Spontaneous Hopf Fibration in the Two-Higgs-Doublet Model.

We show that energetic considerations enforce a Hopf fibration of the standard model topology within the 2HDM whose potential has either an SO(3) or U(1) Higgs-family symmetry. This can lead to monopole and vortex solutions. We find these solutions, characterize their basic properties and demonstrate the nature of the fibration along with the connection to Nambu's monopole solution. We point out that breaking of the U(1)_{EM} in the core of the defect can be a feature which leads to a nonzero photon mass there.

Stable Cosmic Vortons in Bosonic Field Theory.

Stable ring solutions supported by the angular momentum caused by superconducting charge and current have been suggested to exist in the gauged U(1)×U(1) field theory. We construct potentially cosmologically relevant solutions using gradient flow for the first time and present the strongest evidence to date that they are stable to axial and, crucially, nonaxial perturbations. More importantly, we illustrate quantitative agreement with semianalytic predictions based on the thin string approximation, which validates world sheet action approaches to their formation and evolution.

Relationship between histopathological features, MYCN amplification, and prognosis: a UKCCSG study. United Kingdom Children Cancer Study Group.

Histological sections from 231 patients with neuroblastoma were reviewed and morphological features and their relationship to age, stage, MYCN amplification (in 128 tumours by Southern analyses), and clinical outcome (based on Shimada risk grouping) determined. Stage 4 disease was associated with poorly differentiated and undifferentiated tumours (P = 0.001), an MKI of >2% (P< 0.001), and Shimada unfavourable histology (UHi) P< 0.0001. In univariate analysis MKI was significant in predicting a poorer relapse-free survival (RFS), low vs. intermediate and high (P< 0.001). Age, MYCN amplification, and Shimada UH also emerged as significant variables. There was a higher proportion of MYCN-amplified tumours with Shimada UH (P = 0.03), and this group had a decreased RFS (P = 0.002). In patients with Shimada FH, MYCN amplification did not significantly predict a poor prognosis. In those with stage 4 disease, Shimada classification was not significant in predicting survival (P = 0.97); the same was true for those over the age of 1 year (P = 0.66). In multivariate analysis, MYCN amplification and Shimada UH both emerged as independent prognostic factors. In conclusion, morphological features assigned some subsets of patients to prognostic risk groups. Most MYCN-amplified tumours have unfavourable histology and a poorer prognosis. However, in patients with stage 4 disease and those over the age of 1 year, other factors that may influence prognosis should be determined.

Neuroblastoma: changing incidence and survival in young people aged 0-24 years. A report from the North of England Young Persons' Malignant Disease Registry.

BACKGROUND AND PROCEDURE: Population based data for neuroblastoma in children and young adults under 25 years at diagnosis were ascertained from the Northern Region Young Persons' Malignant Disease Registry for the period 1968-1995. Age-standardised incidence rates were calculated (ASR) and changes in incidence and survival were investigated. Over the study period 144 patients were registered, of these 136 were children under 15 years at diagnosis (median age: 2.2 years, ASR: 8.6 cases per million children per year), and 8 were 15-24 years (ASR 0.6). RESULTS AND CONCLUSIONS: Incidence of childhood neuroblastoma in the North of England increased significantly over time; ASRs were 5.8 for 1968-1981 and 9.5 for 1982-1995 (rate ratio: 1.6, 95%; CI 1.2-2.3). The increase in incidence was seen in both infants and older children, and in both low stage and advanced disease. Overall 5 year survival was 15% for 1968-1981 and 40% for 1982-1995 (P < 0.0001). Significant improvements in survival were documented across different stage and age-groups, including those over 1 with stage 4 disease (0% versus 18%, P < 0.0001). Further research is needed to investigate the reasons for the increasing incidence of neuroblastoma.

Late relapse and prognosis for neuroblastoma patients surviving 5 years or more: a report from the European Neuroblastoma Study Group "Survey".

BACKGROUND AND PROCEDURE: Most deaths from neuroblastoma occur within 2 years of diagnosis but there have been several anecdotal reports of relapse and death after much longer periods of follow up. In order to investigate and quantify the risk of late events we analysed data for patients registered with the European Neuroblastoma Study Group between 1982 and 1990. Out of a total of 1,277 children registered, 427 were alive with follow-up beyond 5 years from diagnosis (median follow-up of 8.8 years, range 5-14 years). Of these 406 were in remission with no prior recurrence, 16 were in remission having experienced a relapse prior to 5 years, and 5 were alive with progressive disease. RESULTS: For the 406 patients in remission with no prior relapse the 10 year progression free survival (PFS) was 96% (CI 94-98). For those aged over 1 year with stage 4 disease at diagnosis 10 year PFS was 88% (CI 79-96) compared to 98% (CI 97-99) for other patients combined, P< 0.001. In a multivariate analysis of all 422 patients in remission at 5 years, significant risk factors for subsequent relapse were age > 1 yr with stage 4 disease at diagnosis (relative risk 10.5, P < 0.001) and prior relapse (RR 4.2, P= 0.01). CONCLUSIONS: The results of this study emphasise the importance of longterm follow-up of patients and the need for late monitoring of clinical trials in children with neuroblastoma. They also provide a baseline for comparison with future and hopefully more effective treatment programmes.

Thyroid cancer in children and young adults in the North of England. Is increasing incidence related to the Chernobyl accident?

Population-based data on thyroid carcinomas was obtained from the Northern Region Young Person's Malignant Disease Registry to analyse the incidence of thyroid cancers in young people (<25 years) in the North of England for the period 1968 and 1997 and to assess if changes in incidence were consistent with the spatial and temporal distribution of the fallout from the Chernobyl nuclear accident. We compared incidence rates for differentiated (papillary or follicular) thyroid carcinomas 1968-1986 with those for 1987-1997. There were 75 cases of thyroid carcinoma diagnosed over the study period, of which 63 were differentiated carcinoma and 12 were medullary carcinoma. There were 26 young adults (15-24 years) diagnosed with differentiated thyroid carcinoma in the 19-year period 1968-1986 and 30 in the subsequent 11 years 1987-1997, Age standardised rate (ASR) 3.0 versus 6.5, respectively (rate ratio 2.2, 95% confidence interval (CI): 1.3-3.6). There were three children (aged <15 years) diagnosed with differentiated carcinoma in the period 1968-1986 and four in the period 1987-1997, ASR 0.2 versus 0.6 (rate ratio 2.7, 95% CI: 0.6-12.1). Regression models showed a significant increase in the incidence of thyroid cancer after the Chernobyl accident (P=0.002). In Cumbria, the area receiving the heaviest fallout in the UK, the increase in incidence was much greater (rate ratio 12.19, 95% CI 1.5-101.2). These temporal and spatial changes in incidence are consistent with a causal association with the Chernobyl accident although a greater effect in the younger rather than the older age group would have been anticipated. However, factors including improvements in ascertainment and earlier detection of tumours may also have contributed to the increasing incidence. Further collaborative international studies are needed to investigate changes in the incidence of thyroid cancer in children and young adults.

Prognostic factors in Ewing's tumor of bone: analysis of 975 patients from the European Intergroup Cooperative Ewing's Sarcoma Study Group.

PURPOSE: To further elaborate on prognostic factors for Ewing's sarcoma of bone and to document improvements in relapse-free survival (RFS) and trends in local therapy over the study period (1977 to 1993). PATIENTS AND METHODS: A retrospective analysis was performed on a combined Gesellschaft Für Pädiatrische Onkologie und Hämatologie/Cooperative Ewing Sarcoma Study and United Kingdom Children's Cancer Study Group/Medical Research Council data set of 975 patients registered with the respective trial offices before the current collaborative European Intergroup Cooperative Ewing's Sarcoma Study trial. Both groups independently undertook studies with similar chemotherapy during the period. RESULTS: The key adverse prognostic factor is metastases at diagnosis (5-year RFS, 22% of patients with metastases at diagnosis v 55% of patients without metastases at diagnosis; P: <.0001). For the group with metastases, there was a trend for better survival for those with lung involvement compared with those with bone metastases or a combination of lung and bone metastases (P: <.0001). In the group of patients with no metastases at diagnosis, multivariate analysis demonstrated that site (axial v other), age-group (< 15 v > or = 15 years), and period of diagnosis had significant influence on RFS (all P: <.005). RFS was superior in the period after 1985 compared with the period before 1985 for nonmetastatic patients (45% v 60%, respectively; P: <.0001) and for metastatic patients (16% v 30%, respectively; P: =.016). Patients who relapsed within 2 years of diagnosis had a less favorable prognosis than patients who relapsed later (5-year survival after relapse, 4% v 23%, respectively; P: <. 0001). There were other changes over the period; in particular, radiotherapy or amputation were more common in the period before 1986, whereas endoprosthetic surgery was widely used in the later period. CONCLUSION: Survival and RFS improved over the period. Prognostic factors are metastases at diagnosis, primary site, and age.

Incidence and survival for cancer in children and young adults in the North of England, 1968-1995: a report from the Northern Region Young Persons' Malignant Disease Registry.

The Northern Region Young Persons' Malignant Disease Registry records information on young people under 25 years old diagnosed with cancer in the Northern Region of England. Incidence and survival rates were calculated for children and young adults diagnosed with cancer between 1968 and 1995. There were 2099 (M:F 1.28:1) children (age 0-14 years) and 2217 (M:F 1.23:1) young adults (15-24 years) diagnosed with a first cancer between 1968 and 1995. The age-standardized rate (ASR) for childhood cancer was 121 per million 0 to 14 year-olds per year. For young adults the ASR was 175 per million 15 to 24 year-olds, per year. Incidence of childhood cancer increased over time at a rate of 12 extra cases per million children, per decade (P < 0.001). In young adults incidence rates increased by 16 extra cases per million 15 to 24 year-olds, per decade (P < 0.001). For childhood cancer 5-year survival was 42% for those diagnosed 1968-1977, 57% for 1978-1987 and 71% (95% CI 67-75) for 1988-1995. Survival for young adults over the three periods was 45%, 62% and 73% (95% CI 70-78) respectively. The cumulative risk of developing cancer before the age of 25 is 1 in 285. Over the 28-year period there were significant improvements in survival and modest increases in incidence in both children and young adults.

Risk factors for nephrotoxicity after ifosfamide treatment in children: a UKCCSG Late Effects Group study. United Kingdom Children's Cancer Study Group.

The aim of this multicentre study was to document the nephrotoxicity associated with ifosfamide and evaluate risk factors in 148 children and young people with sarcomas who underwent investigation of renal function on one occasion each, at a median of 6 (range 1-47) months after completion of ifosfamide (median dose 62.0 (range 6.1-165.0) g/m2). Investigations included glomerular filtration rate (GFR), serum bicarbonate (HCO3) and phosphate (PO4), and renal tubular threshold for phosphate (Tmp/GFR). A clinically relevant nephrotoxicity score' was derived. GFR was < 90 ml/min/1.73 m2 in 61 of 123 evaluable patients, Tmp/GFR < 0.9-1.1 mmol/l (age-dependent) in 45/103, serum PO4 < 0.9-1.mmol/l (age-dependent) in 28/135, and serum HCO3 < 20 (< 18 in infants) mmol/l in 22/95. Of 76 fully evaluable patients: 50% had mild, 20% moderate and 8% severe nephrotoxicity. Higher total ifosfamide dose correlated significantly with greater glomerular and tubular toxicity (P < 0.01); other risk factors, including age at treatment, demonstrated no consistent significant independent effect. Chronic ifosfamide-related glomerular and proximal tubular toxicity were common in this large comprehensive study. Restriction of total ifosfamide dose to < 84 g/m2 will reduce the frequency of, but not abolish, clinically significant nephrotoxicity, whilst doses > 119 g/m2 are associated with a very high risk of severe toxicity.

Clinical prognostic factors in 1277 patients with neuroblastoma: results of The European Neuroblastoma Study Group 'Survey' 1982-1992.

In 1982 the European Neuroblastoma Study Group (ENSG) established a prospective registry for patients with newly diagnosed neuroblastoma ('The ENSG Survey'). Clinical information was collected primarily to: (a) establish an ENSG database; and (b) investigate prognostic factors in neuroblastoma. This paper summarises the results of the survey. By 1992, 1277 patients with a median age of 26 months (range: 0-289 months), gender ratio of 1.19 M:F had been registered from 30 centres. The median follow-up of survivors is 9.7 years (range: 1-14 years). Overall 5-year survival (S) is 45% (95% CI 42-48%), and event-free survival (EFS) is 43% (95% CI 40-45%). For both survival and EFS the key established prognostic factors, stage and age, are highly significant (P<0.001). In particular, patients under 1 year of age at diagnosis, whatever the disease stage, had a more favourable prognosis than older patients; stage 2 (EFS 93% (95% (CI 85-97) versus 76% (95% CI 67-86), P=0.02), stage 3 (EFS 91% (95% CI 82-96) versus 52% (95% CI 44-60), P<0.001) and stage 4 (EFS 59% (95% CI 48-69) versus 16% (95% CI 13-19), P<0.001). Multivariate analysis established that the anatomical location of the primary tumour (i.e. abdominal versus other sites) and primary tumour volume also conferred a statistically significant difference. In stage 4 disease the 20% of patients without demonstrable bone marrow involvement had a more favourable prognosis than those with infiltrated marrow (EFS 36% (95% CI 13-19) versus 16% (95% CI 29-45), P<0.001). Urine catecholamine metabolite levels (raised versus normal), histology (ganglioneuroblastoma versus neuroblastoma) and gender had no significant effect on outcome after stage and age were accounted for. 5-year survival following first relapse is only 5.6% (95% CI 2.8-8.4). This ENSG Survey provides secure data for future comparisons with new prognostic factors and treatment programmes.

Cytogenetically cryptic AML1-ETO and CBF beta-MYH11 gene rearrangements: incidence in 412 cases of acute myeloid leukaemia.

The rearrangements t(8;21)(q22;22) and inv(16)(p13q22) are two of the most frequently seen in acute myeloid leukaemia (AML), accounting for 8% and 4% of cases respectively. Detection of these abnormalities is important for disease management as both are associated with good responses to conventional chemotherapy and prolonged disease-free survival. Recent reports using reverse transcriptase polymerase chain reaction (RT-PCR) suggest that significant proportions of AML cases without a visible t(8;21) or inv(16) show expression of an abnormal fusion gene transcript and, consequently, they could not be detected using conventional cytogenetic analysis alone. We present here a four centre study involving 412 cases of AML screened using both standard cytogenetics and RT-PCR for AML1-ETO and CBF beta-MYH11. We detected a cytogenetic t(8;21) in 31 out of 412 (7.5%) cases and an inv(16) or t(16;16) variant in 27 out of 412 (6.6%) cases. RT-PCR detected only two cases (0.5%) of cryptic t(8;21) and no instances of cryptic inv(16). Both cryptic t(8;21) cases had the classic M2 FAB morphology for this type of disease. Our data concur with the established FAB type distribution of the rearrangements and indicate that cryptic t(8;21) and inv(16) may be much less frequent than reported elsewhere.

Local therapy and other factors influencing site of relapse in patients with localised Ewing's sarcoma. United Kingdom Children's Cancer Study Group (UKCCSG).

Relapse patterns have been documented in 191 children with localised Ewing's sarcoma treated with the United Kingdom Children's Cancer Group (UKCCSG) Ewing's Tumour regimen ET2. All received chemotherapy comprising ifosfamide, vincristine, doxorubicin and actinomycin D. Local treatment modality was excision and or radiotherapy depending on tumour site and response to primary chemotherapy. Although not strictly comparable, due to the clinical indications used for each modality, local relapse rates were very low and were similar, irrespective of the type of local treatment modality: radiotherapy (3/56), surgery (7/114) or a combination (0/20). Combined relapse (local + distant) rates were similarly low irrespective of the type of local therapy: radiotherapy (4/56), surgery (4/114) or a combination (0/20). Overall survival was lower in females (P = < 0.04), older children (P = < 0.002) and those with primaries at sites other than long bones (P = < 0.02). It is concluded that with effective intensive chemotherapy combined with either radiotherapy or surgery, local control in this study was excellent at sites other than the pelvis. Preventing distant relapse, predominantly to lung and bone, remains the major challenge.

Long-term results from the first UKCCSG Ewing's Tumour Study (ET-1). United Kingdom Children's Cancer Study Group (UKCCSG) and the Medical Research Council Bone Sarcoma Working Party.

The aim of this study was to evaluate multimodal chemotherapy and radiotherapy in patients with Ewing's sarcoma. 142 (74 male, 68 female) patients were entered into the ET-1 study between 1978 and 1986. They were treated with vincristine, doxorubicin, actinomycin D, and cyclophosphamide with radiotherapy plus or minus surgery to the primary tumour. Of the 120 who had no metastases at diagnosis, 45 remain alive with a median follow-up of 11.2 years. Only 2 of those with metastases at diagnosis remain alive. The major prognostic factor was site of disease, but age and serum lactic dehydrogenase at diagnosis also had an influence on outcome. 45 of the 61 patients who survived 4 years or more had late effects documented. The type and extent were dependent on tumour site, type of local therapy, volume and dose of radiotherapy. 4 patients had second malignancies. Prospects for long-term survival have improved in patients treated for Ewing's sarcoma. However, late sequelae are present in the majority of patients.