Judith E. Kingston

Diagnosis of acute promyelocytic leukaemia by RT-PCR: detection of PML-RARA and RARA-PML fusion transcripts

Summary. Acute promyelocytic leukaemia (APL; AML M3) is identified by a unique t(15;17) translocation which fuses the PML gene to the retinoic acid receptor alpha gene (RARA). Reverse transcription coupled with the polymerase chain reaction (RT‐PCR) has been used to develop a diagnostic test for APL based on the PML‐RARA fusion message. Separate PCR assays were designed to amplify either PML‐RARA (15q+ derived) or RARA‐PML (17q‐ derived) chimaeric transcripts. PML‐RARA transcripts were detected in every case from a series of 18 APL patients with cytogenetically confirmed t(15;17) translocations, whereas RARA‐PML messages were detected in only 67% (12/18) of these patients. This suggests that it is the 15q + derivative which mediates leukaemogenesis. Furthermore the PCR approach (or Southern analysis) may be used to identify in which of the alternative PML introns the breakpoint occurs; 52% of cases (15/29 patients) utilize a 5′ PML intron and 48% the 3′ intron (14/29 cases). Neither the choice of PML intron nor the expression of the 17q‐derivative could be correlated with the microgranular variant of APL (M3V), overall survival rate, age, sex or presence of coagulopathy. Finally, the fusion message is undetectable in five remission samples. This indicates a possible use for RT‐PCR in monitoring remission patients for evidence of relapse.

Retinoblastoma treated with primary chemotherapy alone: The significance of tumour size, location, and age

Aims: To evaluate how tumour size, retinal location, and patient age affect the outcome of retinoblastoma foci treated with chemotherapy. Methods: Retrospective review of retinoblastoma foci treated with primary chemotherapy alone. Individual tumours were coded with regard to their largest basal diameter, location within the eye (macula, macula to equator, equator to ora serrata), and patients age at diagnosis. Successfully treated tumours required no further intervention while those requiring additional treatment were coded as failures. Results: 56 (72%) tumours responded successfully to chemotherapy alone while 22 (28%) required additional therapy. 26 of 31 macular tumours (84%) and 30 of 47 extramacular tumours (64%) responded to chemotherapy (p <0.060). Relative to size, 46 of 60 tumours (77%) greater than 2 mm in basal diameter were successfully treated with chemotherapy, while only 10 of 18 tumours (56%) less than or equal to 2 mm responded (p <0.088). Among the eight tumour foci diagnosed in children less than 2 months of age, five (63%) failed to respond to chemotherapy alone (p <0.032). Conclusion: Retinoblastoma is more likely to respond to primary chemotherapy if it is located in the macula and if the patient is older than 2 months of age. Tumours measuring less than 2 mm in diameter may be less responsive to this treatment.

Ectopic intracranial retinoblastoma in childhood.

Twelve out of a series of 630 children with retinoblastoma, treated in the ocular oncology units at St Bartholomews and Moorfields Eye Hospitals during the past 30 years, have developed ectopic intracranial retinoblastoma. The ectopic tumour occurred in the pineal region in eight children and in the suprasellar region in four. Ten patients had bilateral retinoblastoma, one unilateral disease, and one child presented with an isolated suprasellar tumour but no evidence of retinal disease. The interval from the initial diagnosis of retinoblastoma to the development of ectopic intracranial disease ranged from 4 to 70 months, median 34 months. Methods of treatment for the ectopic tumour varied, but all 12 children died with a median survival of only 8 months following the diagnosis of ectopic retinoblastoma. Subsequent spread of tumour to other sites within the central nervous system proved to be the most frequent cause of death. Ectopic intracranial retinoblastoma is a potentially curable neoplasm, but it requires adequate therapy to the whole neuraxis as well as high dose equivalent radiotherapy to the primary tumour.

External beam radiotherapy for retinoblastoma: I. Whole eye technique.

A retrospective analysis has been performed of the results of external beam radiotherapy for retinoblastoma using a whole eye technique. Local tumour control has been assessed in a consecutive series of 175 eyes in 142 children all of whom received external beam radiotherapy as the primary treatment for retinoblastoma. Follow up ranged from 2 to 17 years (median 9 years). Tumour control rates have been analysed with respect to the Reese Ellsworth classification and the series includes eyes in groups I to V. Focal salvage therapy was given for persistent, recurrent, or new tumours after radiotherapy. Following whole eye radiotherapy alone, the overall ocular cure rate was 57%, though with salvage therapy 80% of eyes could be preserved.

Comparative Genomic Hybridization of 49 Primary Retinoblastoma Tumors Identifies Chromosomal Regions Associated With Histopathology, Progression, and Patient Outcome

Forty‐nine primary retinoblastoma (Rb) tumors were analyzed by the use of comparative genomic hybridization (CGH), and clinical/histological correlations were performed. Adverse histological factors were present in 13 patients. Chromosomal imbalance was a frequent phenomenon, seen in 96% of the tumors. Gain of 6p represented the most frequent event (69% of the tumors), whereas +1q was observed in 57%, confirming that these abnormalities are key secondary events in retinoblastoma tumor progression. Loss of 13q and 16 was significantly associated with tumors displaying adverse histo‐prognostic factors, whereas −16q was significantly associated with tumors without adverse features. In three patients who developed an extra‐ocular relapse, the tumors showed −13q and 2/3 had −5q, suggesting that these abnormalities may be associated with metastasis. Children ≥ 36 months of age at enucleation tended to have more CGH abnormalities per tumor than children < 12 months (median numbers 11 vs. 3). In addition, +1q, +13q, −16, and −16q were more frequent in children with an older age at enucleation. Identical CGH changes were found in both tumors from one patient with bilateral tumors, suggesting a common origin. It is possible that tumors displaying loss of 13q and 5q indicate those patients who may suffer an adverse outcome and who would require alternative or more intensive therapy. CGH analysis on larger cohorts and in prospective clinical trials will be invaluable in determining whether a genetic classification of retinoblastoma represents a reliable measure of prognosis.

Delay in diagnosis of retinoblastoma: risk factors and treatment outcome

BACKGROUND Delay in diagnosis of retinoblastoma causes considerable parental distress; however, the primary healthcare professional (PHP) may have difficulty detecting the most common presenting symptom—leucocoria. Alternatively, the PHP may not appreciate that retinoblastoma is the pathology underlying more common ocular symptoms in infants and young children. METHOD The parents of 100 recently diagnosed patients with retinoblastoma were interviewed to establish the extent of diagnostic delay, ascertain any associated risk factors, and to determine whether or not delay influenced treatment outcome. RESULTS Although nearly 50% of patients were referred to an ophthalmologist within 1 week of first consulting a PHP, one quarter waited more than 8 weeks. There was a significantly increased risk of diagnostic delay in younger patients, those presenting with squint rather than leucocoria, and those first presenting to a health visitor rather than to a general practitioner. The risk of local tumour invasion was significantly increased by diagnostic delay. Treatment with primary enucleation was not increased by diagnostic delay. There were no deaths during the study period. CONCLUSION Primary healthcare professionals require education about the importance of ocular symptoms, especially squint, in paediatric patients.

External beam radiotherapy for retinoblastoma: II. Lens sparing technique.

A retrospective analysis is presented of the results of external beam radiotherapy for retinoblastoma utilising an accurate lens sparing technique. Local tumour control has been assessed in a consecutive series of 67 eyes in 53 children all of whom received external beam radiotherapy as the primary treatment of retinoblastoma. Follow up ranged from 12 to 82 months (median 35 months) with 76% of the children followed for more than 2 years. Tumour control rates have been analysed with respect to the Reese-Ellsworth classification. The role of adjuvant and salvage focal therapy is emphasised. Following lens sparing radiotherapy with prior adjuvant treatment of anterior tumours, where appropriate, the overall ocular cure rate was 72%. With salvage therapy of persistent, recurrent, or new tumours, 93% of eyes could be preserved in this series which includes mainly eyes classified in Reese-Ellsworth groups I-III. These results compare favourably with those of whole eye external beam radiotherapy for comparable tumours, and with those of lens and anterior segment sparing using other techniques. They were achieved without the ocular morbidity associated with whole eye external beam radiotherapy.

Chemotherapy in metastatic retinoblastoma

Eleven children with metastatic retinoblastoma diagnosed during the period 1970-1984 were treated with chemotherapy. Short-term complete responses were observed in three children treated with a four-drug combination which included cisplatinum, and in one child treated with vincristine and cyclophosphamide. The median duration of survival of the 11 children receiving chemotherapy was nine months, whilst the median survival of 13 children with metastatic retinoblastoma who were not given chemotherapy was only 2.3 months (p = 0.06). This suggests that retinoblastoma is a chemosensitive tumour and therefore adjuvant chemotherapy may have a role in children with retinoblastoma who at diagnosis are thought to be at high risk of developing metastatic disease.

Quality of life in survivors of childhood cancer after megatherapy with autologous bone marrow rescue

A questionnaire study was carried out in a group of survivors of childhood cancer to assess their quality of life. The questionnaire was sent to 30 survivors who had completed treatment with megatherapy followed by autologous bone marrow rescue at St Bartholomews Hospital, London. Of the 28 respondents (93%), in 27 (96%) the quality of life was judged to be good, with 11 of these 27 (40%) having no disability whatsoever and a further 9 (33%) reporting only minimal disability. The other 7 patients had moderate to severe disabilities, with pain and depression remaining ongoing problems, and some adolescents felt that they were unable to cope with everyday life alongside their peers. Nine parents and 14 of the children themselves expressed anxiety about the previous illness. The study shows that, by using a postal method, a satisfactory assessment of quality of life in survivors of childhood cancer can be made.

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)