Cerebral microbleeds in adult survivors of childhood acute lymphoblastic leukemia treated with cranial radiation.

Cranial radiation therapy is associated with white matter-specific brain injury, cortical volume loss, mineralization, microangiopathy and neurocognitive impairment in survivors of childhood acute lymphoblastic leukemia. In this retrospective cross-sectional analysis, neurocognitive testing and 3 T brain MRI's were obtained in 101 survivors treated with cranial radiation. Small focal intracerebral hemorrhages only visible on exquisitely sensitive MRI sequences were identified and localized using susceptibility weighted imaging. Modified Poisson regression was used to assess the effect of cranial radiation on cumulative number and location of microbleeds in each brain region, and multiple linear regression was used to evaluate microbleeds on neurocognitive outcomes, adjusting for age at diagnosis and sex. At least one microbleed was present in 85% of survivors, occurring more frequently in frontal lobes. Radiation dose of 24 Gy conveyed a 5-fold greater risk (95% CI 2.57-10.32) of having multiple microbleeds compared to a dose of 18 Gy. No significant difference was found in neurocognitive scores with either the absence or presence of microbleeds or their location. Greater prevalence of microbleeds in our study compared to prior reports is likely related to longer time since treatment, better sensitivity of SWI for detection of microbleeds and the use of a 3 T MRI platform.

Childhood leukaemia survivors' experiences of long-term follow-ups in an endocrine clinic - A focus-group study.

The survival rate after childhood cancer has improved markedly and today more than 80% of patients will survive. Many childhood cancer survivors suffer from late complications due to radiotherapy and chemotherapy. Survivors of Acute Lymphoblastic Leukaemia (ALL), treated with cranial radiotherapy, are at a particularly high risk of having endocrine complications. PURPOSE: To illuminate childhood ALL survivors' experiences of a long-term follow-up in an endocrine clinic. METHOD: Data collection carried out using semi-structured focus-group interviews. Fifteen ALL survivors were included in the study, divided into 4 groups. Data was analysed with conventional qualitative content analysis. RESULTS: The survivors' experiences were captured in the theme: "The need for understanding and support in order to manage daily life". An understanding of their situation, as well as support for managing daily life was fundamental. Lack of understanding and support from the community was connected with a fear for the future. The follow-up at the endocrine clinic was shown to be crucial for increasing the survivors' understanding of late complications. The past feeling of being out of control was replaced with an increased self-confidence. CONCLUSION: Many leukaemia survivors experienced their daily lives as a struggle and as a complicated issue to cope with. The theme "understanding and support to manage daily life" mirrors how the survivors are in need of knowledge and support in order to handle and understand their complex situation after surviving leukaemia. Offering understanding and support with a holistic approach, may be a way in which to strengthen the survivors' health.

Long-Term Effect of Cranial Radiotherapy on Pituitary-Hypothalamus Area in Childhood Acute Lymphoblastic Leukemia Survivors.

OPINION STATEMENT: Survival rates of childhood cancer have improved markedly, and today more than 80 % of those diagnosed with a pediatric malignancy will become 5-year survivors. Nevertheless, survivors exposed to cranial radiotherapy (CRT) are at particularly high risk for long-term morbidity, such as endocrine insufficiencies, metabolic complications, and cardiovascular morbidity. Deficiencies of one or more anterior pituitary hormones have been described following therapeutic CRT for primary brain tumors, nasopharyngeal tumors, and following prophylactic CRT for childhood acute lymphoblastic leukemia (ALL). Studies have consistently shown a strong correlation between the total radiation dose and the development of pituitary deficits. Further, age at treatment and also time since treatment has strong implications on pituitary hormone deficiencies. There is evidence that the hypothalamus is more radiosensitive than the pituitary and is damaged by lower doses of CRT. With doses of CRT <50 Gy, the primary site of radiation damage is the hypothalamus and this usually causes isolated GH deficiency (GHD). Higher doses (>50 Gy) may produce direct anterior pituitary damage, which contributes to multiple pituitary deficiencies. The large group of ALL survivors treated with CRT in the 70-80-ties has now reached adulthood, and these survivors were treated mainly with 24 Gy, and the vast majority of these patients suffer from GHD. Further, after long-term follow-up, insufficiencies in prolactin (PRL) and thyroid stimulating hormone (TSH) have also been reported and a proportion of these patients were also adrenocoticotrophic hormone (ACTH) deficient. CRT to the hypothalamus causes neuroendocrine dysfunction, which means that the choice of GH test is crucial for the diagnosis of GHD.

Associations between Metabolic Risk Factors and the Hypothalamic Volume in Childhood Leukemia Survivors Treated with Cranial Radiotherapy.

Metabolic complications are prevalent in individuals treated with cranial radiotherapy (CRT) for childhood acute lymphoblastic leukemia (ALL). The hypothalamus is a master regulator of endocrine and metabolic control. The aim of this study was to investigate whether the hypothalamic volume would be associated to metabolic parameters in ALL survivors. Thirty-eight (21 women) survivors participated in this study 34 years after diagnosis and with a median age of 38 (27-46) years. All were treated with a median CRT dose of 24 Gy and 11 years (3-13) of complete hormone supplementation. Comparisons were made to 31 matched controls. We performed analyses of fat mass, fat free mass, plasma (p)-glucose, p-insulin, Homa-Index (a measure of insulin resistance), serum (s)-leptin, s-ghrelin and of the hypothalamic volume in scans obtained by magnetic resonance imaging (MRI) at 3 Tesla. Serum leptin/kg fat mass (r = -0.4, P = 0.04) and fat mass (r = -0.4, P = 0.01) were negatively correlated with the HT volume among ALL survivors, but not among controls. We also detected significantly higher BMI, waist, fat mass, p-insulin, Homa-Index, leptin/kg fat mass and s-ghrelin and significantly lower fat free mass specifically among female ALL survivors (all P<0.01). Interestingly, s-ghrelin levels increased with time since diagnosis and with low age at diagnosis for childhood ALL. Our results showed that leptin/kg fat mass and fat mass were associated with a reduced HT volume 34 years after ALL diagnosis and that women treated with CRT after ALL are at high risk of metabolic abnormalities. Taken together our data suggest that the hypothalamus is involved in the metabolic consequences after CRT in ALL survivors.

Bone mineral density among long-term survivors of childhood acute lymphoblastic leukemia: results from the St. Jude Lifetime Cohort Study.

BACKGROUND: The prevalence of low bone mineral density (BMD) in adult survivors of childhood acute lymphoblastic leukemia (ALL), and the degree of recovery or decline, are not well elucidated. PROCEDURE: Study subjects (age ≥ 18 years and ≥10 years post-diagnosis) participated in an institutional follow-up protocol and risk-based clinical evaluation based on Children's Oncology Group guidelines. Trabecular volumetric BMD was ascertained using quantitative computed tomography, reported as age- and sex-specific Z-scores. RESULTS: At median age 31 years, 5.7% of 845 subjects had a BMD Z-score of ≤-2 and 23.8% had a Z-score of -1 to -2. Cranial radiation dose of ≥24 Gy, but not cumulative methotrexate or prednisone equivalence doses, was associated with a twofold elevated risk of a BMD Z-score of ≤-1. The cranial radiation effect was stronger in females than in males. In a subset of 400 subjects, 67% of those who previously had a BMD Z-score of ≤-2 improved by one or more categories a median of 8.5 years later. CONCLUSIONS: Very low BMD was relatively uncommon in this sample of adult survivors of childhood ALL, and BMD Z-scores tended to improve from adolescence to young adulthood. High-dose cranial or craniospinal radiation exposure was the primary predictor of suboptimal BMD in our study. Given that cranial radiation treatment for childhood ALL is used far more sparingly now than in earlier treatment eras, concerns about persistently low BMD among most current childhood ALL patients may be unwarranted.

[Late sequelae of central nervous system prophylaxis in children with acute lymphoblastic leukemia: high doses of intravenous methotrexate versus radiotherapy of the central nervous system--review of literature]. / Odlegle nastepstwa leczenia zapobiegajacego rozwojowi nacieków bialaczkowych w osrodkowym ukladzie nerwowym u dzieci z ostra bialaczka limfoblastyczna: wysokie dozylne dawki metotreksatu versus napromienienie osrodkowego ukladu nerwowego--przeglad pismiennictwa.

Acute lymphoblastic leukemia is the most common malignancy in children. All current therapy regimens used in the treatment of childhood acute lymphoblastic leukemia include prophylaxis of the central nervous system. Initially it was thought that the best way of central nervous system prophylaxis is radiotherapy. But despite its effectiveness this method, may cause late sequelae and complications. In the programme currently used in Poland to treat acute lymphoblastic leukemia, prophylactic radiotherapy has been reduced by 50% (12 Gy) and is used only in patients stratified into the high risk group and in patients diagnosed as T-cell ALL (T-ALL). Complementary to radiotherapy, intrathecal methotrexate is given alone or in combination with cytarabine and hydrocortisone is given, as well as systemic chemotherapy with intravenous methotrexate is administered in high or medium doses (depending on risk groups and leukemia immunophenotype). Recent studies have shown that high dose irradiation of the central nervous system impairs cognitive development causing memory loss, visuomotor coordination impairment, attention disorders and reduction in the intelligence quotient. It has been proved that the degree of cognitive impairment depends on the radiation dose directed to the medial temporal lobe structures, particularly in the hippocampus and the surrounding cortex. Also, methotrexate used intravenously in high doses, interferes with the metabolism of folic acid which is necessary for normal development and the optimal functioning of neurons in the central nervous system. It has been proved that patients who have been treated with high doses of methotrexate are characterized by reduced memory skills and a lower intelligence quotient. The literature data concerning long term neuroanatomical abnormalities and neuropsychological deficits are ambiguous, and there is still no data concerning current methods of central nervous system prophylaxis with low doses of irradiation in combination with high doses of intravenous methotrexate.

Obesity in patients with acute lymphoblastic leukemia in childhood.

Acute lymphoblastic leukemia is the most common malignancy in childhood. Continuous progress in risk-adapted treatment for childhood acute lymphoblastic leukemia has secured 5-year event-free survival rates of approximately 80% and 8-year survival rates approaching 90%. Almost 75% of survivors, however, have a chronic health condition negatively impacting on cardiovascular morbidity and mortality. Obesity can be considered one of the most important health chronic conditions in the general population, with an increasing incidence in patients treated for childhood cancers and especially in acute lymphoblastic leukemia survivors who are, at the same time, more at risk of experiencing precocious cardiovascular and metabolic co-morbidities. The hypothalamic-pituitary axis damage secondary to cancer therapies (cranial irradiation and chemotherapy) or to primary tumor together with lifestyle modifications and genetic factors could affect long-term outcomes. Nevertheless, the etiology of obesity in acute lymphoblastic leukemia is not yet fully understood. The present review has the aim of summarizing the published data and examining the most accepted mechanisms and main predisposing factors related to weight gain in this particular population.

Growth retardation and bilateral cataracts followed by anaplastic meningioma 23 years after high-dose cranial and whole-body irradiation for acute lymphoblastic leukemia: case report and review of the literature.

We report a case of meningioma diagnosed 23 years after high-dose cranial and whole-body irradiation for the treatment of acute lymphocytic leukemia (ALL). Radiotherapy in this case also caused early radiation injury to the lenses and the pituitary gland, with growth retardation and mineralizing angiopathy. Radiation-induced meningiomas are more commonly malignant, more commonly multiple, and more likely to recur after resection than non-radiation-induced meningiomas. Survivors of childhood ALL treated with high-dose cranial irradiation are at risk both for early radiation injury in radiosensitive organs, such as the lens and pituitary gland, and for the later development of a radiation-induced meningioma.

The utility of the growth hormone (GH) releasing hormone-arginine test for diagnosing GH deficiency in adults with childhood acute lymphoblastic leukemia treated with cranial irradiation.

CONTEXT: The insulin tolerance test (ITT) is the current standard diagnostic test for the diagnosis of adult GH deficiency (GHD), but alternative tests, such as the GHRH-arginine test, have been proposed. OBJECTIVE: We investigated the sensitivity and specificity of the GHRH-arginine test using ITT as the gold standard in diagnosing GHD in a group of young adults treated with cranial irradiation (CRT) for childhood acute lymphoblastic leukemia (ALL). We estimated the positive and negative predictive values of the GHRH-arginine test among patients as well as a number of individual characteristics and therapy-related factors during both the GHRH-arginine test and ITT. DESIGN: Forty-three young adults, treated for childhood ALL with 18-30 Gy CRT and chemotherapy, were studied, and comparison was made with matched controls. RESULTS AND CONCLUSIONS: We evaluated four different cutoff levels for GHD in the GHRH-arginine test: 5, 7.5, 9, and 16.5 microg/liter. Using 7.5 microg/liter as the cutoff yielded high specificity (94%), but at the same time the sensitivity was only 66%, which leads to a low negative predictive value (27%). In contrast, a failed GH response to the GHRH-arginine test accurately reflects the presence of radiation-induced GHD, illustrated by a high positive predictive value (95% at 7.5 microg/liter). Only age at CRT and body mass index remained significant predictors of the peak GH during the GHRH-arginine test. Because a high proportion of GHD patients show a normal response to the GHRH-arginine test, it cannot be used reliably to exclude GHD in these patients. Complementary ITT is also warranted to confirm GHD in obese patients.

Endocrine consequences of brain irradiation.

Cranial radiation is routinely used to manage pituitary tumours, craniopharyngiomas, primary brain tumours, tumours of the head and neck and, in the past, for the prophylaxis of intracranial disease in patients with acute lymphoblastic leukaemia. If the hypothalamic-pituitary axis falls within the radiation fields, the patient is at risk of developing hypopituitarism. The effect of radiation is determined by the dose and the time that has elapsed since treatment. Classically, growth hormone (GH) is the most sensitive of the anterior pituitary hormones to irradiation, followed by gonadotrophins, adrenocorticotrophic hormone (ACTH) and thyroid-stimulating hormone (TSH). Low-dose irradiation in prepubertal children can initially cause early or precocious puberty and subsequently gonadotrophin deficiency. Higher doses may cause gonadotrophin deficiency and pubertal delay. The ACTH and TSH axes are relatively resistant to the effects of irradiation, but minor abnormalities may occur. Patients who receive cranial irradiation that affects the hypothalamic-pituitary axis remain at risk of developing multiple hormone deficiencies for many years and require long-term follow-up by an endocrinologist.

Skeletal morbidity in childhood acute lymphoblastic leukemia.

PURPOSE: Treatment for acute lymphoblastic leukemia (ALL) in childhood results in a reduction in bone mineral density (BMD). Whether there is a recovery of this lost bone mass in survivors of ALL is not known. We sought to determine if changes in BMD are common long-term sequelae in children with ALL. METHODS: Bone mineral densitometry of the lumbar spine and femoral neck was performed on 106 patients. The results were compared with those of age-matched normal controls. The effect of treatment was examined in those with low BMD compared with the remainder of the study group. RESULTS: When data were tested with respect to age, sex, and age and sex, no difference was observed in BMD between survivors of childhood ALL and controls. In the subgroup of patients with low BMD, the difference was not related to age, age at diagnosis, or years since diagnosis. Low BMD of the spine was not explained by radiotherapy (RT), methotrexate (MTX) dose, or corticosteroid dose. Low BMD of the femur was not explained by RT. However, those with low femoral BMD were more likely to have received high-dose MTX or higher-dose corticosteroids compared with the remainder of the group. CONCLUSION: It appears that survivors of childhood ALL as a whole recover normal BMD. However, those patients who received a total MTX dose of greater than 40000 mg/m(2) or a total corticosteroid dose of greater than 9000 mg/m(2) may not recover normal BMD and therefore should be screened for decreased BMD of the femoral neck.

Hyperleptinaemia in young adults following cranial irradiation in childhood: growth hormone deficiency or leptin insensitivity?

OBJECTIVE: In order to explore the mechanism of obesity in long-term survivors of childhood leukaemia, fat mass, lean body mass and serum leptin were assessed in a cohort of 32 (17 males) adults who had received cranial irradiation (XRT) in childhood as part of their treatment for acute lymphobiastic leukaemia (ALL), and compared with 35 age and body mass index (BMI) matched young adults (18 male). DESIGN: Thirty-one patients and 18 controls had fat mass and lean body mass assessed by dual x-ray absorptiometry (DEXA), using a lunar DPX-L scanner. Serum leptin concentrations were also measured in 27 patients and all controls. Growth hormone status had previously been determined using an insulin tolerance test and arginine stimulation test. Nine patients were classified as severe growth hormone (GH) deficient (group 1), 12 patients as GH insufficient (group 2) and 11 patients as normal (group 3). RESULTS: BMI and absolute fat mass were not significantly different between the patients and controls regardless of their gender (P = 0.1 and P = 0.14 respectively). In contrast, absolute lean mass was significantly reduced (P < 0.01) and leptin concentrations were significantly increased (P < 0.001) in patients compared with controls. BMI, fat mass and leptin concentrations but not lean mass were significantly different between the three GH status groups (P < 0.01, P < 0.01, P = 0.004, and P = 0.67 respectively). When leptin concentrations were expressed per unit of fat mass, they were increased in the patients compared with the controls (P = 0.03) with significant differences between the GH status groups (P = 0.004), being significantly higher in the severe GH deficient group. CONCLUSIONS: Young adults who receive cranial irradiation in childhood are prone to GH deficiency and hyperleptinaemia. The pathophysiological significance of the hyperleptinaemia remains to be established but it has occurred either as a consequence of radiation induced hypothalamic damage or GH deficiency.

Neurodevelopmental outcome of infants with acute lymphoblastic leukemia: a Children's Cancer Group report.

BACKGROUND: Infants diagnosed with acute lymphoblastic leukemia (ALL) are considered the patient subgroup at the highest risk for central nervous system (CNS) disease, both at presentation and as an isolated extramedullary relapse. In addition, they are highly vulnerable to adverse developmental sequelae from CNS-directed therapy. METHODS: Thirty patients younger than 12 months at diagnosis (12 males, 18 females) in first hematologic remission were evaluated after completion of ALL therapy (mean age = 62.1 months; standard deviation = 17.2 months; range = 38-102 months). CNS-directed treatment included very high dose infusions of methotrexate (MTX) and intrathecal cytarabine and MTX. Three patients had meningeal leukemia that required additional therapy. Children were administered the McCarthy Scales of Children's Abilities, and parents completed a sociodemographic questionnaire to obtain information about occupation and education. RESULTS: Mean scores on all 6 cognitive and motor indices of the McCarthy Scales were in the average range (Verbal = 52.0; Perceptual = 53.6; Quantitative = 49.6; General Cognitive Index [GCI] = 102.1; Memory = 49.2; Motor = 51.0). Score distributions for each neurodevelopmental index were comparable to age-based population standards. One patient obtained a GCI that exceeded 2 standard deviations above the mean; none scored more than 2 standard deviations below. There was no report of developmental disabilities or neurologic disorders for any of the patients. Risk factors, including age at diagnosis, gender, additional CNS-directed treatment, and family socioeconomic status, were not associated with developmental outcome. CONCLUSIONS: Test findings indicated a generally positive neurodevelopmental outcome for ALL patients diagnosed in infancy who were treated with very high dose MTX as CNS-directed therapy. Combined with the reduction in the isolated CNS relapse rate achieved by the Children's Cancer Group (CCG) clinical trial CCG-107, the results of this study represent a substantial improvement in neurodevelopmental outcome for very young patients compared with infants treated for ALL in the past.

Intensive BFM chemotherapy for childhood ALL: interim analysis of the AIEOP-ALL 91 study. Associazione Italiana Ematologia Oncologia Pediatrica.

BACKGROUND AND OBJECTIVE: Since 1988 the AIEOP has used BFM-based chemotherapy for childhood ALL. Current organization and results and role of cranial irradiation in the AIEOP-ALL 91 study are reported. DESIGN AND METHODS: From 1991 to 1995, 1194 children (< 15 years) with non-B ALL, were enrolled and assigned to the standard risk [SR: age > 1 year, non-T-ALL, BFM risk factor (RF) < 0.8], intermediate risk (IR: RF > or = 0.8 but < 1.7, or with RF < 0.8 and age < 1 year, or T-ALL), or high risk [HR: RF > or = 1.7, or t(9;22), or t(4;11) or prednisone poor response or late response or CNS involvement] groups. All patients received initially protocol Ia. Thereafter SR patients received HD-MTX 2 g/m2, a modified protocol II, and continuation therapy with triple intrathecal chemotherapy (TIT); IR patients received protocol Ib, HD-MTX 5 g/m2, protocol II and continuation therapy with TIT; HR patients received 9 polychemotherapy blocks, cranial irradiation and continuation therapy. Duration of treatment was 24 months. A randomized study was conducted to evaluate the impact of high-dose asparaginase in non high risk patients: the results of this study cannot be disclosed yet. RESULTS: One thousand one hundred and fifty-two (96.5%) patients achieved CR. Overall EFS (SE) at 5-years was 71.0% (1.4), with a survival of 80.3% (1.3). Relapse occurred in 262 children (21.9%), either in the marrow (n = 192 isolated and 32 with other sites, 18.7%), in the CNS (n = 18, 1.5%), or elsewhere (n = 20, 1.7%). 5-year EFS (SE) was 83.3% (2.4) in SR, 74.7% (1.8) in IR, and 39.7% (3.5) in HR groups, respectively. INTERPRETATION AND CONCLUSIONS: Overall cure rate was higher than in the previous AIEOP-ALL 88 study. Treatment intensification with polychemotherapy blocks did not improve results in HR. Cranial irradiation can be safely omitted in over 80% of children treated with BFM based chemotherapy.

Demyelination and single-carbon transfer pathway metabolites during the treatment of acute lymphoblastic leukemia: CSF studies.

PURPOSE: To investigate the hypothesis that methotrexate causes demyelination due to a deficiency in S-adenosylmethionine (SAM) during the treatment of acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Twenty-four patients treated on the Medical Research Council United Kingdom ALL trial no. 11 (MRC UKALL XI) were studied. The trial randomized patients at the presymptomatic CNS treatment (PCNS) phase to receive (1) intrathecal methotrexate and cranial radiotherapy (CRTX); (2) high-dose intravenous methotrexate with folinic acid rescue and continuing intrathecal methotrexate (HDMTX); and (3) continuing intrathecal methotrexate alone (ITMTX). Serial CSF samples were collected throughout treatment and concentrations of 5-methyltetrahydrofolate (MTF), methionine (MET), SAM, and myelin basic protein (MBP) were measured. The results were grouped into treatment milestones and compared with an age-matched reference population. RESULTS: There was a highly significant effect of both treatment milestones and trial arm on the metabolite and MBP concentrations. CSF MTF reached a nadir during the induction phase of treatment, while SAM and MET reached their nadir during the consolidation phase. CSF MBP mirrored SAM concentration and there was a significant inverse relationship between the two. MTF, SAM, and MBP returned to normal values by the end of treatment, while MET was increased significantly. The effect of treatment was decremental across the ITMTX, HDMTX, and CRTX groups. CONCLUSION: Treatment of ALL causes marked abnormalities in the single-carbon transfer pathway and subclinical demyelination. Methotrexate is one cause of this. Whether these abnormalities contribute to the late cognitive deficits requires further study.

Acute effects of high-dose chemotherapy followed by bone marrow transplantation on serum markers of bone metabolism.

There is an interplay between the cells in the bone marrow and the surrounding bone tissue, but little is known about the effects of myeloablative treatment followed by bone marrow transplantation on bone metabolism. We have therefore investigated 24 patients undergoing bone marrow transplantation (14 autologous, 10 allogeneic) for hematological malignancies. Serum concentrations of parathyroid hormone (PTH), albumin-modified calcium, and biomarkers for bone turnover--osteocalcin, bone alkaline phosphatase (B-ALP), and carboxyterminal cross-linked telopeptide of type I collagen (ICTP)--were measured. The samples were collected before myeloablative treatment, on the day of bone marrow infusion and 1, 2, 3, and 12 weeks thereafter. A serum PTH peak was consistently seen the day after total body irradiation, but no long-term effects on PTH/calcium homeostasis were observed. Bone formation as reflected by serum osteocalcin and B-ALP decreased, with nadir levels 2 to 3 weeks after marrow infusion. A simultaneous increase in bone resorption (increased S-ICTP) occurred. Pretreatment values were not completely regained 12 weeks after transplantation. The findings indicate that bone tissue is affected by myeloablative treatment, and the changes in biomarkers imply a net loss of bone over the study period.

MACOP-B +/- radiation therapy for diffuse large cell lymphoma. Analysis of the Stanford results according to prognostic indices.

BACKGROUND: The efficacy and toxicity of the MA-COP-B regimen were assessed after outstanding results were reported in diffuse large cell lymphoma (DLCL) by the Vancouver group. The results are reported according to several proposed prognostic indices, including the recent International Prognostic Factors (IPF) Project. METHODS: Forty-seven patients with untreated DLCL received MACOP-B chemotherapy. Thirty patients, most of whom had bulky disease, also received consolidative radiation therapy (RT). Patient characteristics include median age of 42 years, Stage III/IV (57%), bulky or symptomatic Stage II disease (43%), elevated lactic dehydrogenase (81%) and at least one extranodal site (72%). RESULTS: At a median follow-up of 3.3 years, overall survival was 57% and freedom from progression (FFP) was 52%. The 3-year FFP data were related to tumor extent: 74% for limited stage versus 38% for extensive disease. These data correlated well with four prognostic indices reported in the literature. The IPF index accurately identified low-, intermediate-, and high-risk subgroups. CONCLUSIONS: Patients with limited or low-risk DLCL have an excellent prognosis with MACOP-B +/- RT. These results do not support the use of consolidative high-dose therapy and bone marrow transplantation in patients with limited disease, even if bulky or accompanied by an elevated lactic dehydrogenase. Compared to historical CHOP data, MACOP-B +/- RT does not appear to improve outcome for those patients with poor prognostic features, most of whom will fail. The IPF index is a simple, accurate method of distinguishing high-risk patients who require new therapeutic initiatives.

P300 as indicator of effects of prophylactic cranial radiation.

In order to assess the late adverse effects of cranial radiation on the central nervous system, 33 children with acute lymphocytic leukemia were examined through event-related potential P300, brain response analysis. P300 latency was significantly prolonged in children who received both prophylactic cranial radiation and intrathecal methotrexate. Although a longitudinal study is necessary, we believe that P300 is useful in the assessment of the adverse effects of cranial radiation in children with acute lymphocytic leukemia.

Thyroid adenoma following treatment of acute lymphocytic leukemia.

Sequelae of the treatment of children with acute lymphocytic leukemia (ALL) include multiple effects on the endocrine system, especially as it relates to growth and puberty. Thyroid dysfunction, and in particular, the occurrence of thyroid neoplasia, has been only rarely described. We report the development of benign thyroid neoplasms in two patients 9 years following the diagnosis and treatment of ALL. Both patients were clinically and biochemically euthyroid with noncystic "cold" nodules found on thyroid scan. In light of these observations, and along with previous reports of malignant thyroid neoplasia in children with ALL, long-term careful observation of children successfully treated for ALL is indicated.