Treatment of overt meningeal leukaemia in children: results of second MRC meningeal leukaemia trial.

After induction ofmeningeal remission by a course of intrathecal methotrexate patients were randomly allocated to receive either cranial irradiation or craniospinal irradiation. Patients being treated for their first meningeal relapse were randomised separately from those in their second or subsequent relapse. All eight patients in their first relapse who were given cranial irradiation alone developed further meningeal recurrence (median length of remission 15 weeks) compared with only two out of nine given craniospinal irradiation (median length of remission at least 99 weeks). Four of the nine patients given craniospinal irradiation were alive and without further meningeal relapse two and a half to four years after treatment. Craniospinal irradiation produced no such advantage for patients entering the trial in their second or subsequent meningeal relapse.     

Treatment of acute lymphoblastic leukaemia: effect of variation in length of treatment on duration of remission. Report to the Medical Research Council by the Working Party on Leukaemia in Childhood.

Patients with acute lymphoblastic leukaemia (ALL) were allocated at random either to stop maintenance chemotherapy after six 12-week courses or continue with a further six. The main difference between the two groups was in the incidence of bone-marrow relapse within nine months after stopping treatment. Such relapses occurred less in older patients and those with higher leucocyte counts initially than in those who appeared to have the best prognosis--namely, those with typical low-count childhood ALL. No patient given prophylactic irradiation to cranium and spine combined with intrathecal methotrexate suffered meningeal relapses, whereas among those not given such prophylaxis the lack of benefit from continuing treatment was mainly attributable to meningeal relapses.     

Final height in children with medulloblastoma treated with growth hormone

BACKGROUND: Medulloblastoma is the most frequent primary solid central nervous system tumour in children. The 5-year survival rate is at present at about 60%. Height in general is severely compromised in survivors. The present study is an extension of the investigation by the author's group of the effect of exogenous growth hormone (GH) among medulloblastoma patients. METHODS: A total of 113 patients with medulloblastoma (out of 682 cases documented in KIGS, Pfizer International Growth Database) were treated with GH till final height was achieved. At the start of GH therapy (median dose 0.18 mg/kg/week), patients were 8.9 years old and had a median height SDS of -1.6. RESULTS: After 6.8 years of GH, final height SDS was -1.9, reflecting an overall loss in height of 0.3 SDS. This contrasted with an age-matched group of patients with idiopathic growth hormone deficiency (iGHD, n = 1,986), whose gain in height was 1.6 SDS on the same dose. The index of responsiveness averaged -0.9 during the first prepubertal year and -2.0 during total pubertal growth, thus indicating a major impairment in responsiveness to GH as compared to iGHD. Height at GH start, which correlated positively with the age at disease onset, was found to be the major determinant of final height. CONCLUSIONS: Our findings show that attempts to improve the height outcome in medulloblastoma must involve earlier recognition and treatment with higher-than-replacement doses of GH; additionally, modifications in cancer treatment programs need to be considered, such as lowering the dose of craniospinal irradiation or avoiding it as far as possible.     

Patterns of relapse following hippocampal avoidance prophylactic cranial irradiation for small cell lung carcinoma

BackgroundHippocampal avoidance techniques are an evolving standard of care for patients undergoing cranial irradiation. Our aim was to assess the oncological outcomes and patterns of failure following hippocampal avoidance prophylactic cranial irradiation (HA-PCI) as a standard of care in unselected patients with both limited and extensive stage small cell lung carcinoma.Materials and methodsConsecutive patients with small cell lung carcinoma with a complete (limited stage) or good partial (extensive stage) response following chemotherapy were eligible to receive HA-PCI, with a total dose of 25 Gray in 10 fractions. All patients had a negative baseline MRI brain scan with gadolinium prior to HA-PCI. Patients had baseline and follow up Common Toxicity Criteria Adverse Event assessments. Following completion of HA-PCI, all patients had three-monthly MRI brain scans with gadolinium until confirmation of intracranial relapse, as well as three-monthly CT of the chest, abdomen and pelvis. Overall and progression-free survival were calculated using the Kaplan-Meier method.ResultsA total of 17 consecutive patients, 9 men and 8 women, with a mean age of 70 years received HA-PCI between May 2016 and June 2020 after completion of their initial chemotherapy. There were no Grade 4 or greater adverse events. No patient had an isolated hippocampal avoidance zone relapse alone; three of 17 patients had multifocal relapses that included the hippocampal avoidance zone.ConclusionIn our series, there were no hippocampal only relapses and we conclude that HA-PCI is a safe alternative to standard PCI in the setting of small cell lung cancer.     

Leydig cell insufficiency after testicular irradiation for acute lymphoblastic leukemia

Leydig cell function in 21 boys with acute lymphoblastic leukemia who had been treated by bilateral direct testicular irradiation (12 X 2 Gy) at 8.4 +/- 0.7 years, was evaluated 3.8 +/- 0.4 years after irradiation. At the time of irradiation all were prepubertal and at evaluation 12 were prepubertal and 9 pubertal. Leydig cell insufficiency, indicated by a low plasma testosterone response to chorionic gonadotrophin and/or an increase in basal level of plasma luteinizing hormone, was observed in 19/21 patients. The children who were the youngest at testicular irradiation were more vulnerable. Spontaneous virilization occurred in 3 of the older children and resulted from compensated Leydig cell dysfunction.     

Prediction of advanced puberty by height velocity in children with acute lymphoblastic leukemia.

Pubertal development was retrospectively evaluated in 58 children with cancer, mostly acute lymphoblastic leukemia (ALL), who are in complete remission and off chemotherapy. Six girls [5 patients with ALL, and 1 with malignant lymphoma (NHL)] showed advanced puberty (25.0%, 6 of 24 female patients with ALL and NHL) through the evaluation of their growth velocity. No evidence for advanced puberty was seen in the males. All 6 girls had received cranial irradiation for central nervous system prophylaxis and systemic chemotherapy including glucocorticoid. The mean age at onset of the pubertal growth spurt in these 6 girls was significantly lower than for girls with a solid tumor [6.90 +/- 0.10 and 9.00 +/- 0.77 (mean +/- SD) years, respectively (p < 0.01)]. By simply evaluating the height velocity, we could predict advanced puberty which was ultimately associated with short stature.     

Analysis of treatment in childhood leukaemia. I. Predisposition to methotrexate-induced neutropenia after craniospinal irradiation. Report to the Medical Research Council of the Working Party on Leukaemia in Childhood.

The degree of drug-induced neutropenia resulting from a controlled trial (UKALL I) of treatment in acute lymphoblastic leukaemia was analysed. The main agent associated with severe neutropenia was methotrexate, and methotrexate-induced neutropenia was significantly greater in patients who had received craniospinal irradiation. The synergistic toxic effect of irradiation followed by methotrexate treatment seems to have contributed to three of the five deaths which occurred in complete remission in this trial; all deaths in remission occurred in patients who had received central nervous system prophylaxis. Analysis of patients who subsequently relapsed compared with those still in remission after 18 months of treatment indicated that the former, on average, had slightly lower neutrophil counts. This suggests that the children who relapsed did not receive any less aggressive treatment than those who remained in remission.     

Radiation-induced growth hormone deficiency

Deficiency of one or more anterior pituitary hormones may follow treatment with external irradiation when the hypothalamic-pituitary axis falls within the fields of irradiation. Hypopituitarism occurs in patients who receive radiation therapy for pituitary tumours, nasopharyngeal cancer and primary brain tumours, as well as in children who undergo prophylactic cranial irradiation for acute lymphoblastic leukaemia, or total body irradiation for a variety of tumours and other diseases. The degree of pituitary hormonal deficit is related to the radiation dose received by the hypothalamic-pituitary axis. Thus, after lower radiation doses isolated growth hormone deficiency ensues, whilst higher doses may produce hypopituitarism. The timing of onset of the radiation-induced pituitary hormone deficit is also dose-dependent. The main site of radiation damage is the hypothalamus rather than the pituitary, although the latter may be affected directly.     

Growth hormone secretion during sleep. II. Interrelationships between growth hormone secretion, insulin-like growth factor I and sex steroids

The serum levels of insulin-like growth factor I (IGF I), dehydroepiandrosterone sulfate (DHAS), testosterone (T) and estradiol (E2) have been measured in 78 prepubertal and 57 early pubertal patients referred for short stature, at the same time when their secretion of GH was evaluated both during nocturnal sleep and by two conventional stimulation tests. According to the results of GH measurements they were considered as having a normal secretion of GH (group I), a complete GH deficiency (group II), a partial GH deficiency (group III), low responses to stimuli with normal secretion during sleep (group IV) or a nocturnal neurosecretory dysfunction (group V). Though widely scattered, the IGF I levels showed the following characteristics: a significant increase at puberty from 0.77 to 1.29 U/ml (p less than 0.001) in the so-called endocrinologically normal patients of group I, not in the other groups; in the prepubertal patients of group I, a correlation of IGF I with chronological age (r = 0.47, p less than 0.005) and bone age (r = 0.52, p less than 0.002); significantly reduced IGF I levels in patients of group II having complete GH deficiency (p less than 0.001); no significant differences between prepubertal patients with partial or atypical GH deficiency from groups III, IV, V and prepubertal patients from group I; lower pubertal levels in groups III, IV, V than in pubertal patients from group I (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pituitary Hormone Dysfunction After Proton Beam Radiation Therapy in Children with Brain Tumors

Objectiveo characterize endocrine dysfunction in pediatric patients with brain tumors who received proton beam (PB) radiation therapy and to compare those treated with PB radiotherapy only versus combined conventional and PB irradiation.MethodsA retrospective review of medical records of patients ≤ 18 years of age who received PB radiation therapy for a brain tumor between 2000 and 2008 was performed. Variables analyzed included patient demographics, tumor type, therapeutic modalities, radiation doses, and types and timing of endocrine dysfunction.ResultsThirty-eight patients were identified, of whom 31 (19 boys and 12 girls; mean age, 11.9 ± 3.3 years) had undergone endocrine evaluation. Of these patients, 19 received PB radiotherapy only and 12 received conventional plus PB irradiation. Before irradiation, a cranial surgical procedure was performed in 28 study subjects, and 22 received chemotherapy. The mean duration of follow-up after radiation therapy was 1.8 ± 0.8 years. Nine patients (47%) in the PB only group and 4 (33%) in the conventional plus PB group developed endocrine dysfunction (no significant difference) after cranial irradiation. Children with endocrine sequelae treated with PB irradiation alone received fewer cobalt gray equivalents than those treated with conventional plus PB irradiation (5,384 ± 268 versus 5,775 ± 226, respectively; P < .02), and pituitary hormone deficiencies were detected later during follow-up in those who received PB radiotherapy only versus conventional plus PB irradiation (1.17 ± 0.4 years versus 0.33 ± 0.11 year, respectively; P < .01).ConclusionA high rate of endocrine sequelae was seen in our study. Children with brain tumors treated with conventional plus PB irradiation developed endocrine dysfunction faster and received a higher radiation dose than those receiving PB radiotherapy only. Prior surgical treatment and chemotherapy were additional risk factors. Large prospective studies are needed to evaluate further the incidence of endocrine sequelae after PB irradiation in children. (Endocr Pract. 2011;17:891-896)     

Studies on cellular inhibition and serum-blocking factors in 28 human patients given marrow grafts from HLA identical siblings.

Fifteen patients with aplastic anemia and 13 with acute leukemia were studied 36 to 1547 days after treatment with high-dose cyclophosphamide and/or total-body irradiation and marrow transplantation from HLA identical siblings. Peripheral blood lymphocytes from patients and normals (marrow donors and healthy unrelated individuals) were tested for cell inhibition (CI) of cultured skin fibroblasts from both patients and donors by using the microcytotoxicity assay. In addition, blocking of CI by factors in patient serum was studied. Three groups of patients were studied. Patients in group I were stable long-term survivors without evidence of graft-vs-host diseases (GVHD) between 250 to 1547 days postgrafting. Patients in group II were short-term survivors with or without acute GVHD between 36 and 144 days postgrafting. Patients in group III had chronic GVHD either at the time of testing or developed chronic GVHD subsequent to CI testing between days 61 and 960 postgrafting. Eleven of 14 patients in group I showed absence of both CI and serum blocking and three showed CI and blocking. Patients in group II without acute GVHD showed absence of CI and serum blocking on three occasions, presence of CI and blocking on four occasions, and CI without blocking on three occasions. Patients in group II with acute GVHD showed absence of CI on one occasion and presence of CI and blocking on three occasions. Patients in group III showed absence of CI and blocking on seven occasions and CI without blocking on two occasions. These results suggest that the maintenance of stable graft-host tolerance in long-term survivors after marrow grafting from HLA identical donors does not depend on the presence of serum-blocking factors. Short-term survivors with and without GVHD showed a spectrum of in vitro reactivity with 50% of the patients showing serum-blocking factors, and these results did not appear to be correlated with presence or absence of acute GVHD. Finally, results of the microcytotoxicity assays failed to provide insight into the mechanism of chronic GVHD.     

Combination chemotherapy for acute lymphoblastic leukaemia in adults.

Fifty-one adults with acute lymphoblastic leukaemia were entered into a trial of intense initial chemotherapy and early "prophylaxis" of the central nervous system (CNS). Initial treatment with OPAL (Oncovin (vincristine), prednisolone, adriamycin (doxorubicin), and L-asparaginase (colaspase)) followed by craniospinal or cranial irradiation and intrathecal methotrexate produced remission in 36 patients (71%). Seventeen of these patients relapsed three to 18 months after the start of remission; the remainder had been in remission for 12 to 52 months by the end of the study. The predicted median duration of complete remission was 18.5 months. None of the four patients who initially had clinical evidence of CNS disease, three of whom also had leukaemic cells identical to those found in Burkitt''s lymphoma, achieved remission. Those patients who initially had hepatomegaly or splenomegaly had a shorter remission than those without. The predicted median survival was 27 months in those who achieved complete remission, one month in those who did not, and 21 months overall. The addition of colaspase and doxorubicin to vincristine and prednisolone and the use of early CNS treatment clearly improved the remission rate among adults with acute lymphoblastic leukaemia, though the presence and length of remission was affected by the extent of disease at presentation. Burkitt-like leukaemia, which had a poor prognosis, is probably a separate disease and may benefit from a different therapeutic approach.     

Traitement du cancer du testicule

Significant advances have been achieved in testicular cancer treatment for the last 15 years. Almost 100% of the non seminomatous tumors seen at the precocious stages I and II are cured because of the efficacy of chemotherapy in relapses. For clinical stages I, tendancy is to survey after castration without lymphadenectomy. For advanced metastatic stages, platinum has changed chemotherapy performances, allowing to cure 75 to 80% of these patients. The results of a bad pronosis group with large tumor remain to be improved. Seminomas at a localized stage (the most frequent case) are cured by radiotherapy; at an advanced stage, they are as sensitive to chemotherapy as non seminomatous tumors.     

Cryoconservation du tissue testiculaire chez l’enfant: comment préserver la fertilité chez le jeune garçon?

Survival rates for almost all types of childhood cancer have improved over the last 30 years. Estimates suggest that, in 2010, 1 out of 715 adolescents and young adults will be a long-term survivor of childhood cancer. With current therapy, 70% of children are cured. The increased number of survivors has focused attention on the many long-term or late sequelae of treatment. Most of the effects cannot be detected at the end of therapy, but only become apparent with puberty, growth and the normal aging process. Among the various sequelae, gonadal dysfunction is observed and the degree of gonadal damage depends on the type and total doses of chemotherapy and/or radiotherapy. The male gonald is also more sensitive to cancer therapy than the female gonad. Cryopreservation of ejaculated spermatozoa should be proposed for sexually mature boys. However, when ejaculated semen samples cannot be collected, or in the case of prepubertal boys who are not yet able to produce spermatozoa, another strategy must be used: testicular biopsy associated with cryopreservation of (i) testicular tissue, or (ii) isolated testicular spermatozoa or (iii) immature germ cells. The future use of immature testicular tissue will depend on the development of novel technologies in humans such as germ cellin vitro maturation, or autologous or xenogeneic germ cell transplantation.     

Medulloblastoma—Treatment and Prognosis A Study of Seventeen Cases in Ten Years

In a series of 17 biopsy-proved cases of medulloblastoma all patients were treated by megavoltage irradiation in the Stanford University Division of Radiation Therapy. The entire craniospinal axis was treated in each case. The five-year survival in the series was 27 percent.Two ten-year survivors were studied in detail. The major longterm disability was inhibition of growth of the vertebral column.In this series, a normal tissue nominal standard dose of at least 1275 rets was necessary for tumor control.     

Secondary brain tumors after cranial radiation therapy: A single-institution study

AimTo study the probability of developing secondary brain tumors after cranial radiotherapy.Background Patients treated with cranial radiotherapy are at risk for developing secondary brain tumors.Patients and methodsWe planned an institutional survey for secondary brain tumors in survivors after cranial irradiation and reviewed the 30-year duration data. Event analysis and cumulative proportion curves were performed to generally estimate the cumulative proportion of developing secondary brain tumors, cavernoma and meningioma at different periods of time.ResultsSecondary brain tumors occurred in 21% of cases: 10% were cavernomas, 6% were meningiomas, 3% were skull osteomas, and 1% were anaplastic astrocytoma. The cumulative proportion of developing secondary brain tumor was 6% at 10 years and 20% at 20 years, while the cumulative proportion for developing cavernomas and meningiomas was 16% and 7% at 20 years, respectively.ConclusionOur study shows that patients who received cranial irradiation were at risk of secondary brain tumors such as cavernomas and meningiomas. Thus, a meticulous follow-up of cancer survivors with history of cranial irradiation by an annual MRI scan is justifiable. This will help clinicians to detect secondary brain tumors early and make its management much easier.     

Desensitization at the first stage of IGE-mediated response as hay fever prophylaxis

The aim of our work was to assess the prophylactic aspects of desensitization at the first stage of IgE-mediated response to grass pollen antigens (GPA). Forty six patients aged 10-45 (Me = 20.45) years (group I) and 50 patients aged 11-45 (Me = 19.17) years (group II) were included in to the study. All of them: 1) suffered from allergic rhinitis due to house dust (HD), feathers (F), weed (W) or tree (T) pollen, 2) had also some other allergic diseases, 3) had positive family history of allergic disorders, 4) had reproducible, strongly positive skin reaction of type I to GPA, but 5) did not show any clinical symptoms of hypersensitivity to GPA. Specific immunotherapy with HD, F, W, and T aqueous extracts was administered to both groups for at least 3 successive years, while parallel desensitization with GPA aqueous extract was carried out in group I, only. The symptoms of grass pollinosis were searcher for and the effects of immunotherapy were evaluated in all the patients over the period of at least 5 successive years after the complete course of vaccines administration. Clinical signs of hypersensitivity to GPA became evident in 6 patients (13.04%) of group I and in 27 patients (54.00%) of group II (p less than 0.001). Thus the desensitization at the first stage of IgE-mediated response to GPA effectively prevented development of the symptomatic hay fever. However, the disease revealed itself in few cases still much later and its course was much milder than in people who were not subjected to such a preventive desensitization.(ABSTRACT TRUNCATED AT 250 WORDS)     

The Ocular Sequelae of Third Cranial Nerve Palsy

The ocular sequelae in nineteen patients who had suffered from a complete paralysis of the third cranial nerve were analyzed. In eleven of these patients, the paralysis was associated with an aneurysm of the internal carotid artery system. None of the cases in this group showed complete recovery of the third nerve function; however, six recovered sufficiently to permit binocular single vision in most fields of gaze. Two cases of aberrant regeneration of the third nerve were diagnosed.Trauma accounted for four cases of third nerve paralysis. One of these recovered completely and one showed features of aberrant regeneration. Of the cases of oculomotor paralysis associated with herpes zoster ophthalmicus, encephalitis, or an obscure etiology (two cases), all recovered completely.     

The Optimal Parathyroid Hormone Cut-Off Threshold for Early and Safe Management of Hypocalcemia After Total Thyroidectomy

ObjectiveTo define optimal intact parathyroid hormone (iPTH) cut-off threshold predictive of hypocalcemia after total thyroidectomy for safe and effective postoperative management.MethodsThis prospective single center study was done in 2 phases. In phase I, predictors of symptomatic hypocalcemia were analyzed and the receiver operating characteristic curve was used to define the optimal iPTH cut-off threshold predictive of hypocalcemia. Phase II studied giving prompt prophylactic supplemental calcium and vitamin D to all patients who had iPTH levels below the calculated threshold, while phase I patients were given prompt selective supplementation if they had postoperative hypocalcemia or symptoms.ResultsUnivariate analysis of patients in phase I showed that postoperative iPTH was the only significant variable that can predict symptomatic hypocalcemia. Using receiver operating characteristic curve and Youden index, the confirmed optimal cut-off threshold predictive of hypocalcemia was iPTH 19.95 pg/mL, with area under the curve of 0.903, 100% sensitivity, negative predictive value, and highest Youden index, while iPTH 15 pg/mL and iPTH 10 pg/mL were less optimal. Symptomatic hypocalcemia occurred in 30% of the phase I cohort who received selective supplementation versus 3% of those in the phase II cohort who received prophylactic supplementation. Return to emergency department and need for intravenous calcium were also significantly better in phase II.ConclusioniPTH cut-off for post-thyroidectomy hypocalcemia was 19.95 pg/mL. Low-risk patients were discharged with no supplementation while all high-risk patients received prompt calcium and vitamin D supplementation, which led to effective hypocalcemia management and safe 24-hour discharge.