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Medical Care




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Professor C C de Silva Oration 2000 Multimodal treatment in the management of paediatric malignancies in Sri Lanka R S Jayatilake1 Sri Lanka Journal of Child Health, 2000; 29: 70-84 (Key words: paediatric malignancy, multimodal treatment, Sri Lanka) Introduction The success brought about by the rational com- Childhood cancers form a specific group of tumours bination of the three important therapeutic mo- which differ markedly in clinical behaviour, histology dalities - surgery, radiotherapy and chemotherapy. and sites of origin. In the last decade, childhood mortality from infections and congenital diseases has The dawn of multi-disciplinary team approach. been so greatly reduced that cancers, albeit rare, are the second principal cause of death. Only accidents cause The growth of specialized centres of management more deaths in children less than 12 years of age in Sri for children with cancer i.e. Institutions expecting Lanka. Childhood cancers make up 2% of all cancers in to provide state of the art care for children with Sri Lanka. 50% of them are haematological. The cancer. They have teams consisting of experts as epithelial tumours of adult life are rare in children and well as coordinated programmes for total the spectrum of malignancies in childhood is not varied as seen in adult population. The common types of tumours of childhood, number less than a dozen. The use of rational study protocol. History records some solid tumours undergoing All of the above factors have become norms of spontaneous remission. Neuroblastoma, hepatoblastoma, management. The state of the art care is well seen in the and sacrococcygeal tumours are some of them. USA. 75% of children with cancer are treated according Nasopharyngeal carcinoma, hepatocellular carcinoma, to a national study protocol. Although cure is being and Ewings Sarcoma are tumours children share with achieved in an increasing number of children, the late adults. Genetic factors account for several childhood effects from these treatments have been identified in a tumours. Few are associated with chromosomal significant number of survivors. As this population of abnormalities. Such modes of genetic oncogenesis children and young adults continue to increase, the need appear to occur in patients with retinoblastoma, Wilms for health professionals, both specialist and primary care tumour, osteogenic sarcoma, hepatoblastoma and practitioners to monitor and treat long term survivors, rhabdomyosarcoma. has greatly increased. Some genetic disorders are associated with increased Aims of the study incidence of cancer, e.g. Trisomy 21 has increased incidence of acute lymphoblastic leukaemia. With the This study spans from 1975 to 1999. From 1980 to 1995 use of combined modalities of treatment, such as data of all patients visiting the Institute was correctly recorded; this number included 1959 cases. The purpose chemotherapy over 65% of children with cancer will be of this study was to: cured of their disease. This means that by the year 2000 an estimated one out of 900 young adults will be Present the data available from the National Cancer survivors of childhood cancer1. There has been Institute, Maharagama, Paediatric Oncology Unit, tremendous advances during the last two decades in the in relation to types of malignancy, age at management of paediatric cancers. This has resulted presentation, the frequency and the ethnic dis- Successive clinical trials of new treatment strate- Study the results of treatment and cure and com- gies, based upon the best treatment known at that pare them with international results. Record complications and late effects due to treat- Consultant Oncologist Material and methods 1959 cases have been entered into this study and all of Paediatric malignancies in Sri Lanka: them have undergone standard investigation and Distribution of solid tumours (RSJ/1999) treatment according to international protocols. Certain special investigations such as CT scans MRI scans, routine bone scans and tumour markers were not done as these facilities were not available. Pathology reports Soft tissue sarcoma which were sent from district and provincial hospitals were all reviewed by the Cancer Institute Pathologist for examinations were repeated and verified. Acute Lymphoblastic Leukaemia (ALL) was distinguished from Non-Hodgkin's Lymphoma (NHL) on the percentage of blasts at the time of diagnosis using Murphy's classification2. More than or equal to 25% blasts indicated ALL and less than 25% NHL. Main disease groups were defined using an altered ICDO French-American-British (FAB) classification was used classification scheme as it is commonly used in pae- to sub type the acute leukaemias. Table 4 shows the sub diatric cancer3. types in ALL. 304 (40.9%) were grouped as Unclassified. L1 accounted for 39% and L2 18.2%. In Sri Lanka the upper limit of the paediatric age is 12 87.9% of ALL were Sinhalese and Muslims showed a years, Hence in this series the age group is classified as higher incidence even though the Tamil population was below 1 year, 1 to 4 years, 5 to 8 years and 9 to 12 higher. The war in the North may have contributed to years. There were 1156 (59%) male and 803 (41%) female children. 86.8% were Sinhalese, 6.6% Tamil and 6.7% Muslims. 34.4% and 33.6% of the cases were in the 1 to 4 and 5 to 8 year age groups. Except for the Sub types of acute lymphoblastic leukaemia below 1 year group others had a male preponderance. 1075 cases (54.9%) were haematological malignancies and 884 (44.1%) were solid tumours and accounted for 38%. NHL was second with 5.6% (Tables 1, 2 and 3). Brain tumours and retinoblastomas accounted for 11.1% and 6.7% respectively. 113 (5.7%) were classed as 'Others'. This group was separated into 'Frequent' and 'Infrequent' types. Ovarian cancers stood out at 2.3%. Epithelial cancers were rare and less than 1%. Table 5 shows the age distribution in ALL. 42.7% was in the 1 to 4 age group with a median age of 4.9 years. 50% of acute myeloblastic leukaemias (AML) were Paediatric malignancies in Sri Lanka: unclassified and 30.1% were M4. 42.4% were in the 9 to Distribution of malignancies (RSJ/1999) 12 age group, with a median age of 7.6 years. The presenting age between ALL and AML showed a distinct difference. Once again the Muslim community had a higher representation - 11.3%. Paediatric malignancies in Sri Lanka: Age distribution in acute lymphoblastic leukaemia Distribution of haematological malignancies All the cases of Non-Hodgkin's Lymphomas (NHL) were of the diffuse type with 95.5% having bone marrow involvement (Table 6). Age distribution of NHL is shown in Table 7. The median age was 7years. 83.4% of STS were distributed in the 1 to 8 age group. Tamils showed a higher incidence than Muslims. Neuroblastomas were unique in that 63.6% were in the abdominal cavity and in 29.8% the site was unknown. The age distribution was remarkable in that 54.5% were Types of Non Hodgkins Lymphoma (NHL) below the age of 4 years. Except for a solitary case of chondrosarcoma, the rest of the bone tumours were in two groups, Ewing sarcoma 56% and osteogenic sarcoma 43%. 60% of Ewing sarcomas were in long bones, and affected the upper third of the shaft of long bones and rarely showed the Bone marrow infiltration 'onion peel' appearance radiologically. Flat bones were affected in 30% and ileum was the common site. In osteogenic sarcomas femur was the disease site in NHL – Age distribution (RSJ/1995) 87.5%. Both Ewing and osteogenic sarcomas were seen in the second half of childhood. There were 40 cases Langerhan cell histiocytosis; however the sub types affected different age groups (Tables 8-11). Letterrer-Siwe disease was the least common type, where 75% of them were seen in less than one-year age group (Table 9). 90% of Hand- Schuller-Christian Syndrome and 100% of eosinophilic Classically Hodgkin's Lymphomas (HL) are grouped granuloma were found in the second half of childhood into four sub types. However, 25.9% were grouped as (Tables 7 and 8). In the unclassified type 66.6% were in unclassified due to the poor status of the slides on the 5 to 8 year age group (Table 9). reassessment. Mixed cellular sub type was the commonest (25.9%). 91.3% of HL were in the latter half of childhood. 16% of HL were Tamils with Paediatric malignancies in Sri Lanka: Muslims having 9%. Langerhan-Cell-Histiocytosis (RSJ/1995) On presentation, brain tumours were categorised into Letterer-Siwe-Disease subtentorial 72.5% (158) and supratentorial 27.5% (60) Hand-Schuller-Christian types. In the subtentorial group there were three main types, medulloblastomas 22.5% (49), brain stem glioma Eosinophilic granuloma 34.4% (75) and posterior fossa astrocytoma 15.6% (34). Nearly 80% of the brain tumours were in the 5 to 12 year age group. Unique feature in the posterior fossa tumours was that it spared the below one year age childhood solid tumour, made up 6.7% and 80% were Letterrer-Siwe-Disease - Age distribution unilateral at the time of presentation. Both eyes were equally affected. Unlike brain tumours 81% of retinoblastomas were below 4 years of age. All bilateral tumours were below 4 years of age, suggesting genetic origin. Retinoblastomas occurring above 5 years were unilateral and may have occurred due to spontaneous mutations. All unilateral and some bilateral tumours had enucleation done at the time of referral. Hand-Schuller-Christian-Syndrome 98% of nephroblastomas (Wilms tumours) were Age distribution unilateral; equal representation was observed from both sides. 80.5% were below the age of 4 years. Histologically, Wilms tumours occurring after the age of 5 years had more of epithelial component. There were two main types of soft tissue sarcomas (STS) - 44.5% were rhabdomyosarcoms and 55.5% were other types. 38.7% of rhabdomyosarcomas originated in the head and neck region, which was the highest individual site. free survival. Cases lost for follow up has been indicated Eosinophilic Granuloma - Age distribution as 'lost'. 5 year disease free survival figures has not been given for Period 3. Patients lost ranged from 8 to 23 % in the haematological malignancies and less than 10% for solid tumours. Remission rates (CR) in haematological malignancies CR rates for ALL during the three periods are shown in Table 12. Even though the total number of patients differed in the first period, CR rate was low (55.5%), The results of paediatric malignancies have been compared to 76% in the second period and 80% in the categorized in to three periods ie.1980 to 1985 - Period third period. The protocols adopted were different A 1; 1986 to 1990 - Period 2; 1991 to 1995 - Period 3. similar trend was seen with AML, 37.5% in period 1 This has been done according to the facilities and man and 57.1% and 60% in period 2 and period 3 power available. During Period 1 there was no respectively (Table 13). The management protocols Oncology training programme and facilities were mini- were different. CR rate for NHL in period 1 was half mal. Period 2 saw the dawn of Oncological training that seen period 2 and period 3 (Table 12). CR rate was programme. Period 3 was blessed with trained Oncolo- 40% vs 81.3% vs 79.2%. 'COP' schedule was used in gist, Oncology nursing staff and the availability of first period 1 and 'CHOP' schedule in the other two periods. CT scanner in the private sector and at the National The CR rates in Hodgkin's Disease were 42.8%, 69.4% Hospital, Colombo. National Cancer Institute had the and 78.8% in the three periods respectively. All the establishment of the Blood Bank and facilities to obtain cases had chemotherapy irrespective of the stage. blood components. The protocols adopted for various Customarily stage 1, Stage 11 A in adults had involved conditions underwent change according to the nodal irradiation. 'MOPP' schedule was the standard availability of resources. Results have been compiled as chemotherapy protocol used during period 1. However Complete Remission (CR), 3 year and 5 year disease this was changed to alternating 'MOPP' with 'ABVD'. . Table 12 Remission rate and survival figures in ALL Table 13 Remission rate and survival figures in AML Three and five year survival figures same CNS prophylaxis and maintenance schedule - 5. In AML routine CNS prophylaxis was not given. In ALL and NHL remission induction was followed by Maintenance therapy was given for one year in period 1 consolidation, CNS prophylaxis and maintenance and for two years in periods 2 and 3. Management of therapy for three years. Hodgkin's Lymphoma had only solid tumours involved utilization of all three modalities remission induction therapy. ALL and NHL had the of treatment. Except for brain tumours all others had chemotherapy up-front. Chemotherapy was used for two 9.3% survived 5 years. In period 3 children lost for years. Termination of chemotherapy was dependant on follow up was the same for ALL and AML (Table 13). the status of bone marrow. NHL showed a definite difference in 3 year survival from period 1 to period 3, with different induction ALL, the commonest malignancy in children, had schedules 33% to 79% with 22 to 23% lost for follow up improvement of three-year survival from period 1 to 3, (Table 14). In Hodgkin's Lymphoma the 3 year and 5 the recorded figures being 27.7% to 39.8% to 51.8%. year survival was the same 28% and 55.5%. This is an Once uncomplicated survival was completed by three indication that if HL children survived 3 years disease years, they had greater than 90% chance of surviving 5 free, then they had the same chance of surviving 5 years. years. Lost for follow up during period 1 was up to 22% On this assumption 73.6% successfully treated HL (Table 12). There were no survivors in AML in period 1 children will survive 5 years irrespective of the stage and no significant three-year survival difference between the periods 2 and 3 (23.2% vs. 26.6%). Only Table 14 Remission rate and survival figures in NHL Table 15 Remission rate and survival figures in HL In brain tumours, chemotherapy schedules were tumours. They had surgery followed by radiation different in period 1 and period 2. Medulloblastoma therapy and had an overall three year survival figure of showed a significant difference in three year survival rates in the three periods from 40% to 46.6% to 58.2% (Table 16). Brain-Stem-Gliomas (BSG) during period 3 was diagnosed on CT scans and none had surgery; all Survival figures in brain tumours – had chemotherapy followed by radiation therapy. In medulloblastomas periods 1 and 2, diagnosis was made on radiology, worsening clinical signs and on patients who did not respond to anti TB drugs. They were unfit to have any chemotherapy and only radiation therapy. None sur- vived 3 years in period 1 and 10% (2/20) survived 3 years in period 2. There were no 5 year survivors. Period 3 had 26.6% (12/45) surviving 3 years which is more than double that seen in period 2 (Table 17). Posterior fossa astrocytoma had the best survival figures for brain tumours. 60% three-year survival was seen in periods 2 and 3 and 30% survived 5 years in period 2 (Table 18). Supra tentorial tumours ranged from craniopharyngiomas to gliomas and choroid plexus unilateral tumours had routine enucleation and bilateral Survival figures in brain tumours – BSG tumours had enucleation of the worst affected eye. In period 1 all had oral cyclophosphamide with or without radiation therapy. Due to the alarming survival figures in period 1, treatment protocol was changed. With the change of protocol 5 year survival rose from 17% in period 1 to 54.9% in period 2. Three-year survival in period 3 was 69.5% (Table 20). Survival figures in Wilms tumours is shown in Table 21. Changes in Survival figures in brain tumours –posterior fossa survival rates are due to changed management protocol. In period 1 patients had six weekly Actinomycin D for one year postoperatively. In periods 2 and 3, children had Actinomycin D during surgery and postoperatively in combination with doxorubicin for a year. Radiotherapy was given in indicated cases only. Five- year survival changed from 52.3% to 65.5% from period 1 to 2. Three-year survival rate of 78.5% was seen in period 3. Cases lost for Wilms tumour was less than 4%. In Wilms tumour there was one case with aniridia and one with hemihypertrophy of the body; both cases died Survival figures in supra tentorial brain within one year. In soft tissue sarcoma, the 110 cases recorded are confined to periods 2 and 3. Abdominal rhabdomyosarcomas did poorly as all of them were referred after inadequate surgery and most patients were not fit to have chemotherapy. There were no 5 year survivals and the three year survival was confined to rhabdomyosarcomas did better with the combined modality of treatment with three year and five year survival figures of 39% and 26% respectively. Other Treatment of retinoblastoma was a success story when soft tissue sarcomas had survival figures of 36% and figures are compared in the different periods. All 24.5% at three and five years respectively. Table 20 Survival figures in retinoblastoma Table 21 Survival figures in Wilms tumour In Neuroblastoma, too, the management protocol management's of bone tumours in period 1 was dismal, differed in the three periods. In periods 1 and 2 the five basically due to inability to give high dose methotrexate year survival was almost half the figure seen in the three with folinic acid rescue in osteogenic sarcoma. Schedule year period, showing that almost 50% developed variation was seen in periods 2 and 3 with change in recurrent disease once being in remission and clinically disease free at three years (Table 22). Results of Table 22 Survival figures in neuroblastoma Three-year survival of 44.4% and 43.3% was seen 100% survival (Table 23). In frequent paediatric Ewing sarcoma and osteogenic sarcoma respectively. In malignancies gonadal tumours had the best survival Langerhan cell histiocytosis 72.9% overall three-year figure, 62.5% three-year survival, nasopharyngeal carci- survival was seen with eosinophilic granuloma having noma having 54.5%. Table 23 Survival figures in Langerhan-cell histiocytosis Letterer-Siwe-Disease Hand-Schuller-Christian Syndrome Eosinophilic granuloma same reason the aggressiveness of the induction schedules used in the treatment. Hence our CR rate Childhood cancers are rare, but with modern treatment a being 80% and a cure of 37.5% in period 2 and three high cure rate can be expected. The same cannot be said year survival of 51.8% in period 3. Apart from bone for adult cancers. This has been possible because a team marrow relapse, recurrent CNS disease was the major approach that incorporate the skills of the paediatrician, complication that was encountered. In a follow up of paediatric surgeon, radiation oncologist, paediatric 593 cases of ALL 40 (6.7%) had recurrent CNS disease. Majority was in ALL (L3-25%). Table 24 shows the specialist and social workers are imperative to ensure different types of CNS disease. Meningeal leukaemia that patients receive treatment, supportive care and accounted for 80%. Tables 25 and 26 shows the survival rehabilitation in order to ensure optimal survival and after recurrent CNS disease and the survival of sub quality of life. This type of 'state of the art' treatment types. Only 25 % survived over one year. The survival should be given at specialized centres, using protocols figures for AML were dismal - 9.3% 5 year survival in that have been tried out and proved effective. period 2 and 26.6% three year survival in period 3. United Kingdom national statistics show survival in Approximately 70% of children with ALL are cured AML has improved from 8% at 4 to 5 years during with current protocol-based treatments, while 95% of 1974-1976 to 25% from 1983-19855. With more the patients can be expected to attain complete re- aggressive chemotherapy recent disease free survival mission4. Cure is correlated to a number of prognostic has risen to 30 to 40%6. Majority of them need bone variables. These include clinical parameters and bio- marrow transplants if we are to achieve a high cure rate. logic variables. With the limited resources available we Rate of cure after transplant is 60 to 70%7. have been able outline the clinical variables. For the Incidence of sub-types of recurrent CNS disease Survival figures in recurrent CNS disease Meningeal leukaemia Hypothalamic syndrome Localized CNS disease Table 26 Survival of sub types of R-CNS disease after treatment Meningeal leukaemia Hypothalamic syndrome Localized disease We have had excellent survival figures for NHL i.e. a fold; to cure the disease and to preserve as much vision cure rate of 69%, with most studies reporting over 60% as possible. In this series cases referred were after cure rate8. A possible reason may be the use of 'CHOP' enucleation and 3 year survival increased from 28.5% to 69.5% basically because all had intrathecal methotrexate maintenance therapy for three years, as we now know with combination chemotherapy. CNS seeding was the that 'CHOP' is the best schedule for NHL. More than primary site of disease recurrence and with the new 75% of newly diagnosed HL in children are cured with approach of treatment CNS seeding was overcome. modern radiation therapy and/or combination therapy9. Patients with retinoblastoma, particularly the hereditary Our results show 55.5% 5 year survival in period 2 and type, have an increased frequency of second 73.6% three year survival in period 3, using malignancies, most often bone tumours, occurring in up combination chemotherapy alone. Use of combination to 8% after 18 years of follow-up12. Wilms tumour is a chemotherapy judiciously has spared muscle atrophy curable condition in the majority of affected children. that can occur with the use of radiation therapy. Greater than 90% of patients survive 4 years after diagnosis13. Our series recorded 78.5% three-year Primary brain tumours are a widely varying group of disease free survival in all cases pooled together. The diseases and form the most common solid tumours in major drawback in this series was the absence of data on children. The clinical distribution of these tumours does the subtypes and operative findings and inability to not vary globally and more than 50% of children recover the original slides of second opinion. diagnosed with brain tumours will survive 5 years from Pathologist's reluctance to release slides for second diagnosis10. For a good many of childhood brain opinion remained an obstacle in obtaining good tumours, the optimal treatment regimen has not been histological reports. This was true for all solid tumours. determined. In this series for medulloblastomas and Paediatric surgeons other than at Lady Ridgeway BSG the chemotherapy schedule was changed from Children's Hospital carried out surgery without vincristine + procarbazine + methyl CCNU to 8-drugs- consultation with the Oncologists and patients never had in-one-day-regime ("8 in 1") and immediate survival advantage was seen. In medulloblastoma from 40% management was according to international protocol; three year survival in period 1 to 58.2% in period 3. In hence the lower survival figure is because of inadequate BSG no survival in period 1 to 26.6% three year staging and proper subtyping. survival in period 3. BSG is classified according to location, extent of spread and histology. BSG may occur Nearly 70% of neuroblastoma patients have metastatic in pons, mid brain, the tectum, the cervico-medullary disease at diagnosis14 and it is of paramount importance junction, or the dorsum as exophytic growths. However, to identify them and to see the extent of disease prior to majority are in the pons and are diffuse and intrinsic. treatment. It is also necessary to perform catecholamine One third spread by the CSF channel. The less common assays in urine prior to and during management. MIBG tumours of mid brain, especially in the tectal plates, scan facilities were not available in Sri Lanka and have slow growth and long term survival. There is catecholamine assays took nearly a month, which would approximately 80% five year progression free survival mean that the disease will become far too advanced if vs. 20% for tumours in pons and medulla11. All the BSG this test was done on a routine basis. In spite of this, by were treated without a biopsy; however biopsy may be adopting a established protocol it was possible to cure indicated for BSG that are not diffuse and intrinsic, one third of the patients during period 2 and to a 68.7% when the tumour is progressive or when surgical three year survival in period 3. According to children debulking is possible. New approaches with stereotactic cancer group (CCG) staging system, stages I, II, III, needle biopsy may make biopsy safer. These facilities (unresected negative nodes) the probability of long term were not available in Sri Lanka during this study. survival is 75 to 90% depending on the age and for stage IV 50% to 70%15,16. Majority of patients with retinoblastoma have extensive disease within the eye at diagnosis with either massive 90% of patients with apparently localized Ewing tumour involving more than one half of retina, multiple sarcoma have occult metastatic disease17 and survival is tumours diffusely involving the retina, or obvious poor if an aggressive treatment approach is not adopted. seeding of the vitreous. The goals of therapy are two This is quite evidently seen in our series. There were no

survivors in period 1. In periods 2 and 3 survival rates Our experience with limited number of nasopharyngeal improved and in period 3 the philosophy of radical cancer is that they remained local and loco-regional. surgery for "expendable bones" (like the fibula) was Systemic spread was not seen and 54.5% survived 3 adopted. This reduced the tumour burden and better years. Yolk sac tumours were extensive (Stage III/IV) results were seen with chemotherapy. Hence, three-year survival figure of 44.4% in period 3. Soft tissue uncontrollable with chemotherapy. Different results sarcomas (STS) consists of a malignant tumour presumably originating in the primitive mesenchymal Dysgerminomas gave good results with radiation tissue and exhibiting no rhabdomyoblastic differen- therapy. No chemotherapy was used in the treatment of tiation formed a definite entity when compared to rhabdomyosarcoma. Abdominal rhabdomyosarcomas did poorly as almost all the tumours were inadequately Langerhan-cell-histiocytosis gave mixed results. As debulked, resulting in a large tumour burden. There classically stated, eosinophilic granuloma was treated were no 5 year survival in this group. CNS extension with surgical 'scooping' followed by low dose radiation has been reported as a complication in head and neck therapy which gave 100% survival. Low dose radiation rhabdomyosarcomas, none were seen in this series; therapy had a definite place in the management of however their presentation is late. 26% five year sur- 'punched out' areas in bone with 100% local control. vival was seen in this group. It is reported to be more than 60% in those children who receive optimal treat- Although cure is being achieved for a sizeable number ment18. Our results are way below the best figures given, of children with multimodal therapy, late effects from in view of the late presentation and lack team these treatment have been identified in a significant number of long term survivors. Children withstand all forms of treatment remarkably well; however the late Osteogenic sarcoma was one other tumour that had effects will manifest when the child matures. Hence, dismal survival figures in our series - 43.3% three year observation of late effects has been documented in this survival in period 3. Patients who survived were those series 5 years after being pronounced cured. Table 27 consented to amputation/disarticulation as these cases outlines the possible delayed effects. had extensive tumours. Presentation was late because all were treated by Ayurvedic practitioners.

Linear growth is an important aspect in the growth and normal counterparts19. It has been suggested that lower development of a child; two factors contribute to this height in ALL children was present at diagnosis20 or (Table 28). Sixty six children cured of ALL have been consequence of disease. This is consistent with a recent compared with normal children using Sri Lankan study documenting an abnormality in endocrine function height/weight chart18a (Table 29). 21 (38.2%) boys and 5 as a manifestation of ALL21. Cranial irradiation of doses (44.5%) girls had growth retardation possibly due to 2400cGy to children less than 10 years shows an IQ of effects of cranial irradiation. Pituitary hormone studies 85 to 99 - a drop of 10 to 11 points22. A proportion of were not done due lack of facilities. Neuropsychological ALL children in this series above 6 years who had this effects have been studied in children who have had dose of radiation showed inability to compete and was cranial prophylaxis and interesting results have been inactive at school. A comparison of cranial irradiation observed (Table 30). A significant proportion of doses of 1800cGy versus 2400cGy has shown normal children over 6 years of age (90%) did not attend growth rate and IQ with 1800cGy and not with the school, the primary cause being that they were not able latter23. Higher doses of radiation to the brain show to compete with the normal children and 65% of significant neurological and mental disturbances24. 20 to children in this group were not active in school. It is 30% of medulloblastomas receiving higher dose of possible that this is a direct effect of the radiation radiation showed CNS disturbances with up to 50% of therapy given. Recent investigations have revealed that them needing special educational institutions25. children treated for ALL were significantly smaller than

In this series all cases of HL had chemotherapy and Acute myelomonocytic leukaemia (AMML) and no endocrine dysfunction was seen. 44% of HL and supratentorial gliomas made up 27.2% each. Char- 17% of NHL had elevated levels of TSH when acteristically the gliomas were all supratentorial treated with radiation therapy to the neck with mean which is not in keeping with classical presentation of interval of occurrence of 18 to 31 months26. brain tumours in children. Table 33 shows the distribution of the second malignancies. The cumulative risk of developing a second malig- nant neoplasm following radiation therapy in long term survivors of childhood cancer has been Incidence of second malignancy after 7 years of estimated as high as 10% by 10 years following disease free follow up initial treatment and 17% by 20 years27,28. The annual Total number of cases evaluated risk of developing second malignancy during or after Number of cases surviving 5 years treatment for ALL is 62.5 per 100.00029. Number of second malignancies malignancy. In many instances it is difficult to Types of second malignancy chemotherapy is given before during or after radiation therapy. Both modalities may affect DNA- Acute myelomonocytic leukaemia RNA moieties and nucleic acid metabolism. Both these modalities are also immunosuppressive. Table 31 shows 1268 cases in this series evaluated, of Acute undifferent leukaemia (AUL) which 528 (41.6%) cases survived beyond 5 years and 11(2%) had a second malignancy. The types of Follicular carcinoma of thyroid second malignancies are shown in Table 32. Table 33 Distribution of second malignancies Children who were treated for HL and retinoblastoma malignancy following treatment for HL in children had the highest number of second malignancies viz. and adolescents is 18.7% at 15 years after diagnosis, 36.3% (4/11). The cumulative risk of second with predominance of bone sarcoma30. In our series, one out of 4 cases were bone sarcomas;Three out of 4 8. Magrath I. Malignant Non Hodgkin's Lymphoma in were acute leukaemias. One case of follicular children In; Pizzo PA, Poplack DG: Principles and carcinoma was seen in a patient with a practice of Paediatric Oncology. Philadelphia retinoblastoma, who had chemotherapy. It has been JB.Lippincott, 2nd.ed, 1993; pp 537-5. estimated that 20 to 30% of individuals exposed to external thyroid irradiation had developed single or 9. Levanthal B G, Donaldson S S, Pizzo P A, Poplack multiple thyroid nodules; approximately 30% of them D G. Principle and Practice of Paediatric Oncology. are malignant-follicular or mixed types rarely Philadelphia JB. Lippincott, 2nd ed. 1993 pp 577-94. anaplastic. A single case in our series had a bone sarcoma and this was in a case of retinoblastoma. 10. Cohen M E, Duffman P K, editors. Brain tumours Retinoblastomas are known to get bone sarcomas. All in children. Principles of Diagnosis and treatment. our cases of second malignancies had a fatal outcome 2nd. ed. New York: Raven Press 1994. within a year in spite of active treatment. 11. Halperin E C, et al. Selection of a management strategy for paediatric Brain Stem Gliomas. Medical and Paediatric Oncology 1989; 17(2): I wish to thank all my Registrars from 1980 to 1999. It is too long a list to name them separately. 12. Gallie B L, Dunn J M, Chan H S, et al: The genetics of Retinoblastoma, relevance to the patient. Paediatric Clinics of North America 1991; 1. Meadows A T, Krejmas N L, Belasco J B. The medical cost of cure. 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Op-gbev120037 1046.1053

Weak 50-mRNA Secondary Structures in Short EukaryoticGenes Yang Ding, Premal Shah, and Joshua B. Plotkin* Department of Biology, University of Pennsylvania *Corresponding author: E-mail: [email protected]. Accepted: September 21, 2012 Experimental studies of translation have found that short genes tend to exhibit greater densities of ribosomes than long genes ineukaryotic species. It remains an open question whether the elevated ribosome density on short genes is due to faster initiation orslower elongation dynamics. Here, we address this question computationally using 50-mRNA folding energy as a proxy for translationinitiation rates and codon bias as a proxy for elongation rates. We report a significant trend toward reduced 50-secondary structure inshorter coding sequences, suggesting that short genes initiate faster during translation. We also find a trend toward higher 50-codonbias in short genes, suggesting that short genes elongate faster than long genes. Both of these trends hold across a diverse set ofeukaryotic taxa. Thus, the elevated ribosome density on short eukaryotic genes is likely caused by differential rates of initiation, ratherthan differential rates of elongation.