Motoko Omura

Large intracranial vessel occlusive vasculopathy after radiation therapy in children: Clinical features and usefulness of magnetic resonance imaging

PURPOSE To assess the relationship between large intracranial vessel occlusive vasculopathy (vasculopathy) and radiation therapy, and to clarify the clinical efficacy of magnetic resonance (MR) imaging in the diagnosis and screening of the vasculopathy. METHODS AND MATERIALS We retrospectively evaluated the medical records and serial MR images for 32 pediatric patients, in whom radiation therapy had been given to fields including the circle of Willis and major cerebral arteries. All children had periodically undergone follow-up neurologic assessment and MR imaging examinations at Kanagawa Childrens Medical Center for more than one year after radiation therapy (range 1.3-14 years). Patients who had not remained free of tumor progression up to the time of final evaluation were excluded. RESULTS Vasculopathy developed in 6 of 32 patients 2-13 years after radiation therapy. Three of them presented with transient ischemic attacks (TIA) and the other three showed infarctions without preceding TIA. Steno-occlusive changes of major cerebral arteries were identified by MR imaging in all six patients, but not obtained in the remaining 26 patients. In the patients with TIA, MR imaging demonstrated steno-occlusive changes at the time of TIA, before irreversible infarction. They have been doing well subsequent to encephaloduroarteriosynangiosis. In the three patients who presented infarction without preceding TIA, MR imaging did not demonstrate the vascular change before the onset of infarction, and two of them developed neurologic deficits. The mean exposure dose for the circle of Willis and major cerebral arteries in these six patients was significantly higher than that in the remaining 26 patients without this sequela (61 Gy vs. 50 Gy, p < 0.05). The mean age at radiation therapy of the six patients was lower, but the difference was not significant. CONCLUSION The incidence of vasculopathy after radiation therapy has a considerable correlation with radiation dose and age at radiation therapy. MR examination is useful for the diagnostic evaluation of vasculopathy, and it is also effective in screening for vasculopathy in patients with TIA, and may be helpful in the prevention of neurologic sequela.

SN-38, a metabolite of the camptothecin derivative CPT-11, potentiates the cytotoxic effect of radiation in human colon adenocarcinoma cells grown as spheroids

BACKGROUND AND PURPOSE CPT-11 (7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) is anew semisynthesized derivative of camptothecin. SN-38 (7-ethyl-10-hydroxycamptothecin), a metabolite of CPT-11, plays a key role in the action of CPT-11. MATERIALS AND METHODS To determine whether SN-38 potentiates the cytotoxic effect of radiation, we investigated the interaction of SN-38 and radiation in vitro in monolayer cultures and multicellular spheroids of HT-29 human colon adenocarcinoma cells. RESULTS HT-29 spheroids were more resistant to both SN-38 and irradiation than monolayer cells. SN-38 at a concentration of 2.5 microg/ml, which by itself was not cytotoxic, greatly increased the lethal effects of radiation in spheroids, but not in monolayer cultures. Exposure to SN-38 following irradiation inhibited the potentially lethal damage repair (PLDR) in spheroids. It is suggested that the mechanism of the radiosensitization by SN-38 is due to the PLDR inhibition. CONCLUSIONS These results indicate that CPT-11 may play a role as radiosensitizer and that a combination of CPT-11 and irradiation could prove to be a particularly effective strategy with which to treat human colon adenocarcinoma.

Role of Radiotherapy as Curative Treatment of Extramammary Paget’s Disease

PURPOSE Extramammary Pagets disease (EMPD) is a relatively rare malignancy that usually arises in the genital areas. Wide surgical excision remains the standard and most reliable curative treatment of EMPD. However, surgery is sometimes not possible, because many patients are elderly, and complete excision can be difficult owing to the tumor location. We, therefore, performed a review to determine the role of radiotherapy (RT) for EMPD. METHODS AND MATERIALS A total of 22 patients with EMPD in their external genitalia (4 men and 18 women, age 52-94 years at RT) underwent RT with curative intent. Nine patients had regional lymph node metastases. A total dose of 45-70.2 Gy (median, 60) was delivered to the pelvis, including the tumors, in 25-39 fractions (median, 33). RESULTS In all but 3 patients, the irradiated tumors were controlled during a follow-up period of 8-133 months (median, 42). Of the 22 patients, 13 developed recurrences, including local progression within the radiation field in 3 and lymph node and/or distant metastases outside the radiation field in 10, at 3-43 months after treatment. The 2- and 5-year local progression-free rates were 91% and 84%, respectively. Of the 22 patients, 7 patients had died at 33-73 months after RT. The cause of death was tumor progression in 4, infectious pneumonia in 2, and renal failure in 1 patient. The overall and cause-specific survival rates were 100% for both at 2 years and 53% and 73% at 5 years, respectively. No therapy-related Grade 3 or greater toxicity was observed. CONCLUSIONS RT is safe and effective for patients with EMPD. It appears to contribute to prolonged survival as a result of good tumor control.

Prophylactic cranial irradiation of acute lymphoblastic leukemia in childhood: outcomes of late effects on pituitary function and growth in long-term survivors.

It is well known that prophylactic cranial irradiation is highly effective in preventing central nervous system (CNS) relapse of acute lymphoblastic leukemia (ALL). Nevertheless, there have been very few reports on the late effects, especially pituitary function and growth, in long‐term survivors who were treated with 18 Gy cranial irradiation in childhood. The subjects consisted of 35 children with ALL who were treated with prophylactic 18 Gy cranial irradiation at Kanagawa Childrens Medical Center between October 1981 and February 1995. All patients received cranial irradiation after first attaining complete remission with induction chemotherapy, according to the treatment protocols prescribed by the Tokyo Childrens Leukemia Study Group (TCLSG) and Tokyo Childrens Cancer Study Group (TCCSG). Their ages at the time of cranial irradiation ranged from 2.2–15.0 years (mean 6.8). We evaluated their pituitary functions by measuring their pituitary hormone values 0.7–11.3 years (mean 6.0) after cranial irradiation and their growth by analyzing their height standard deviation score (SDS) at diagnosis of ALL and their final height SDS at the mean follow‐up period of 8.2 years after cranial irradiation. Height SDS is defined as the difference between the patients height and the mean height of their age and sex, divided by the standard deviation of their age and sex. Eight of 35 patients had ALL relapse, involving the bone marrow in seven patients and the CNS in only one. Six of the eight patients with relapse died 1.5–6.6 years after cranial irradiation and the other two patients were salvaged by further intensive therapies. The remaining 27 relapse‐free patients have survived for 1.4–15.8 years (mean 10.1) after cranial irradiation. Twenty‐six of the 29 survivors are long‐term survivors of more than 5 years. Although there was one patient with an abnormal result in each value of growth hormone (GH), adrenocorticotropic hormone (ACTH), and prolactin (PRL), and two patients with abnormal results in thyroid‐stimulating hormone (TSH) values, none of the patients had clinical symptoms of pituitary hormone abnormality and none required hormone supplements. The final height SDS decreased significantly compared with the height SDS at diagnosis of ALL in the long‐term survivors (P = 0.001) and the height SDS of the patients who had received cranial irradiation at a young age tended to decrease gradually (P = 0.019). However, no patient showed severe growth failure. It is considered that prophylactic 18 Gy cranial irradiation plus chemotherapy for ALL in childhood can effectively prevent CNS relapse and is unlikely to produce clinically significant late effects, although it may cause slight pituitary hormone abnormality.

Noninvasive and Curative Radiation Therapy for Sebaceous Carcinoma of the Eyelid

PURPOSE Sebaceous carcinoma of the eyelid is a rare malignancy. Surgical excision remains the standard and most reliable curative treatment. However, surgery is sometimes not possible because many patients are elderly, and it frequently causes functional and cosmetic impairment of the eyelid. We therefore carried out a study to determine the role of radiation therapy in relation to sebaceous carcinoma of the eyelid. METHODS AND MATERIALS Thirteen patients with sebaceous carcinoma of the eyelid underwent radiation therapy with curative intent. There were 6 men and 7 women, and their ages at irradiation ranged from 60 to 85 years (median, 78 years). Only 1 patient had cervical lymph node metastasis, and none of the patients had distant metastasis. A total dose of 50 to 66.6 Gy (median, 60 Gy) was delivered to tumor sites in 22 to 37 fractions. RESULTS All irradiated tumors were controlled at a median follow-up period of 55 months. Only 1 patient had recurrence of cervical lymph node metastasis outside the radiation field, at 22 months after irradiation. The 5-year local progression-free and disease-free rates were 100% and 89%, respectively. The overall and disease-free survival rates at 5 years were 100% and 89%, respectively. Although acute and transient therapy-related reactions of Grade 2 or less were observed, there were no severe toxicities of Grade 3 or greater. CONCLUSIONS Radiation therapy is a safe and effective treatment for patients with sebaceous carcinoma of the eyelid. It appears to contribute to prolonged survival as a result of good tumor control, and it also facilitates functional and cosmetic preservation of the eyelid.

Development of an orthotopic transplantation model in nude mice that simulates the clinical features of human lung cancer

The objective of the present study was to establish an orthotopic tumor transplantation model in nude mice that closely resembles the clinical features of human lung cancer. The human lung adenocarcinoma A549 cell line and the squamous cell carcinoma SQ5 cell line were used. Tumor cells suspended in serum‐free medium were injected directly into the main bronchi of anesthetized female Balb/c athymic nude mice (7–9 weeks old) with or without simultaneous administration of 0.01 M ethylenediaminetetracetic acid (EDTA). In some experiments, lung carcinoma cells harvested from tumors transplanted subcutaneously were recultured and used for intratracheal implantation. Tumor nodules that formed in the lung were counted and confirmed by histological examination. Administration of A549 cells with EDTA resulted in a 70% engraftment rate (n = 10). Recultured A549 cells without and with EDTA resulted in 20% (n = 5) and 80% (n = 5) engraftment rates, respectively. Administration of SQ5 cells without or with EDTA formed 50% (n = 4) and 67% (n = 6) engraftment rates, respectively. Recultured SQ5 cells with EDTA further increased the engraftment rate to 100% (n = 6). Multiple tumors formed mainly in the left lung and the upper lobe of the right lung. Simultaneous administration of EDTA resulted in greater numbers of tumor nodules in the lung. Histological findings revealed that A549 tumor nodules were distributed primarily in alveoli. The SQ5 solid tumors invaded bronchioles and occupied the alveoli. This reproducible orthotopic transplantation model produced tumor growth that simulated the clinical features of human lung cancer. (Cancer Sci 2006; 97: 996–1001)

Treatment Effects and Sequelae of Radiation Therapy for Orbital Mucosa-Associated Lymphoid Tissue Lymphoma

PURPOSE Among extranodal lymphomas, orbital mucosa-associated lymphoid tissue (MALT) lymphoma is a relatively rare presentation. We performed a review to ascertain treatment efficacy and toxicity of radiation therapy for orbital MALT lymphoma. We also evaluated changes in visual acuity after irradiation. METHODS AND MATERIALS Thirty patients with orbital MALT lymphoma underwent radiation therapy with curative intent. Clinical stages at diagnosis were stage IEA in 29 patients and stage IIEA in 1 patient. Total doses of 28.8 to 45.8 Gy (median, 30 Gy) in 15 to 26 fractions (median, 16 fractions) were delivered to the tumors. RESULTS All irradiated tumors were controlled during the follow-up period of 2 to 157 months (median, 35 months) after treatment. Two patients had relapses that arose in the cervical lymph node and the ipsilateral palpebral conjunctiva outside the radiation field at 15 and 67 months after treatment, respectively. The 5-year local progression-free and relapse-free rates were 100% and 96%, respectively. All 30 patients are presently alive; the overall and relapse-free survival rates at 5 years were 100% and 96%, respectively. Although 5 patients developed cataracts of grade 2 at 8 to 45 months after irradiation, they underwent intraocular lens implantation, and their eyesight recovered. Additionally, there was no marked deterioration in the visual acuity of patients due to irradiation, with the exception of cataracts. No therapy-related toxicity of grade 3 or greater was observed. CONCLUSIONS Radiation therapy was effective and safe for patients with orbital MALT lymphoma. Although some patients developed cataracts after irradiation, visual acuity was well preserved.

Treatment Outcomes, Growth Height, and Neuroendocrine Functions in Patients With Intracranial Germ Cell Tumors Treated With Chemoradiation Therapy

PURPOSE We carried out a retrospective review of patients receiving chemoradiation therapy (CRT) for intracranial germ cell tumor (GCT) using a lower dose than those previously reported. To identify an optimal GCT treatment strategy, we evaluated treatment outcomes, growth height, and neuroendocrine functions. METHODS AND MATERIALS Twenty-two patients with GCT, including 4 patients with nongerminomatous GCT (NGGCT) were treated with CRT. The median age at initial diagnosis was 11.5 years (range, 6-19 years). Seventeen patients initially received whole brain irradiation (median dose, 19.8 Gy), and 5 patients, including 4 with NGGCT, received craniospinal irradiation (median dose, 30.6 Gy). The median radiation doses delivered to the primary site were 36 Gy for pure germinoma and 45 Gy for NGGCT. Seventeen patients had tumors adjacent to the hypothalamic-pituitary axis (HPA), and 5 had tumors away from the HPA. RESULTS The median follow-up time was 72 months (range, 18-203 months). The rates of both disease-free survival and overall survival were 100%. The standard deviation scores (SDSs) of final heights recorded at the last assessment tended to be lower than those at initial diagnosis. Even in all 5 patients with tumors located away from the HPA, final height SDSs decreased (p = 0.018). In 16 patients with tumors adjacent to the HPA, 8 showed metabolic changes suggestive of hypothalamic obesity and/or growth hormone deficiency, and 13 had other pituitary hormone deficiencies. In contrast, 4 of 5 patients with tumors away from the HPA did not show any neuroendocrine dysfunctions except for a tendency to short stature. CONCLUSIONS CRT for GCT using limited radiation doses resulted in excellent treatment outcomes. Even after limited radiation doses, insufficient growth height was often observed that was independent of tumor location. Our study suggests that close follow-up of neuroendocrine functions, including growth hormone, is essential for all patients with GCT.

The effect of iodine-based contrast agents on the levels of radiation-induced chromosomal aberrations

The effects of iodine-based contrast agents on the repair of radiation-induced chromosomal damage were investigated employing peripheral blood from a healthy male donor. The blood samples were irradiated with 0.5-4.0 Gy 137Cs gamma rays. Contrast agents and NaCl solutions of various concentrations were added to the blood within the first 15 min or at 60 min after irradiation, and the samples were subsequently cultured for 45 h at 37 degrees C. Significantly elevated frequencies of chromosomal abnormalities caused by postirradiation treatment with hypertonic contrast agents appeared to increase with increasing hypertonicity. Elevated aberration frequencies were found to be greatest in the samples treated within 15 min of irradiation. The contrast agents had little effect if they were added at 60 min after irradiation, probably because the process of chromosome rejoining had been completed. Isotonic iodine-based contrast agents did not enhance the frequencies of chromosomal aberrations to a significant degree.

DNA fragmentation induced by a cytoplasmic extract from irradiated cells

Apoptosis is a mode of cell death characterized by distinct morphological features and DNA fragmentation. The program that leads to apoptosis has been considered to be predominantly extranuclear, and a signal transduction pathway to the nucleus exists during apoptosis, while characteristic events occur in the nucleus. As for radiation-induced apoptosis, the signal transduction pathway remains unclear, especially the sites where the primary effect of radiation occurs. In this study, we demonstrate that a cytoplasmic extract prepared from irradiated cells has the ability to cause DNA fragmentation and that caspase-3 is activated in this extract. Normal nuclei of HeLa S3 cells were added to a cytoplasmic extract made from HL60 cells which had been irradiated with 30 Gy of 137Cs gamma rays and were incubated. Agarose gel electrophoresis of the added nuclei showed a characteristic DNA laddering pattern. This reaction was blocked by a caspase-3 inhibitor but not by an ICE inhibitor. These observations suggest that a signal transduction pathway from an unknown target of gamma radiation may exist upstream of caspase-3 during radiation-induced apoptosis.