Impact of pediatric hematopoietic stem-cell transplantation on craniofacial growth

OBJECTIVES: To assess the craniofacial skeletal growth in pediatric hematopoietic stem-cell transplantation (HSCT) survivors in comparison with age-sex matched-paired controls. METHODS: A case-controlled retrospective comparison of the craniofacial growth in 25 HSCT children and 25 matched-paired controls was conducted. Craniofacial growth was quantitatively assessed by linear and angular measurements in panoramic radiographic images using ImageJ¯. Stature growth and body weight were obtained through physical examination. Cancer diagnosis, myeloablative conditioning, and HSCT were retrieved from medical records. RESULTS: Patients aged 12.2 years (±3.8; 16 male, 9 female). Radiographic images were obtained on an average of 2.43 (±2.0) years after HSCT. The main malignant diagnosis was acute lymphoblastic leukemia (56%), followed by acute myeloid leukemia (36%) and myelodysplastic syndromes (8%). Total body irradiation was associated with chemotherapy at 80%. Mean age at transplantation was 10 (±4.7) years. HSCT survivors showed reduced a vertical growth of the mandibular ramus (p=0.003). This persisted among individuals below 12 years of age (p=0.017). The HSCT group showed delayed dental eruption, though there was no statistically significant difference (p=0.3668). The HSCT group showed stature deficit, increased weight, and body mass index (Z-score stature: -0.28; Z-score weight: 0.38, respectively). CONCLUSIONS: Pediatric HSCT has decreased vertical craniofacial growth compared to their matched controls. There might be an association between reduced craniofacial vertical growth and reduced estature growth. Further studies to quantitatively investigate the impact of different myeloablative regimens in craniofacial skeletal growth and development.

Evaluation of a novel decorporation approach to prevent radioactivity uptake by using acidosis in experimental animals.

With an aim to devise a prophylactic and/or therapeutic approach for preventing internalization of radiothallium (201Tl), and more importantly by implication, its chemical analogue radiocesium (137Cs) during any nuclear emergency, different ex vivo and in vivo animal models were created to determine the role of pH in absorption of 201Tl across jejunum/muscle tissue and whole body retention of 201Tl respectively. Movement of Tl+ under simulated pH conditions proved that pH had direct influence on its absorption. Oral intake of acidified water or parenteral administration of lactic acid was able to reduce the body burden of 201Tl by up to 12 and 50% respectively. The results indicate that acidification of gut, within physiological range may be used as an option for decorporation/inhibition of incorporation of radiothallium and radiocesium, particularly in cases of mass casualty.

Proteins and liver function changes in rats following cumulative total body irradiations / Proteínas y cambios de función hepática en ratas tras irradiación corporal total cumulativa

OBJECTIVE: Total body irradiation (TBI) is a choice therapy for the management of some malignancies; it is also a major cause of oxidative stress. The aim of this research is to sequentially document the effect of total body radiation on body function utilizing the sequential changes in liver function enzymes and proteins in rats. METHODS: Serum protein and liver enzymes were assessed using kits in rats exposed to total body radiations of 1.27 Gy/minute in cumulative doses to the fourth radiation at five-day intervals. RESULTS: Aspartate aminotransferase (AST), alanine transaminase (ALT) and serum protein were significantly (p < 0.05) elevated with increasing radiation. No significant differences between experimental and control groups for bilirubin concentrations were noted at any time. Serum levels of albumin were significantly (p < 0.05) increased with the first to third radiation exposures but reduced at the fourth cumulative dose exposure. CONCLUSION: Variations are associated with acute stress, inflammation which could be due to non-specific stress reaction, while fluctuations could arise as a result of tolerance and repair within the liver. These tests are significant for diagnosis of radiation-induced injury and can be important for evaluation of its severity and correct management.

OBJETIVO: La irradiación corporal total (ICT) es una terapia de elección para el tratamiento de algunos tumores malignos. También es una de las causas principales del estrés oxidativo. El objetivo de esta investigación es documentar el efecto de la radiación corporal total sobre las funciones corporales utilizando los cambios secuenciales en las enzimas de la función hepática y las proteínas en las ratas. MÉTODOS: Se evaluaron las proteínas séricas así como las enzimas hepáticas mediante el uso de kits en ratas expuestas a radiaciones corporales totales de 1.27 Gy/minuto en dosis cumulativas hasta la cuarta radiación con cinco días de intervalo. RESULTADOS: La aspartato transaminasa (AST), la alanina aminotransferasa (ALT) y la proteína sérica fueron elevadas significativamente (p < 0.05) con el aumento creciente de la radiación. No hubo diferencias significativas entre el grupo experimental y el grupo control, observándose concentraciones de bilirrubina todo el tiempo. Los niveles séricos de albúmina aumentaron significativamente (p < 0.05) con la primera de tres exposiciones a la radiación, pero experimentaron una reducción a partir de la cuarta exposición de dosis cumulativa. CONCLUSIÓN: Las variaciones están asociadas con estrés agudo e inflamación que podría deberse a una reacción a estrés no específico, mientras que las fluctuaciones podrían surgir como resultado de la tolerancia y la regeneración dentro del hígado. Estas pruebas son importantes para el diagnóstico de lesiones inducidas por radiación, así como para la evaluación de la severidad y el tratamiento correcto de las mismas.

Therapeutic potential of green tea extract and low doses of gamma-irradiation on diabetic nephropathy of rats

Diabetic nephropathy is one of the most frequent and serious complications of diabetes mellitus. This study was designed to evaluate the effect of green tea [GT] extract and low doses of 0.5 G gamma-radiation [R] on diabetic nephropathy [DN] of rats. Male Swiss albino rats were used in this study. DN was induced in rats using streptozotocin [45 mg/kg.body weight]. The rats were divided into five groups DN, DN+R, DN+GT, DN+GT+R and a sham treatment control group. Throughout the experimental period [3and 6 weeks] animals body weight, glucose and insulin levels were evaluated. Kidney functions assay [serum urea and creatinin] were recorded. Histopathological observations in kidney tissue, DNA and glycogen intensity were also detected. Diabetic rats exhibited many symptoms including loss of body weight, increase in blood glucose level and decrease in serum insulin levels. Increase in serum urea and creatinin levels. Diabetic kidney showed a moderate renal damage, multifocal clarifications and vacuolations. Carbohydrates intensity showed a significant increase and DNA intensity showed many alterations. Improvements in glomerular and tubulointerstitial lesions were demonstrated in the diabetic rat group exposed to low doses of gamma-radiation or supplemented by green tea either alone or combined in addition to amelioration in glucose, insulin urea and creatinin levels. The present study demonstrates the efficacy of low doses of gamma- radiation and in reducing diabetes-induced functional and histological alterations in the kidneys. The longterm control of blood glucose levels using low doses of gamma-radiation or green tea either alone or combined could prevent the progression of diabetes mellitus, and therefore, nephropathy could be prevented

Endocrine Complications after Hematopoietic Stem Cell Transplantation during Childhood and Adolescence

Long-term survivors of hematopoietic stem cell transplantation (HSCT) during childhood and adolescence are at risk of developing endocrine complications. The purpose of this study was to evaluate the long-term endocrine complications and their associated risk factors among such patients. We reviewed the data from 111 patients (59 males and 52 females) who underwent HSCT at the mean age of 8.3+/-4.1 yr. Thirty patients (27.0%) had growth impairment, and seven (21.2%) out of 33 patients who attained final height reached final height below 2 standard deviation (SD). The final height SD score of the patients conditioned with total body irradiation (TBI) was significantly lower than that of the patients conditioned without TBI (-1.18+/-1.14 vs. -0.19+/-0.78, P=0.011). Thirteen patients (11.7%) developed hypothyroidism (11 subclinical, 2 central) 3.8+/-1.8 (range 1.6-6.2) yr after HSCT. Nineteen (65.5%) out of 29 females had evidence of gonadal dysfunction, and 18 (64.3%) out of 28 males had evidence of gonadal dysfunction. The risk for gonadal dysfunction was significantly higher in females conditioned with busulfan/cyclophosphamide (P=0.003). These results suggest that the majority of patients treated with HSCT during childhood and adolescence have one or more endocrine complications. Therefore, multiple endocrine functions should be monitored periodically after HSCT until they reach adult age.

radioprotective efficiency of combined administration of natural antioxidants [rutin and vitamin e] and a sulfhydryl compound in irradiated rats

In the present study, the radioprotective effects of natural antioxidants, rutin alone, vitamin E alone or both of them combined with a synthetic radioprotector, cysteine, have been investigated in irradiated rats. Furthermore, the oxidative stress biomarkers and certain liver function tests of the whole body irradiated rats were examined. The effect of irradiation was evaluated by exposing the whole body of rats to gamma radiation at acute single dose of 6.5 Gy. Rutin [1.064 mmol/kg] was daily administered orally for two weeks before irradiation, vitamin E [50 mg/100g] was injected intraperitoneally daily for seven days before irradiation, while, cysteine [30 mg/kg] was intra-peritoneally administered 30 mm. only before irradiation. Blood and liver malondialdehyde [MDA], glutathione [GSH] and plasma superoxide dismutase [SOD] levels were evaluated. Serum aspartate aminotransferase [AST], alanine aminotransferase [ALT] and alkaline phosphatase [ALP] activities were also measured in various groups. The data revealed deleterious damage of radiation exposure which was manifested as a significant increase in lipid peroxidation measured as MDA. On the other hand, the activity of SOD and the level of GSH were reduced after irradiation. In addition, the activities of serum ALP, AST and ALT were markedly elevated after radiation exposure. Administration of rutin or vitamin E alone or combined with cysteine before radiation provided a protective effect as measured by the tested parameters. It could be concluded that treatment with the natural antioxidants can control radiation-induced oxidative damage in the biological system. This study indicates that the use of combination of agents is a promising approach for maximizing radioprotection with minimal adverse effects. Administration of cysteine iucreases the radioprotective effects of rutin and vitamin E against the damaging effects of ionizing radiation

Study of the radioprotective efficiency of combined administration of cysteine and natural antioxidants [rutin and vitamin E] in feverish irradiated rats

In the present experiments, a study of the radioprotective effects of natural antioxidants, rutin alone, vitamin E alone or each of them combined with synthetic radioprotector, cysteine, have been investigated in feverish irradiated rats. Furthermore, the oxidative stress biomarkers of the feverish whole body irradiated rats were examined. The data revealed deleterious damage of radiation exposure which was manifested as significant increase in lipid peroxidation measured as malondialdehyde [MDA]. On the other hand, the activity of plasma superoxide dismutase [SOD] and the blood level of glutathione [GSH] were reduced after irradiation. Effect of hyperthermia on oxidative stress biomarkers in rats were studied in this work and data showed that the increase in body temperature intensified lipid peroxidation processes where MDA in plasma and liver homogenate was increased, GSH level in blood and liver homogenate was also increased while plasma SOD activity was reduced. Effect of rutin alone, vitamin E alone or each of them combined with cysteine on oxidative stress biomarkers in hyperthermic irradiated rats was investigated. Results indicated that, pretreatment with vitamin E and rutin alone or combined with cysteine before the onset of hyperthermia significantly attenuated fever-induced increase in free radical formation and lipid peroxidation. Radiation exposure at acute single dose of 6.5 Gy did not change the body temperature when measured on the 3[rd] day following exposure. In order to determine any antipyretic effect of the drugs used, the body temperature of each animal was measured before induction of hyperthermia as well as 18 hours following yeast injection. Rats were treated with the tested drugs before induction of fever then exposed to whole body gamma radiation at acute single dose of 6.5 Gy and body temperature of each animal was measured 3 days after irradiation. Only rutin had an antipyretic effect in yeast-induced hyperthermia in rats

Acute renal toxicity of 2 conditioning regimens in patients undergoing autologous peripheral blood stem-cell transplantation. Total body irradiation-cyclophosphamide versus ifosfamide, carboplatin, etoposide

To compare acute renal toxicity of 2 conditioning regimens of total body irradiation/cyclophosphamide TBI-Cy and Ifosfamide, Carboplatin, and Etoposide ICE. Between August 1996 and February 2004, patients treated with autologous peripheral stem cell transplantation in the Department of Medical and Radiation Oncology, Gulhane Military Medical School, Ankara, Turkey with 2 different conditioning regimens was comparatively analyzed for acute renal toxicity in the early post-transplant period. Forty-seven patients received ICE regimen with 12 g/m2; 1.2 g/m2; and 1.2 g/m2 divided to 6 consecutive days, whereas 21 patients received 12 Gy TBI 6 fractions twice daily in 3 consecutive days and 60 mg/m2/day cyclophosphamide for 2 days. Sixty-eight patients were evaluated in this study. There was no significant difference in baseline renal function between patients in the ICE and TBI-Cy groups. Eleven patients developed nephrotoxicity 23.4% in the ICE group while one patient 4.8% in the TBI-Cy group developed nephrotoxicity p=0.06. Five out of 11 patients developing nephrotoxicity in ICE group required hemodialysis and subsequently 4 8.5% of them died. In contrast, one patient 4.8% died due to nephrotoxicity despite hemodialysis in the TBI-Cy arm. This study reveals that the TBI-Cy conditioning regimen seems no more nephrotoxic than an ICE regimen particularly in patients who had used cisplatin prior to transplantation

Perturbations in phosphoinositide metabolism and protein kinase C activity in mouse liver following whole body irradiation.

The involvement of the signal transduction pathway in mouse liver following whole body irradition was investigated. Mice were exposed to 60Co gamma rays (3 Gy) and sacrificed after different time intervals. Various elements of phosphatidyl inositol signal transduction pathway were investigated. Alterations could be seen as early as 15 min of irradiation. These changes are reflected in elevation in DAG levels and increased activation of PKC, an enzyme which is involved in tumorigenesis. The chronological appearance of various transducers following whole body irradiation is of significance since these early effects may set the stage for radiation-induced tumorigenesis and hence may be used to manipulate tumor response to radiotherapy.

Avaliaçäo de distúrbios do crescimento e da puberdade de origem idiopática ou após tratamento de neoplasias / Evaluation of growth and puberty disorders of idiopathic etiology or after neoplasms therapy

Em uma coletânea de artigos säo discutidos aspectos referentes aos distúrbios de crescimento e puberdade de origem idiopática ou decorrentes do tratamento de neoplasias. CAPÍTULO I: determinaçöes de IGF-1 e IGFBP-e além de desaceleraçäo precoce do crescimento (< 5 anos) säo marcadores diagnósticos de deficiência idiopática permanente de GH, enquanto que atraso de idade óssea, velocidade de crescimento diminuída e dois picos de GH < 10 ng/mL näo distinguem deficiência permanente de trasitória. Em adolescentes masculinos com retardo puberal a deficiência de GH é rara; a aceleraçäo do crescimento tem associaçäo positiva com a testosterona plasmática e o volume testicular, e näo com o pico de GH. Pequenas doses de testosterona näo reduzem a estatura final. CAPÍTULO II: O tratamento da puberdade precoce central com GnRHa baseado no cálculo da estatura projetada e da diferença entre esta e a estatura-alvo, pico LH/FSH, estradiol sérico e avanço de idade óssea possibilita uma estatura final adequada. Quando associam-se puberdade precoce e deficiência de GH, o tratamento combinado (GnRHa + GH) deve ser iniciado concomitantemente. Formas lentamente evolutivas de puberdade precoce sem tratamento näo apresentam reduçäo da estatura final. Em pacientes que receberam radioterapia craniana (24 Gy) por leucemia, a estatura final depende do pico de GH e da idade ao início da puberdade, e näo do protocolo quimioterápico. Nessa populaçäo, IGF-1 e IGFBP-3 näo säo bons marcadores de deficiência de GH, a qual é mais freqüente em pacientes irradiados antes de cinco anos. CAPÍTULO III: em pacientes com meduloblastoma que receberam radioterapia e quimioterapia, a reduçäo de GH-BP, IGF-1 e IGFBP-3 com secreçäo normal de GH sugere um mecanismo de resistência parcial ao GH, induzida pela quimioterapia. Entretanto, a longo prazo esta resistência trasitória näo impede a retomada de crescimento normal em pacientes submetidos a TMO. Em pacientes que receberam TBI, a näo-associaçäo entre pico de GH e perda estatural reflete o efeito associado da radioterapia sobre as cartilagens de crescimento. Níveis normais de IGF-1 e IGFBP-3 em pacientes com deficiência de GH sugerem um mecanismo de resistência parcial ao IGF-1. O tratamento da radioterapia näo reduz os efeitos deletérios desta sobre o crescimento.

Avaliaçäo de proteçäo ocular em feixes de elétrons / Evaluation of eye shield for electron beams

Nos tratamentos por radiaçäo, nos quais a regiäo ocular é exposta ao campo de tratamento, uma proteçäo é colocada entre a pálpebra e o globo ocular para proteger as estruturas oculares mais sensíveis à radiaçäo. Isto é importante, pois uma dose de 500 cGy na córnea pode provocar catarata. A efetividade de uma proteçäo ocular construida em chumbo e uma outra proteçäo comercial (Ace Medical Supply Co., New York) foi avaliada para feixes de elétrons de 5,4 MeV e 3,7 MeV. Na avaliaçäo do efeito de concavidade, verificou-se que o formato côncavo desse tipo de proteçäo permite que o dobro de radiaçäo seja transmitida, comparada a uma proteçäo plana. A proteçäo comercial testada apresentou proteçäo suficiente para o feixe de 3,7 MeV/ entretanto, para o feixe de 5,4 MeV a dose na interface proteçäo-material absorvedor foi 56 por cento da dose na profundidade de dose máxima, dmax, sem a proteçäo. A espessura encontrada para uma dose transmitida de aproximadamente 5 por cento da dose em dmax`, para uma proteçäo desse tipo, para este último feixe, foi de 3mm em chumbo. Um aumento significativo da dose na interface externa da proteçäo ocorre devido ao efeito de retroespalhamento dos elétrons. Para que este efeito seja reduzido a um nível de dose próximo à dose em dmax, espessura mínima de 3mm de poliestireno é necessária para ambos os feixes testados