features of metastatic disease and incomplete surgical resection. A subgroup with HGG and CPC are long-term survivors without RT. This study highlights the differing therapeutic challenges presented by the malignant brain tumours of early childhood, the importance of surgical approaches and the need to explore individualised brain sparing approaches to the range of malignant brain tumours that present in early childhood.

Palliative care in Yorkshire, UK 1987-2008: survival and mortality in a hospice.

OBJECTIVE: To provide new epidemiological evidence base of information on models of hospice care for children and young adults. DESIGN: Retrospective cohort study of children referred to a hospice. SETTING: Martin House Children's and Young Person's Hospice in Boston Spa, North Yorkshire, UK. PARTICIPANTS: All children who had been referred for care at Martin House Children's Hospice since it opened in August 1987, until May 2008. MAIN OUTCOME MEASURES: Demographic profiles and survival times overall and by diagnostic group classified by the Association of Children's Palliative Care (ACT) Diagnostic Categories, calculated using the Kaplan- Meier and log rank pair-wise methodology. RESULTS: Over a 20-year period, 1554 children aged from birth to 19 years were referred to Martin House, of whom 89.5% (mean age 7.45 years) were accepted. The deprivation profile, referral source and distribution of diagnoses of these children have changed over time with recently increasing numbers of non-progressive disorders (ACT category 4). The ethnicity profile has changed with an increase in the numbers of South Asian children. The overall mean survival time was 5.6 years (95% CI 5.1 to 6.1) but this differed by ACT category. Diagnostic category was significantly associated with differing survival patterns. CONCLUSIONS: There are a disproportionate number of children from areas of higher deprivation being referred for palliative care services. There has been a recent increase in the number of children from South Asian families being referred to palliative care services in Yorkshire. Survival times for children and young people receiving care from a hospice can vary from hours and days to more than 20 years.

Visual symptomatology in patients with sight-threatening diabetic retinopathy.

AIMS: To assess the level of visual symptomatology in patients with sight-threatening diabetic retinopathy. METHODS: Questionnaires were completed by patients undergoing first photocoagulation treatment for diabetic maculopathy or proliferative retinopathy during a 2-month period throughout the UK, and at 9 months' follow-up. RESULTS: There were high levels of visual symptomatology prior to the first laser treatment and at follow-up for both patients with maculopathy or with proliferative retinopathy. Only 25.1% of patients with maculopathy and 17.2% of patients with proliferative retinopathy were asymptomatic in terms of reading, seeing the television screen, recognizing faces or with their night vision at baseline. For those with maculopathy 20.1% were aware of colour vision abnormality in the eye to be treated at baseline and 9.5% were aware of new central scotomata since the treatment. Of those with proliferative retinopathy, 13% said that they had given up driving due to poor eyesight and 19% were aware of new peripheral field defects since the treatment. CONCLUSIONS: There are high levels of visual symptomatology for patients with sight-threatening diabetic retinopathy in the UK despite that fact that screening should aim to detect retinopathy prior to visual loss occurring. Patients should be aware that there may not be any significant improvement in their vision with laser treatment, and that the main aim of treatment is to reduce the likelihood of further visual deterioration.

Down's syndrome and acute lymphoblastic leukaemia: clinical features and response to treatment.

AIMS: To examine the clinical and biological features of acute lymphoblastic leukaemia in children with Down's syndrome (DS), to compare their survival with other children, and to determine if entry to trials and survival has improved. METHODS: Examination of presenting features and response to treatment in patients treated in two consecutive national trials, MRC UKALL X and XI. RESULTS: The proportion of children with DS was significantly higher in UKALL XI (1.9%) than UKALL X (0.9%). Children with DS tended to be under 10 years and to have the common ALL subtype. Cytogenetic analysis showed that favourable features, such as high hyperdiploidy and t(12;21) were less frequent but also that there was a lack of translocations associated with a poor prognosis. Children with DS showed no increase in risk of relapse at any site but their survival and event free survival were inferior to other children. These results were caused by an increased number of infective deaths during remission (11% compared to 2%). At five years overall survival was 73% in DS children compared with 82% in other children; event free survival was 53% compared to 63% in non-DS children. CONCLUSIONS: Entry of children with DS to national trials has increased and survival has improved. However they remain at risk of relapse and also of treatment related mortality. These findings emphasise the need for both intensive chemotherapy and optimal supportive care.

Progressive reduction in treatment-related deaths in Medical Research Council childhood lymphoblastic leukaemia trials from 1980 to 1997 (UKALL VIII, X and XI).

In the last 20 years, the survival rate for children with acute lymphoblastic leukaemia (ALL) has markedly improved, largely owing to a decrease in relapses. However, children still die from complications of treatment and these are potentially preventable. We have analysed data from three large consecutive national protocols for ALL from 1980 to 1997 [Medical Research Council United Kingdom ALL (MRC UKALL) trials VIII, X and XI] to compare the incidence and causes of treatment-related deaths (TRD). The percentage of TRD has fallen from 9% to 2% (UKALL VIII to XI), largely as a result of a decrease in fatal infections. Deaths during induction have fallen from 3% to 1%, the main causes of death being bacterial, followed by fungal infection, while other causes, chiefly haemorrhage, have not declined. Remission deaths also decreased from 6% to 1%, particularly those deaths due to measles and pneumocystis carinii. More guidelines for surveillance and treatment of infections have been included within progressively more intensive protocols. Risk factor analysis showed increased TRD in patients with Down's syndrome, high leucocyte count and older age in UKALL XI. In contrast, the introduction of blocks of intensification was not associated with an increased death rate. While improved supportive care has reduced the incidence of TRD, there is still scope for further reduction by prompt treatment of suspected infection. Maintenance of herd immunity remains of vital importance in avoiding deaths from measles.

Co-morbidity in patients with sight-threatening diabetic retinopathy.

PURPOSE: To describe the level of co-morbidity in patients with sight-threatening diabetic retinopathy in the United Kingdom. METHODS: Questionnaires were completed by patients undergoing first photocoagulation treatment for diabetic maculopathy or proliferative retinopathy during a 2 month period throughout the UK. RESULTS: Overall 15% of patients described angina, 9% had suffered a myocardial infarction and 6% a stroke. Self-reported renal disease was present in 8.5%. Foot ulceration was described by 10% of patients, and 4% had undergone an amputation. 35.5% of patients were on treatment for hypertension. 17.5% of patients had been hospitalised in the previous 6 months, and 3% of patients had died within 9 months of the laser treatment. CONCLUSIONS: There was significant co-morbidity in these patients, which may affect the management of their retinopathy.

Bone marrow transplantation versus chemotherapy in the treatment of very high-risk childhood acute lymphoblastic leukemia in first remission: results from Medical Research Council UKALL X and XI.

The role of bone marrow transplantation (BMT) in first remission of children with high-risk acute lymphoblastic leukemia (ALL) remains unclear. There were 3676 patients (aged 1 to 15 years) entered into the United Kingdom (UK) Medical Research Council (MRC) trials UKALL X and XI from 1985 to 1997. Of these patients, 473 patients (13%) were classified as very high (VH) risk and were eligible for a transplantation from a matched histocompatible sibling donor (MSD). We tissue-typed 286 patients; 99 patients had a matched related donor, and 76 patients received transplantations. Additionally, 25 children received transplantations from a matched unrelated donor (MUD) despite trial guidelines for MSD transplantations only. The median time to transplantation was 5 months (range, 2 to 19 months), and the median follow-up was 8 years. The 10-year event-free survival (EFS) adjusted for the time to transplantation, diagnostic white blood cell (WBC) count, Ph chromosome status, and ploidy was 6. 0% higher (95% confidence interval (CI), -10.5% to 22.5%) for 101 patients who received a first-remission transplantation (MSD and MUD) than for the 351 patients treated with chemotherapy (transplantation, 45.3%, vs chemotherapy, 39.3%). The transplantation group had fewer relapses (31%) compared to relapses in the chemotherapy group (55%); however, the transplantation group had more remission deaths (18%) compared to remission deaths in the chemotherapy group (3%). In contrast the adjusted 10-year EFS was 10. 7% higher (95% CI, -2.6% to 24.0%) for patients without a human leukocyte antigen (HLA)-matched donor than for those patients with a donor (no donor, 50.4%, vs donor, 39.7%). In conclusion, for the majority of children with VH-risk ALL, the first-remission transplantation has not improved EFS.

Long-term follow-up of the United Kingdom Medical Research Council protocols for childhood acute lymphoblastic leukaemia, 1980-1997. Medical Research Council Childhood Leukaemia Working Party.

Results of three consecutive completed UK trials (1980-1997) for childhood lymphoblastic leukaemia are presented. National accrual has progressively increased so that over 90% of all the country's ALL cases were treated on the latest trial reported, UKALLXI. From 1980 to 1990, event-free and overall survival progressively improved, following adoption of an American therapy template and use of two post-remission intensification modules. Since 1990 despite demonstration of the benefit of a third intensification module overall event-free survival (EFS) has not improved further. Survival remains high due to a good retrieval rate especially for those relapsing off treatment after receipt of two intensification pulses. Possible reasons for the plateau in event-free survival (including type and dose of induction steroid, dropping of induction anthracycline, type and dose of asparaginase, gaps early in therapy following intensification, and overall lack of compliance in maintenance) are being explored in the latest protocol ALL '97. Cranial irradiation had been successfully replaced by a long course of intrathecal methotrexate injections for the majority of patients. Age (<1 year >10 years) sex (male) and white count >50 x 10(9)/l plus slow initial bone marrow clearance were consistently the most important independent prognostic indicators during this time period. Rome/NCI criteria accurately predict standard and high-risk groups for B cell lineage, but not consistently for T cell disease. This international collaborative venture might help us to define those truly at highest risk, and how we can optimise therapy for specific subgroups including T-ALL and those with unfavourable cytogenetics.

The National Diabetic Retinopathy Laser Treatment Audit. III. Clinical outcomes.

PURPOSE: To describe the short-term clinical outcomes for a cohort of patients undergoing first photocoagulation treatment for proliferative retinopathy or maculopathy in the United Kingdom. METHOD: Nine-month follow-up of the Royal College of Ophthalmologists' national audit of laser treatment for diabetic retinopathy. RESULTS: For eyes with maculopathy, 9.2% had had a deterioration in visual acuity equivalent to a doubling of the visual angle and 3.3% of eyes had a visual acuity of less than 6/60 at follow-up. There had been an improvement in the macular oedema or exudate in 64.6% and 77.3% respectively. Prognostic factors for a poorer visual acuity at follow-up were worse visual acuity at baseline, the presence of diffuse (vs focal) oedema and grid (vs focal) treatment. For eyes with proliferative retinopathy, the retinal neovascularisation had regressed fully in 50.8% of cases, whilst there had been no change or a deterioration in 10.3%. A visual acuity of less than 6/60 at follow-up was present in 8.6% of eyes. There was a poor morphological outcome at follow-up (as defined by rubeosis, new tractional detachment or having had a vitrectomy) in 7.2%. Risk factors for poor morphological outcome were the presence of 'high-risk characteristics', female sex and the presence of concurrent maculopathy at baseline. Regression of neovascularisation was associated with greater areas of retinal ablation at the initial treatment session. Although some eyes with proliferative retinopathy appeared to be undertreated initially compared with DRS and ETDRS protocols, some of these eyes did respond to lower amounts of treatment. CONCLUSION: For maculopathy, poorer outcome was related to worse visual acuity at baseline, diffuse (vs focal) maculopathy, and grid treatment. For proliferative retinopathy, poorer outcome was related to 'high-risk characteristics' and coexistence of maculopathy at baseline, and improvement was related to larger areas of ablation. The relationship of poor outcome with worse initial disease argues for earlier detection of retinopathy.

Ifosfamide/etoposide alternating with high-dose methotrexate: evaluation of a chemotherapy regimen for poor-risk osteosarcoma.

Fifteen patients with relapsed osteosarcoma were treated with an intensive combination chemotherapy schedule. Ifosfamide 2.5 g m(-2) daily and etoposide 150 mg m(-2) daily coincidentally for 3 days and high-dose methotrexate 8 g m(-2) (with folinic acid rescue) on days 10-14 in a planned 21 -day cycle. Feasibility, toxicity and response to this alternative combination for the treatment of relapsed osteosarcoma was assessed. There were 98 evaluable cycles for toxicity and tolerability. The majority of cycles were well tolerated. Haematological toxicity of grade 3/4 (common toxicity criteria) was seen in all courses. Renal tubular loss of electrolytes, particularly magnesium, occurred in 71% of cycles. Thirteen per cent of cycles were repeated within 21 days and 61% within 28 days. In the thirteen patients evaluable for response, a partial response rate of 31% was seen after two cycles. However, patients with stable disease continued on therapy, and an overall consequent response rate of 62% was observed. Four patients were alive with no evidence of disease at 8-74 months. Three are alive with disease (at 8-19 months). There were six deaths, all disease related. This regimen exhibits an encouraging response rate in a group of children with poor prognosis disease, with a tolerable toxicity profile.

Survival from childhood cancer in Yorkshire, U.K.: effect of ethnicity and socio-economic status.

The effect of ethnicity and socio-economic status on the survival of a population-based cohort of 1979 children diagnosed with cancer between 1974 and 1995 was investigated. Ethnicity was assigned by computer algorithms and visual inspection as south Asian (or not) for each child, based on their full name. Socio-economic status was measured using the Carstairs index, based on census areas of case residence at diagnosis. 15 children (0.8%) were lost to follow-up. Log-rank tests showed survival from all cancers did not differ between south Asians and other children and no increased risk was observed for south Asians in any diagnostic category, although numbers were small. Increasing levels of deprivation were associated with significant trends of poorer survival from all cancers, leukaemias and brain tumours. Risk of death was typically higher for children from the most deprived areas although differences were not statistically significant after accounting for other factors including ethnicity. Taking all children with malignant disease together, neither ethnicity nor socio-economic status appear to influence survival after taking other factors into consideration.

Epidemiology of childhood brain tumours in Yorkshire, UK, 1974-95: geographical distribution and changing patterns of occurrence.

From a high-quality population-based register of children with cancer, 455 cases diagnosed with central nervous system (CNS) tumours were analysed to examine patterns of occurrence and geographical distribution. There was a significant increase of 1.8% (95% CI 0.5-3.1, P < 0.01) in average annual incidence for all CNS tumours, mainly accounted for by a 3.1% rise (95% CI 0.1-6.1, P < 0.05) in primitive neuroectodermal tumours (PNETs) over the 22-year period 1974-95. These increases were not explained by an increase in the proportion of histologically verified tumours. In the most recent time period (1986-95), astrocytomas occurred more commonly than previously in 0 to 4-year olds. Geographical differences in incidence were evident at a large scale, between counties, for all tumours and astrocytomas, with lower rates in the most urbanized areas. At the level of census district and electoral wards, no association between incidence of CNS tumours and socioeconomic group, person-based population density or ethnicity was observed using Poisson regression modelling. Based on small-scale census geography, the patterns of distribution of CNS tumours do not suggest strong associations with geographical determinants of risk. This study finds a rising incidence of all CNS tumours and particularly primitive neuroectodermal tumours and shows that astrocytomas appear to be occurring at a younger age, most probably because of improved diagnosis with non-invasive technology.