Faculty Bibliography

OBJECT: The purpose of this study was to devise an improved method of treating high-grade gliomas of the spinal cord in children who have a dismal prognosis following conventional treatment. METHODS: Eighteen children with newly diagnosed high-grade astrocytomas arising in the spinal cord were enrolled in the Children's Cancer Group (CCG) protocol 945. Following surgery, they were all assigned to receive two cycles of '8-drugs-in-1-day' (8-in-1) chemotherapy prior to radiotherapy and eight additional cycles thereafter. A centralized neuropathology review was used to confirm the diagnosis of high-grade astrocytoma in 13 of the 18 children: anaplastic astrocytoma (eight patients), glioblastoma multiforme (four patients), and mixed malignant glioma (one patient). Diagnoses were discordant in five patients. There were eight boys and five girls in the group with confirmed diagnoses, with a median age of 7 years (range 1-15 years). The extent of resection was confirmed by computerized tomography or magnetic resonance (MR) evaluation in five of 13 patients. There were six gross-total or near-total resections (> 90%), four partial or subtotal resections (10-90%), and three biopsies. Six patients showed evidence of leptomeningeal metastases at diagnosis based on staging MR examinations. Eight of the 13 patients completed at least eight of the prescribed 10 cycles of chemotherapy; five received craniospinal radiotherapy and five spinal radiotherapy. CONCLUSIONS: The 5-year progression-free and total survival rates for the 13 children were 46 +/- 14% and 54 +/- 14%, respectively. Seven patients suffered a relapse at the primary site, four of whom also had leptomeningeal metastases. Seven of the 13 patients (54%) remain alive at the time of this report at a median of 76 months (range 51-93 months) from study entry. Six patients died between 8 and 38 months after diagnosis, all with active disease. Intensification of therapy may further improve outcome in this high-risk population

In order to assess the relative ability of general practitioners (GPs) to detect diabetic retinopathy (DR), especially sight-threatening diabetic retinopathy (STDR) by direct ophthalmoscopy or by examining, on a separate occasion, retinal images as 35 mm colour transparencies, a South and Mid Wales primary care-based study was performed in four general practices (six GPs). The participating GPs were provided with standardized training and equipment. Both methods were compared to the 'reference' grade of DR provided by the Diabetic Retinopathy Reading Centre (London), based on the same retinal images. Ophthalmoscopy and retinal photography (Canon CR4 45NM) with mydriasis were all practice based. The clinical assessments were based on a protocol developed for screening for DR in Europe. A total of 996 people with diabetes were identified, representing a prevalence of known diabetes of 2.1%. After exclusions on medical grounds, 897 patients were available for screening, of whom 605 (68%) were photographed. Based on the retinal images, the reference centre identified DR in 43% and STDR in 14.4%. In total, 597 valid comparisons between GPs and the reference centre were obtained; of these, 462 (77%) were high quality photographs which were used in subsequent analysis. The sensitivity for detecting any DR increased from 62.6% (95% CI 55.9-69.4) with ophthalmoscopy to 79.2% (95% CI 73.6-84.9) using retinal photographs, specificity remaining essentially unchanged at 75.0 (95% CI 69.5-80.5) and 73.5% (95% CI 68.0-79.1) with the positive predictive value (PPV) increasing from 67.2 (95% CI 60.4-74.0) to 71.0% (95% CI 65.0-77.0), respectively. The detection of STDR sensitivity increased from 65.7 (95% CI 54.4-77.1) with ophthalmoscopy alone to 87.3% (95% CI 79.4-95.2) based on retinal photographs with specificity falling from 93.8 (95% CI 91.4-96.3) to 84.8% (95% CI 81.2-88.5) and PPV from 65.7 (95% CI 54.4-77.1) to 51.2% (95% CI 42.1-60.3), respectively. We conclude that the use of standardized 35 mm colour transparency retinal photographs for screening by trained GPs in a primary care setting achieves an acceptable detection rate (>87%) for STDR, contrasting with ophthalmoscopy alone (66%), which was below the proposed UK standard of 80%.

PURPOSE: Medulloblastoma is a highly lethal disease when it recurs. Very few patients survive with conventional treatment. This study evaluated the use of high-dose carboplatin, thiotepa, and etoposide with autologous stem-cell rescue (ASCR) in patients with recurrent medulloblastoma. METHODS: Chemotherapy consisted of carboplatin 500 mg/m2 (or area under the curve = 7 mg/mL x min via Calvert formula) on days -8, -7, and -6; and thiotepa 300 mg/m2 and etoposide 250 mg/m2 on days -5, -4, and -3; followed by ASCR on day 0. In addition to the study-prescribed therapy, 21 patients received other treatment: neurosurgical resection in seven, conventional chemotherapy in 17, and external-beam irradiation in 11 cases. RESULTS: Twenty-three patients with recurrent medulloblastoma, aged two to 44 years (median, 13 years) at ASCR, were treated. Three patients died of treatment-related toxicities within 21 days of ASCR; multiorgan system failure in two, and Aspergillus infection with venoocclusive disease in one. Seven of 23 patients (30%) are event-free survivors at a median of 54 months post-ASCR (range, 24 to 78 months). Kaplan-Meier estimates of event-free (EFS) and overall survival are 34% +/- 10% and 46% +/- 11%, respectively, at 36 months post-ASCR. CONCLUSION: This strategy may provide long-term survival for some patients with recurrent medulloblastoma

PURPOSE: To evaluate a strategy that avoids radiotherapy in children less than 6 years of age with newly diagnosed malignant brain tumors, by administering myeloablative consolidation chemotherapy with autologous bone marrow reconstitution (ABMR) after maximal surgical resection and conventional induction chemotherapy. PATIENTS AND METHODS: Between March 1991 and April 1995, 62 children (median age, 30 months) with newly diagnosed malignant brain tumors were enrolled onto this trial. Children received conventional induction chemotherapy with vincristine, cisplatin, cyclophosphamide, and etoposide, repeated every 3 weeks for five cycles. Children without disease progression on induction chemotherapy were offered consolidation with myeloablative chemotherapy that incorporated carboplatin, thiotepa, and etoposide followed by ABMR. Irradiation was used only for residual tumor at consolidation or for progressive/recurrent disease. RESULTS: Induction chemotherapy was well tolerated by most patients; however, progression was noted in 17 children (27%) and four (6%) died of treatment complications. Of 37 children who received consolidation chemotherapy with ABMR, 15 are free of disease progression (median post-ABMR without further treatment, >44 months). The remaining 22 all progressed within 15 months of ABMR; three of 37 (8%) died of treatment-related complications. The 3-year overall survival (OS) and event-free survival (EFS) rates from diagnosis for all children are 40% (95% confidence interval [CI], 28% to 52%) and 25% (95% CI, 13% to 37%), respectively. Radiotherapy was administered to 19 of 62 children: 17 for progressive disease (PD) and two for residual disease at the time of ABMR. CONCLUSION: A significant proportion of children with malignant brain tumors can avoid radiotherapy and prolonged maintenance chemotherapy yet still achieve durable remission with this brief intensive chemotherapy regimen

Over 90% of childhood ependymomas arise within the cranium, two-thirds below and one-third above the tentorium, and they comprise 8-10% of all childhood CNS neoplasms. This is in contradistinction to the presentation in adults where over 75% of the ependymomas arise within the spinal canal. The incidence of 2.2 cases per million appears to be increasing over the past 30 years. The biology of the disease resembles that of a low-grade glioma where local control measures are most important and less than 5% of children present with metastatic disease. Thus, total resection is the optimum therapy. The value of adjuvant therapy for children with no postoperative residual disease is unclear. Adjuvant radiotherapy is reserved for children with postoperative residual disease and appears to prolong survival. A brief review of our current understanding of the incidence, sites of origin, clinical presentations, prognostic factors and controversial treatment issues will be presented

The Welsh Community Diabetic Retinopathy Study was designed to assess the effectiveness of the Field Guide Book for screening for diabetic retinopathy in Europe. A community-based sample (prevalence 2%) of diabetic patients was recruited from four general practices. Standardised training and equipment were provided. All patients were invited to attend practice-based screening sessions on two occasions over 3 years (phases 1 and 2). After mydriasis, clinical ophthalmoscopy was performed by a study optometrist and general practitioners (GPs). 2 x 45 field 35 mm retinal slides were obtained according to EURODIAB protocol. Anonymised slides were assessed by GPs, diabetologists and the optometrist. All the findings were graded externally (reference standard). In phase 2 community optometrists also performed ophthalmoscopy and assessed photographs. For detecting sight threatening diabetic retinopathy using ophthalmoscopy, GPs achieved a sensitivity of 65.7%, specificity 93.8% and positive predictive value (PPV) 65.7%. Community optometrists achieved a sensitivity of 82.2% with a PPV of 50.7%; the study optometrist 79.2 and 55.9%, respectively. The use of 35 mm slides improved sensitivity for the detection of sight threatening retinopathy to 87.3, 91.1 and 97.2% for GPs, community optometrists and the study optometrist, respectively. PPV fell to 51.2% for GPs, 40.6% for community optometrists, but increased to 58.8% for the study optometrist. Diabetologists achieved a sensitivity of 88.7% and a PPV of 65.6%. It is concluded that the European field guide is an effective tool for screening for retinopathy in clinical practice.

Monozygotic twin brothers, clinically discordant for Leber's hereditary optic neuropathy (LHON), had a heteroplasmic point mutation at position 14484 in the mitochondrial DNA that was not detected in their mother. Moreover, the mutation occurred on the rare European haplogroup X, rather than the haplogroup J commonly associated with the 14484 mutation. These data indicate that the 14484 mutation in this family was a new mutation, indicating that it was the de novo occurrence of a common, primary LHON mutation.