Sincronía de diferentes tumores radioinducidos en superviviente de leucemia linfoblástica aguda / Different radioinducid tumors synchrony in an acute lymphoblastic leukemia survivor

La aparición de tumores craneales inducidos por radiación en pacientes pediátricos tratados de enfermedades hematológicas como la leucemia/linfoma linfoblástico T (T-ALL/LBL) es un fenómeno conocido que puede incluir lesiones de diferentes grados de malignidad y precisar tratamiento neuroquirúrgico. Presentamos el caso de un varón de 38 años remitido a nuestro servicio por la aparición brusca de diplopía con hemiparesia izquierda progresiva de 6 meses de evolución y caídas frecuentes. Tras realización de pruebas de imagen, se objetivan distintas lesiones intraaxiales y extraaxiales con diferente comportamiento radiológico decidiéndose un abordaje quirúrgico único para su exéresis. La anatomía patológica confirma cuatro variantes histológicas: meningioma (grado 1 y 2 [atípico]), subependimoma y cavernoma. Discutimos el papel teratogénico y efectos biológicos de las radiaciones ionizantes (AU)

The cranial radiation-induced tumors appearance in pediatric patients treated for hematological diseases such as leukemia/T-lymphoblastic lymphoma (T-ALL/LBL) is a known phenomenon that may include lesions of different malignant degrees and require neurosurgical treatment. We present the case of a 38-year-old man referred to our department for a sudden diplopia with 6-month progressive left hemiparesis and frequent falls. After imaging tests, different intra and extraxial lesions with different radiological behavior were observed, performing a single surgical approach for their resection. The pathological anatomy confirms four histological variants: meningioma (grade 1 and 2 [atypical]), subependymoma, and cavernoma. We discuss the teratogenic role of ionizing radiation (AU)

Experiences in the treatment of refractory chylothorax associated with lymphoproliferative disorders.

BACKGROUND: Chylothorax is a rare condition which can be associated with malignant lymphoproliferative disorders (LPDs). We retrospectively analyzed the results of the conservative treatment of 10 patients with persistent non-traumatic malignant chylothorax. RESULTS: Conservative treatment lead to a decline of chylothorax after mean of 66 days and consisted of the treatment of the underlying disease and of simultaneous long-term supportive care (drainage of the thoracic cavity, dietary measures and nutrition management). In most cases (80%), chylothorax disappeared only after a successful therapeutic response of the underlying disease. Low-dose radiotherapy had very good effects in two patients. CONCLUSION: Conservative treatment of malignant chylothorax can be considered a suitable method. Based on our results, successful treatment of the lymphoproliferative disorder seems to be a very important factor for the disappearance of chylothorax.

Accumulation of DNA damage and cell death after fractionated irradiation.

The purpose of this work was to determine how fractionated radiation used in the treatment of tumors affects the ability of cancer as well as normal cells to repair induced DNA double-strand breaks (DSBs) and how cells that have lost this ability die. Lymphocytic leukemia cells (MOLT4) were used as an experimental model, and the results were compared to those for normal cell types. The results show that cancer and normal cells were mostly unable to repair all DSBs before the next radiation dose induced new DNA damage. Accumulation of DSBs was observed in normal human fibroblasts and healthy lymphocytes irradiated in vitro after the second radiation dose. The lymphocytic leukemia cells irradiated with 4 × 1 Gy and a single dose of 4 Gy had very similar survival; however, there was a big difference between human fibroblasts irradiated with 4 × 1.5 Gy and a single dose of 6 Gy. These results suggest that exponentially growing lymphocytic leukemia cells, similar to rapidly proliferating tumors, are not very sensitive to fraction size, in contrast to the more slowly growing fibroblasts and most late-responding (radiation therapy dose-limiting) normal tissues, which have a low proliferation index.

Radioterapia esplénica: a propósito de 8 casos. Indicaciones y revisión de la literatura / Splenic irradiation: a proposal of 8 cases. Clinical indications and literature review

Las indicaciones de la radioterapia (RT) esplénica en los desórdenes hematológicos incluye la irradiación del bazo en aquellos procesos linfoproliferativos, que cursan con infiltración del mismo, el tratamiento paliativo de la esplenomegalia en las enfermedades malignas como la leucemia linfoide crónica o los síndromes mieloproliferativos, que cursan con dolor por la distensión capsular del bazo, y las citopenias secundarias al hiperesplenismo. En este trabajo presentamos la experiencia acumulada en el tratamiento de la esplenomegalia con RT del Hospital General Universitario Gregorio Marañón en los últimos 5 años, analizando sus indicaciones, resultados y toxicidad así como una revisión actualizada de la literatura

Clinical indications of splenic irradiation in haematological disorders include the irradiation in lymphoproliferative disorders with spleen infiltration, palliative treatment of splenomegaly in malignant diseases like chronic lymphocytic leukaemia or myeloproliferative disorders, with the purpose of relief from abdominal pain associated with capsular enlargement size and decrease cytopenias secundaries to hypersplenism. This paper reports our experience with spleen irradiation in the Hospital General Universitario Gregorio Marañón in the last five years, and analizes indications, results and toxicity, and an actual review of the literature

Glioblastoma multiforme in a child with acute lymphoblastic leukemia: case report and review of literature.

An 11-year-old boy with acute lymphoblastic leukemia had received prophylactic cranial irradiation (1800 cGy /10 fractions) and intrathecal methotrexate. Five years later, he developed a glioblastoma multiforme in the right frontal region while the leukemia was in remission. It is possible that the glioma may have been induced by radiation and /or chemotherapy.

Thyroid neoplasms after therapeutic radiation for malignancies during childhood or adolescence.

BACKGROUND: Recent data indicate that the risk of developing a thyroid neoplasm clearly is increased after high-dose, therapeutic radiation therapy during childhood. To better understand the time course, natural history, and histopathology of thyroid lesions that develop after high-dose irradiation, the authors undertook a retrospective study of all survivors of childhood and adolescent malignancies who were treated at Memorial Sloan-Kettering Cancer Center and who developed a clinically apparent thyroid neoplasm. METHODS: The authors searched the data base of the Department of Pediatrics, the hospital-based tumor registry, and the hospital medical records database for patients with thyroid neoplasms. RESULTS: Thirty-three patients were identified who developed a thyroid neoplasm after therapeutic radiation. Primary diagnoses were Hodgkin disease (n = 18 patients), non-Hodgkin lymphoma (n = 10 patients), acute lymphoblastic leukemia (n = 2 patients), acute myeloid leukemia (n = 1 patient), Wilms tumor (n = 1 patient), and neuroblastoma (n = 1 patient). The median age at the time of diagnosis of the primary malignancy was 12.0 years (range, 3.7-18.3 years), the median radiation dose to the thyroid gland was 2400 centigrays (cGy; range, 1000-4200 cGy), and the median interval from the time of radiation therapy until the recognition of thyroid disease was 13.0 years (range, 6.2-30.1 years). Thirteen of 33 thyroid lesions (39%) were malignant (11 papillary carcinomas and 2 follicular carcinomas). Age at diagnosis, gender ratio, and time elapsed since initial treatment did not differ between patients with malignant and benign lesions, but the median radiation dose to the thyroid was lower in patients who had malignant disease compared with patients who had benign disease (2000 cGy vs. 2950 cGy; P = 0.03). Disease was confined to the neck in all patients who had malignant thyroid lesions; after a median follow-up of 6.5 years (range, 0.9-12 years), none of the patients developed progressive or recurrent disease. CONCLUSIONS: Data from this study suggest that a high proportion of clinically apparent thyroid neoplasms that develop after therapeutic radiation for a childhood malignancy are malignant. However, most of these thyroid malignancies do not appear to behave in an aggressive fashion. Because thyroid neoplasms may not become evident for decades after radiation therapy, all individuals who are at risk require life-long follow-up.

High levels of chromosome aberrations correlate with impaired in vitro radiation-induced apoptosis and DNA repair in human B-chronic lymphocytic leukaemia cells.

PURPOSE: To investigate the relationship between the susceptibility of B-chronic lymphoid leukaemia (B-CLL) cells to DNA damage-induced apoptosis, the kinetics of DNA strand-break rejoining, and chromosome damage after exposure to ionizing irradiation. MATERIALS AND METHODS: Lymphocytes from B-CLL patients were gamma-irradiated in vitro with 0.2-5 Gy and stimulated by Staphylococcus aureus cowan I (SAC I) for estimation of chromosomal damage. Induction of apoptosis after irradiation was studied in 50 patients by two methods: morphological characterization of apoptotic cells after fluorescent staining (Hoechst), and specific quantification of mono- and oligonucleosomes in cytoplasmic cell fractions (ELISA assay). Morphological chromosome damage was scored in the first cell generation after irradiation (13 patients). In parallel, the kinetics of DNA single-strand break rejoining were investigated by the alkaline comet assay (12 patients). RESULTS: Ionizing irradiation did not induce apoptosis in lymphocytes from a subset of B-CLL patients. The results suggest that B-CLL cells resistant to radiation-induced apoptosis could repair DNA strand-breaks more rapidly and showed a higher level of chromosome aberrations than radiation-sensitive B-CLL cells. CONCLUSION: Each of three biological effects observed (apoptosis, kinetics of DNA single-strand-break repair, chromosomal damage) might be explained by different modifications occurring in irradiated B-CLL cells. Their convergence strongly suggests that resistance to apoptotic death initiation by DNA damage may be impeded by a rapid engaging of the DNA repair mechanisms. The higher level of chromosome aberrations observed in these cells suggests that the type of DNA repair system involved may generate inaccurate repair.

Acute T-lymphoblastic leukemia relapsed with the character of myeloid/natural killer cell precursor phenotype: a case report.

The leukemic lymphoblasts of a patient expressed CD7, CD13, CD33, CD34, HLA-DR and cytoplasmic CD3varepsilon. He was diagnosed with acute lymphoblastic leukemia (ALL), and successfully treated with a conventional chemotherapy for ALL. The disease relapsed three times, and the character of the cells gradually altered, i.e. CD56 expression increased and CD13, CD7 and cCD3 epsilon decreased. The phenotype of the relapsed ALL was, therefore, compatible with myeloid/natural killer cell precursor acute leukemia (M/NK-AL). Some of M/NK-AL may be closely related with T/myeloid-biphenotypic pro-T blasts, and both types of acute leukemia may develop a tendency to express myeloid antigens, and they may belong to the category of immature T lymphoid precursors.

Clinical progression of transplanted large granular lymphocytic leukemia in Fischer 344 rats exposed to 60 Hz magnetic fields.

The purpose of this study was to determine if 60 Hz magnetic fields can alter the clinical progression of leukemia in an animal model. Large granular lymphocytic (LGL) leukemia cells from spleens of leukemic rats were transplanted into young male Fischer 344 rats, producing signs of leukemia in approximately 2-3 months. The animals were randomly assigned to 4 treatment groups (108/group) as follows: 1) 10 G (1.0 mT) linearly polarized 60 Hz magnetic fields, 2) sham exposed [null energized unit with residual 20 mG (2 microT) fields], 3) ambient controls [<1 mG (0.1 [microT)], and 4) positive controls (a single 5 Gy whole body exposure to 60Co 4 days prior to initiation of exposure). All rats were injected intraperitoneally (ip) with 2.2 x 10(7) LGL leukemic cells at the initiation of exposure or sham exposure. The magnetic fields were activated for 20 h/day, 7 days/week, allowing time for animal care. The experimental fields were in addition to natural ambient magnetic fields. Eighteen rats from each treatment group were bled, killed, and evaluated at 5, 6, 7, 8, 9, and 11 weeks of exposure. Peripheral blood hematological endpoints, changes in spleen growth, and LGL cell infiltration into the spleen and liver were measured to evaluate the leukemia progression. No significant or consistent differences were detected between the magnetic field exposed groups and the ambient control group, although the clinical progress of leukemia was enhanced in the positive control animals. These data indicate that exposure to sinusoidal, linearly polarized 60 Hz, 10 G magnetic fields did not significantly alter the clinical progression of LGL leukemia. Furthermore, the data are in general agreement with previous results of a companion repeated-bleeding study in which animals were exposed for 18 weeks.

Mitochondrial and intracellular free-calcium regulation of radiation-induced apoptosis in human leukemic cells.

PURPOSE: To investigate the mechanisms and pathways of X-ray apoptosis in Molt-4 cells, focusing on mitochondrial and cytosolic Ca2+ ([Ca2+]i) regulation. MATERIALS AND METHODS: X-irradiated Molt-4 cells and cell extract (CE) were used to analyse: (1) induced apoptosis (Giemsa stain), (2) p53, Bcl-2 and Bax expressions (immunoblot), (3) mitochondrial potential deltapsi(m) and (4) [Ca2+]i (flow cytometry), (5) caspase-3 activity, and (6) roles of [Ca2+]- and caspase-3-mediated pathways by inhibiting either or both pathways for induced apoptosis. RESULTS: Molt-4 cells were sensitive to apoptosis since 5 Gy induced 57 and 94% apoptosis at 6 and 24 h. After 5Gy, p53 was accumulated that upregulated Bax but which repressed Bcl-2 with time, resulting in a 7-fold increase in Bax/Bxl-2 at 6 h. Predominant Bax reduced deltapsi(m), and low-deltapsi(m) cells increased 45 min earlier than apoptosis after 5 Gy. Caspase-3 was activated in apoptotic CE. The caspase-3 inhibitor Ac-DEVD-CHO inhibited apoptosis and DNA-ladder formation by approximately 50%, suggesting a approximately 50% role of caspase-3-activated DNase (CAD). [Ca2+]i was increased after 5 Gy. [Ca2+]i-chelating BAPTA-AM (5 microM) and/or DNase gamma-inhibiting Zn2+ (0.5 mM) inhibited approximately 50% of induced apoptosis and DNA-laddering, indicating a 50% participation of Ca2+/Mg2+-dependent DNase gamma. CONCLUSIONS: The p53-Bax-mitochondria-caspase-3-CAD pathway and the [Ca+2]i-mediated DNase gamma pathway were involved in the regulation of X-ray apoptosis in sensitive Molt-4 cells.

[Recovery of ovarian function after radiation-induced menopause. Does follicle-stimulating hormone (FSH) have a definitive prognostic value?]. / Récupération de fonctionnement ovarien après ménopause radio-induite. L'hormone folliculostimulante (FSH) a-t-elle une valeur pronostique définitive?

Menopause, conventionally defined as the permanent cessation of menstruation as a result of loss of ovarian follicular activity, is biologically expressed by the collapse of plasma estradiol levels and increased plasma levels of the gonadotrophins FSH (follicle stimulating hormone) and LH (luteinizing hormone). At present, estimation of the ovarian follicle reserve is based on endocrine capacity tests of the ovaries, with increased FSH representing the first sign of exocrine ovarian failure. We report the case of one of our amenorrhoeic patients after chemotherapy, total body radiation and allogenic bone marrow transplantation for acute immunoblastic leukaemia. This patient was included in an in vitro fertilization with oocyte donation (IVF-OD) programme for iatrogenic premature ovarian failure with increased FSH levels. Instead of high levels of gonadotrophins, this young woman recovered spontaneous follicular development, benefited from standard IVF with her own oocytes and brought a twin pregnancy to term. This observation shows that a high FSH level is not a definitive prediction of ovarian exocrine capacity. In young women of child-bearing age such as these wanting a child and showing signs of endogenous estrogen impregnation, evaluation of the existence and quality of follicular development is an important factor.

Basal cell carcinoma in a girl after cobalt irradiation to the cranium for acute lymphoblastic leukemia: case report and literature review.

A 12-year-old girl had a lesion located on the upper part of the scalp that was clinically interpreted as a melanocytic nevus and corresponded histologically to a basal cell carcinoma. At age 2 years she had been diagnosed as having acute lymphoblastic leukemia L1, for which she was treated with systemic chemotherapy. She also received telecobalt therapy to the whole cranium for prophylaxis of meningeal leukosis. Having rejected other possible causes that can favor the appearance of basal cell carcinoma during childhood (basal cell nevus syndrome, nevus sebaceus, albinism, etc.), we believe that this case should be added to the five previously reported in the literature as basal cell carcinoma developing at an early age in cranial radiation portals with megavoltage radiotherapy. We draw attention to the need to explore radiated areas of skin as part of the long-term follow-up of these patients, and to the advisability of obtaining a biopsy from any persistent lesion in these areas.

Neuropsychological and neurological outcome after relapse of lymphoblastic leukaemia.

Fourteen children who relapsed after initial remission of leukaemia were studied. Six received a second course of cranial radiotherapy, while the remaining eight children were given total body irradiation before bone marrow transplantation. The postirradiation somnolence syndrome was common after cranial radiotherapy. All children had mild/soft neurological signs, mostly of coordination. None had a major motor disability. All but the youngest child had cataracts; two children required an operation for these. All children were growth hormone deficient. Verbal IQ, attention, and concentration were selectively reduced (with respect to normative levels). The time between the two treatments, age at relapse, and higher doses of radiotherapy all correlated with cognitive outcome, with girls showing greater impairments than boys. Only two children were performing at age appropriate levels on measures of academic achievement. It is concluded that neurological and neuropsychological morbidity is significantly increased by the current treatments prescribed after the relapse of leukaemia.

Time-gated fluorescence spectroscopy of porphyrin derivatives and aluminium phthalocyanine incorporated in vivo in a murine ascitic tumour model.

The effect of systemic administration on drug uptake at cellular level was evaluated using time-gated fluorescence spectroscopy performed on a murine ascitic tumour model. Mice bearing L1210 leukaemia were injected intraperitoneally or intravenously with 25 mg per kg body weight hematoporphyrin derivative (HpD), 12.5 mg per kg body weight photofrin II (PII), 25 or 5 mg per kg body weight disulphonated aluminium phthalocyanine (AlS2Pc). Every 2 h and for up to 22 or 30 h, mice were sacrificed, leukaemic cells extracted from the peritoneum, washed, and resuspended in buffer for fluorescence measurements. HpD and PII emission spectra were almost identical 12 h after intraperitoneal injection with main peaks at 630 nm and no appreciable changes afterwards. In the first 12 h, the PII fluorescence spectrum was constant, while in the case of HpD a shoulder at 615 nm was detectable. Similar fluorescence behaviour was observed after intravenous administration of porphyrin derivatives. These results seem to confirm that the tumour localizing fraction is the part actually retained by the cells. The AlS2Pc spectrum peaked at 685 nm and did not change in any of our experiments. AlS2Pc is incorporated more rapidly with respect to porphyrins, as was clearly observed in the case of intravenous administration, where the AlS2Pc fluorescence was readily detectable after 2 h, whereas the PII emission became apparent only after 4-6 h.

Proteínas totais no LCR antes e após radioterapia / Csf protein contents before and after radiotherapy

Com o uso da radioterapia e quimioterapia intratecal associados, passou-se a observar alteraçöes do sistema nervoso central que denotaram lesöes neuronais e vasculares. A atribuiçäo da causalidade dessas alteraçöes a um dos dois fatores terapêuticos passou a ser estudada. Quanto ao papel da radioterapia, há trabalhos experimentais e clínicos que apontam para a possibilidade de ser um fator lesivo. E cogitada a possibilidade da radioterapia lesar a barreira hematencefálica, permitindo com isso a entrada de amethopterin no sistema nervoso. Como as dosagens de irradiaçäo usadas experimentalmente säo bem amiores que as terapêuticas, a analogia feita com o tratamento profilático de pacientes leucêmicos näo parece bastante clara. O propósito desse trabalho é estudar a taxa de proteínas totais no líquido cefalorraquino de pacientes com leucemia aguda, sem comprometimento do sistema nervoso, submetidos a radioterapia, como parametro de avaliaçäo de pertubaçäo da barreira hematencefálica. Para esse estudo foram selecionados 18 pacientes com leucemia aguda, sendo 16 com leucemia linfóide aguda, 2 com leucemia mielóide aguda e que näo tinham sinais ou sintomas clínicos de comprometimento neurológico, nem células blásticas no LCR. As amostras de LCR para este estduo foram colhidas até 8 dias antes do início da radioterapia e de 1 semana até 6 meses após o término dessa mesma sequência radioterápica. A dosagem da taxa de proteínas totais foi feita pelo método de Denis & Ayer. Em conclusäo, pelo método de avaliaçäo empregado, näo se pode evidenciar alteraçäo de permeabilidade da barreira hematencefálica, decorrente de irradiaçäo do sistema nervoso central para profilaxia da neuroleucemia.

Lymphoblastic lymphoma in adult patients: clinicopathological features and response to intensive multiagent chemotherapy analogous to that used in acute lymphoblastic leukemia.

This paper analyzes the clinicopathological features of 31 consecutive adult patients with lymphoblastic lymphoma (LBL) and reports on our experience in treating them with two successive multidrug programs analogous to those used in acute lymphoblastic leukemia (ALL) in adults. Protocol 1 (18 patients) consisted of an intensive four-drug induction therapy (daunorubicin, cyclophosphamide, vincristine, prednisone), CNS prophylaxis (cranial irradiation and intrathecal methotrexate), and continuous maintenance with methotrexate and mercaptopurine for three years, with periodical reinductions with vincristine and prednisone. Protocol 2 (13 patients) included a similar induction regimen (doxorubicin instead of daunorubicin, dexamethasone instead of prednisone), followed by post-remission intensification with alternating courses of non-cross-resistant agents (amsacrine and high dose cytarabine; vincristine, cyclophosphamide and doxorubicin; etoposide and conventional dose cytarabine) given in a cyclical eight-month program. CNS prophylaxis consisted of intrathecal methotrexate and systemic high-dose cytarabine. The patient characteristics of the two therapy groups were comparable. The complete remission (CR) rate for both groups was 77%, with a median overall and relapse-free survival of 18 and 29 months, respectively. The three-year overall survival of complete remitters was 59%. No correlation was found between CR rate and age, mediastinal, or bone marrow involvement. Stage I disease had a significantly higher CR rate (100%) than did stages II-IV (64%). Leukemic evolution occurred in 32% of cases, within a median time of 11 months from diagnosis; meningeal disease developed in six cases (19%); in four of them leukemia was concomitant. No significant differences were found between the two successive treatments for CR rate, survival, CNS relapses or toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of the number of fractions of cranial irradiation on growth in children with acute lymphoblastic leukaemia.

Growth was documented over a period of 7 years in all long-term survivors treated for acute lymphoblastic leukaemia (ALL) with the DAL-70- (n = 15) and BFM-70-protocol (n = 27). Normal growth was documented in patients of the DAL-70-protocol during and after therapy. In contrast, in children treated with the BFM-70-protocol the mean height standard deviation score (SDS) decreased significantly from 1.21 SDS prior to therapy to 0.80 SDS at the end of therapy (p less than 0.001) and remained unchanged thereafter. Prophylactic cranial irradiation was given in total doses of 15 to 30 Gy. Ten children of the DAL-70- and 20 children of the BFM-70-protocol received 24 Gy of cranial irradiation. No significant change in height-SDS was observed in any patients of the DAL-70- and in 8 patients of the BFM-70- group, who received 24 Gy of cranial irradiation in 16-26 fractions. Adult height in 7 girls and 6 boys was normal and 3.15 cm and 5.06 cm above target height. In the remaining 12 patients of the BFM-70-protocol the total dose of 24 Gy of cranial irradiation was applied in 11-14 fractions. Their height-SDS had fallen significantly from 1.24 SDS before to 0.66 SDS (p less than 0.001) at the end of therapy. Adult height in 4 girls and 6 boys was also normal, but the height increase was comparatively smaller, -2.20 cm below target height in the girls and 1.91 cm above in the boys.(ABSTRACT TRUNCATED AT 250 WORDS)