VHL: Trends and Insight into a Multi-Modality, Interdisciplinary Approach for Management of Central Nervous System Hemangioblastoma.

Von Hippel-Lindau (VHL) is a multi-system disease which results in significant morbidity from central nervous system (CNS) involvement as well as ocular, renal and neuro-endocrine effects. Haemangioblastomas of the CNS present a number of challenges. The natural history of these lesions is varied, as is the size and location within the CNS. Whilst surgery is considered the mainstay of treatment and best chance at curing these lesions, this is also often associated with significant risks due to the anatomical location of these lesions, most commonly the posterior fossa and spinal cord.We review the literature and describe our experience across two separate European VHL referral centres. Alternative treatment options and combined modalities are increasingly being used in the context of managing CNS haemangioblastomas. We analyse the increasing use of stereotactic radiosurgery and the evolution of medical treatments as potential future adjuncts to surgery. The availability of multiple modalities in our armamentarium is essential in tailoring a personalised treatment approach to these patients. Owing to the multi-systemic nature of the disease, in our experience, managing the care of patients with VHL is best delivered using an interdisciplinary approach utilising multiple specialties and adopting an individually tailored holistic approach.

Visual functioning and quality of life in the SubFoveal Radiotherapy Study (SFRADS): SFRADS report 2.

AIMS: To determine whether or not self reported visual functioning and quality of life in patients with choroidal neovascularisation caused by age related macular degeneration (AMD) is better in those treated with 12 Gy external beam radiotherapy in comparison with untreated subjects. METHODS: A multicentre single masked randomised controlled trial of 12 Gy of external beam radiation therapy (EBRT) delivered as 6 x 2 Gy fractions to the macula of an affected eye versus observation. Patients with AMD, aged 60 years or over, in three UK hospital units, who had subfoveal CNV and a visual acuity equal to or better than 6/60 (logMAR 1.0). METHODS: Data from 199 eligible participants who were randomly assigned to 12 Gy teletherapy or observation were available for analysis. Visual function assessment, ophthalmic examination, and fundus fluorescein angiography were undertaken at baseline and at 3, 6, 12, and 24 months after study entry. To assess patient centred outcomes, subjects were asked to complete the Daily Living Tasks Dependent on Vision (DLTV) and the SF-36 questionnaires at baseline, 6, 12, and 24 months after enrolment to the study. Cross sectional and longitudinal analyses were conducted using arm of study as grouping variable. Regression analysis was employed to adjust for the effect of baseline co-variates on outcome at 12 months and 24 months. RESULTS: Both control and treated subjects had significant losses in visual functioning as seen by a progressive decline in mean scores in the four dimensions of the DLTV. There were no statistically significant differences between treatment and control subjects in any of dimensions of the DLTV at 12 months or 24 months after study entry. Regression analysis confirmed that treatment status had no effect on the change in DLTV dimensional scores. CONCLUSIONS: The small benefits noted in clinical measures of vision in treated eyes did not translate into better self reported visual functioning in patients who received treatment when compared with the control arm. These findings have implications for the design of future clinical trials and studies.

Visual outcomes in the subfoveal radiotherapy study: a randomized controlled trial of teletherapy for age-related macular degeneration.

OBJECTIVE: To determine whether teletherapy with 6-mV photons can reduce visual loss in patients with subfoveal choroidal neovascularization in age-related macular degeneration. DESIGN: A multicenter, single-masked, randomized controlled trial of 12 Gy of external beam radiation therapy delivered to the macula of an affected eye vs observation only. SETTING: Three United Kingdom-based hospital units. PARTICIPANTS: Patients with age-related macular degeneration, aged 60 years and older, who had subfoveal choroidal neovascularization and a visual acuity of 20/200 (logMAR 1.0) or better. METHODS: Two hundred three patients were randomly assigned to radiotherapy or observation. Treatment was undertaken at designated radiotherapy centers, and patients assigned to the treatment group received a total dosage of 12 Gy of 6-mV photons in 6 fractions. Follow-up was scheduled at 3, 6, 12, and 24 months. After excluding protocol violators, the data from 199 patients were analyzed. MAIN OUTCOME MEASURES: The primary outcome measure was mean loss of distance visual acuity in the study eye at 12 and 24 months. Other outcome variables analyzed were near visual acuity and contrast sensitivity. The proportions of patients losing 3 or more or 6 or more lines of distance and near acuity and 0.3 or more or 0.6 or more log units of contrast sensitivity at each follow-up were also analyzed. RESULTS: At all time points, mean distance visual acuity was better in the radiotherapy-treated group than in the control group, but the differences did not reach statistical significance. At 24 months, analysis of the proportions of patients with loss of 3 or more (moderate) (P =.08) or 6 or more (severe) (P =.29) lines of distance vision showed that fewer treated patients had severe losses, but there was no statistically significant difference between groups. For near visual acuity, although there was no evidence of treatment benefit at 12 and 24 months, a significant difference in favor of treatment was present at 6 months (P =.048). When analyzed by the proportions of patients losing 3 lines of contrast sensitivity, there was a significant difference in favor of treatment at 24 months (P =.02). No adverse retinal effects were observed during the study, but transient disturbance of the precorneal tear film was noted in treated patients. CONCLUSION: The results of the present trial do not support the routine clinical use of external beam radiation therapy in subjects with subfoveal choroidal neovascularization in age-related macular degeneration.

A multidisciplinary team approach to skull base chordomas.

OBJECT: A multidisciplinary team devised a protocol for long-term care of patients with skull base chordomas. In this study they describe their approach. METHODS: Forty-two patients presented between 1986 and 1998 and were treated by maximum surgical cytoreduction and photon radiation therapy. Tumor volume-doubling time determined on the basis of magnetic resonance imaging, immunostaining, and cell proliferation (Ki67 labeling index [LI]) studies indicated growth rates of individual chordomas. The best outlook was associated with the greatest extent of tumor removal achieved during the first operation. There were no deaths associated with patients who underwent first-time surgery, but there was a 7.1% mortality rate associated with those who underwent subsequent operations. Cerebrospinal fluid leaks, additional cranial nerve palsies, and pharyngeal wound problems were the most difficult management problems encountered after second and subsequent surgeries. The time interval between operations was usually between 2 years and 3 years after the first surgery; very few patients required a second surgery, with a quiescent period in excess of 5 years. Life-table 5- and 10-year survival rates were 77% and 69%, respectively. CONCLUSIONS: The authors believe that this series of skull base chordomas provides new insights into the management of these lesions, particularly with regard to techniques that increase survival times and studies that aid in formulating prognoses.

A multidisciplinary team approach to skull base chondrosarcomas.

OBJECT: The authors review their experience with treating skull base chondrosarcomas, which are much rarer than skull base chordomas and differ from them in prognosis and treatment. METHODS: Seventeen patients (12 male and five female patients) with histologically verified chondrosarcomas were followed up prospectively over a 12-year period. The mean age at presentation was 35.9 years. Most patients presented with cranial nerve palsies. Seven had undergone surgery prior to referral to the authors' unit. All underwent maximum surgical cytoreduction by the most direct surgical approach; only the two patients harboring the mesenchymal variant underwent radiotherapy. CONCLUSIONS: One patient died of a pulmonary embolus; the patients harboring mesenchymal chondrosarcomas died at 20 and 36 months, respectively, after treatment. Of the remaining patients, 93% were alive 5 years postsurgery and had a projected 10-year survival rate of 84% (mean survival time 9.3 years). These data emphasize the very slow progression of this tumor compared with skull base chordoma.

Histological features of ocular adnexal lymphoma (REAL classification) and their association with patient morbidity and survival.

BACKGROUND: The histological characteristics of ocular adnexal lymphomas have previously provided only a limited guide to clinical outcome for affected patients. This clinicopathological relation was re-examined using the Revised European American Lymphoma (REAL) system to classify the tumours in a large cohort of patients. METHODS: The biopsies and clinical follow up data for 192 patients with ocular adnexal lymphoma were reviewed, the biopsies being regraded in accordance with the REAL classification. For each of five histological groups, logistic regression analysis was used to determine the odds ratios (OR) for the presence of systemic disease at the time of orbital diagnosis and Cox regression analysis was used to assess the hazard ratios (HR) for disseminated disease and lymphoma related death. For 108 patients in whom extraorbital spread occurred, the histological category of lymphoma was compared with the sites of dissemination. RESULTS: At presentation, the frequency of previous or concurrent extraorbital disease increased from marginal zone lymphoma (OR 1.0), diffuse lymphoplasmacytic/lymphoplasmacytoid lymphoma (OR 2.3), follicle centre lymphoma (OR 3.8), diffuse large B cell lymphoma (OR 4.0) to other histological lymphoma variants (OR 26.8). For all histological types, the estimated risk of extraorbital disease and lymphoma related death continued for many years and the proportion of patients with at least one extraorbital recurrence after 5 years was 47% for MZL, 48% for LPL, 64% for FCL, 81% for DLCL, and 95% for other lymphoma variants. The corresponding estimated rates for 5 year lymphoma related mortality were 12%, 19%, 22%, 48%, and 53% respectively. CONCLUSIONS: Patients with ocular adnexal lymphoma can be classified by REAL into five distinct groups, which show a progressive increase in the risks of extraorbital disease at diagnosis, of disease dissemination with time, and of tumour related death.

Identification of a defect in DNA ligase IV in a radiosensitive leukaemia patient.

The major mechanism for the repair of DNA double-strand breaks (DSBs) in mammalian cells is non-homologous end-joining (NHEJ), a process that involves the DNA-dependent protein kinase [1] [2], XRCC4 and DNA ligase IV [3] [4] [5] [6]. Rodent cells and mice defective in these components are radiation-sensitive and defective in V(D)J-recombination, showing that NHEJ also functions to rejoin DSBs introduced during lymphocyte development [7] [8]. 180BR is a radiosensitive cell line defective in DSB repair, which was derived from a leukaemia patient who was highly sensitive to radiotherapy [9] [10] [11]. We have identified a mutation within a highly conserved motif encompassing the active site in DNA ligase IV from 180BR cells. The mutated protein is severely compromised in its ability to form a stable enzyme-adenylate complex, although residual activity can be detected at high ATP concentrations. Our results characterize the first patient with a defect in an NHEJ component and suggest that a significant defect in NHEJ that leads to pronounced radiosensitivity is compatible with normal human viability and does not cause any major immune dysfunction. The defect, however, may confer a predisposition to leukaemia.

Blood to cerebrospinal fluid human chorionic gonadotropin-beta ratios in intracranial germ cell tumors.

Levels of human chorionic gonadotropin-beta (HCG-beta) are elevated in up to 43% of patients with intracranial germ cell tumors (GCTs) and are useful in the diagnosis of these tumors and the follow up of such patients. The ratio of blood HCG-beta to lumbar cerebrospinal fluid (CSF) HCG-beta in these patients at presentation has not been defined. Twenty-two patients with intracranial GCTs have been treated at St. Bartholomew's Hospital over the past 15 years. Two (17%) of 12 germinomas and seven (70%) of 10 nongerminomatous GCTs had elevated blood HCG-beta at presentation. Four cases of pineal region GCTs (one of 12 germinomas and three of 10 nongerminomatous GCTs) had paired, elevated, blood and lumbar CSF HCG-beta levels. The mean blood to CSF ratio was 1:10 (range 1.7-18.4), which is substantially lower than the ratio of 286:1 reported in systemic GCTs. The authors confirm the finding of a previous single report showing that ventricular CSF HCG-beta sampling via an accessible ventriculoperitoneal shunt reservoir may give a spuriously negative result, and they discuss the pathophysiology of the blood-brain barrier in the pineal region and the implications of the intrathecal administration of chemotherapy.

Is there a danger in delaying radiotherapy in childhood medulloblastoma?

Approximately 45-50% of children with medulloblastoma are cured by conventional surgery and radiotherapy, but survivors may face severe late neuropsychological toxicity. Studies showing good partial responses to platinum-based chemotherapy in relapsed patients and the theoretical possibility of a therapeutic window immediately after surgery have prompted neoadjuvant treatment studies which are ongoing. However, the absolute benefit of chemotherapy for the treatment of medulloblastoma in childhood is, as yet, not proven. There is a danger that chemotherapy may simply delay radiotherapy, and in so doing reduce the radiological impact of this known effective treatment. We report four children with medulloblastoma presenting consecutively to this unit over a 6-month period, whose management was problematic because of either failure to respond to neoadjuvant chemotherapy or their very young age. These cases are discussed in the light of the current literature and future treatment strategies that must seek to improve the therapeutic ratio of multimodality therapy.

Giant cell tumors of the sphenoid bone.

Giant cell tumors of the sphenoid are rare; there are 36 previously reported cases. We report two cases of these tumors in women in their thirties, both associated with pregnancy. In the first patient, the tumor was removed via a transnasal transsphenoidal approach. In the second patient, a Le Fort maxillotomy was required. In these cases, an interoperative diagnosis was made, and in both, this diagnosis directed surgical tactics towards a more radical excision. Reported experience with the outcome of giant cell tumors in other sites suggest that total removal by curettage is the ideal treatment; the main principle is to prevent local recurrence because the metastatic potential of this tumor is low. A combination of surgery and radiotherapy is essential for giant cell tumors occurring in sites where access is difficult, such as the sphenoid bone. Previous objections to radiotherapy have included poor response rate and malignant change. Recent studies suggest that neither of these problems is significant when modern therapeutic techniques are employed.

The usefulness of serum thyroglobulin in the follow-up of differentiated thyroid carcinoma in children.

Serum thyroglobulin has been measured serially in ten children aged 5-17 years presenting with differentiated thyroid carcinoma. At presentation 4 had intra-thyroidal disease, 3 had lymph node metastases, and 3 had lung metastases. During follow-up for a median of 37.0 months (range 21-108) 3 patients have been disease-free, 4 have had a local relapse, and 3 have had persistent disease. Seventy-seven separate serum thyroglobulin measurements have been performed; 36 on and 41 off thyroid replacement therapy. A level of thyroglobulin of less than 5 ng/ml was taken as indicative of absence of disease, and compared against combined clinical examination and 131I scanning. Overall sensitivity of thyroglobulin measurement was 36/37 (97%), and although specificity was 30/40 (75%), this rose to 30/32 (94%) if raised thyroglobulin levels noted within 3 months of 131I therapy in otherwise asymptomatic patients (n = 4) or in subjects with intact thyroid tissue (n = 4) were excluded. Concordance with clinical status was 30/31 (97%) in measurements taken on, and 31/32 (94%) in those taken off, thyroid replacement. These data indicate that thyroglobulin measurement is a sensitive and specific means of detecting residual, recurrent, and metastatic thyroid carcinoma in children.

Langerhans-cell histiocytosis--excellent response to etoposide.

We describe an adult with progressive LCH who received oral etoposide as primary treatment. The response is documented and the strategical implications of this drug in Langerhans-cell histiocytosis discussed. Langerhans-cell histiocytosis (LCH) is the term recognized since 1987 for the group of diseases previously designated histiocytosis X. It is not now regarded as a malignant neoplastic process and there is some evidence to suggest that it is due to abnormal immunity, but cytotoxic drugs and steroids are still the mainstay of systemic treatment. Etoposide (VP16) is a semisynthetic epipodophyllotoxin derivative effective in the treatment of malignancies of the monocyte-macrophage lineage and used in resistant or relapsed childhood LCH. There are no previous reports of its use as firstline monotherapy in adults with LCH.

Pelvic rhabdomyosarcoma in children.

Twenty children with pelvic rhabdomyosarcoma treated between 1976 and 1983 are reviewed. The survival rate was 55% (11/20), with a bladder salvage rate of 54.5% among survivors. Systemic chemotherapy combined with radiotherapy and/or surgery was most effective in producing cure.

Orbital recurrence of retinoblastoma.

There were 16 cases of orbital recurrence in a consecutive series of 317 children with retinoblastoma referred to a specialist centre. The incidence of orbital relapse amongst children treated at the centre from the outset of their disease was 2.5%. In every case the patient was the first affected family member. The ocular tumour was therefore not anticipated and had commonly been detected at an advanced stage. Systemic staging investigations detected extraorbital spread in six of the 16 and none of these children survived. One of the remaining ten children with no evidence of dissemination at the time of diagnosis of orbital recurrence is a long-term survivor. No child survived after orbital exenteration or radical orbital radiotherapy alone. Three children received a combination of radiotherapy and adjuvant chemotherapy. Only one of the three was free from systemic disease at relapse and this child is the only survivor. In children apparently free from widespread retinoblastoma at diagnosis of orbital recurrence, distant relapse was the commonest cause of death though several children died from direct intracranial extension. It is advocated that orbital recurrence of retinoblastoma is treated by excision biopsy of the tumour mass followed by radical orbital radiotherapy to a dose of 50 Gy. This should be combined with adjuvant chemotherapy and, where a risk of direct intracranial extension exists, by neuraxis irradiation. No other child in this series with evidence of local extraocular extension of retinoblastoma at enucleation and who had received radical orbital radiotherapy to a full dose of 50 Gy subsequently recurred in the orbit.(ABSTRACT TRUNCATED AT 250 WORDS)