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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., (Copyright © 2012 Elsevier Inc. All rights reserved.)

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., (Copyright © 2012 Elsevier Inc. All rights reserved.)

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., (Copyright © 2011. Published by Elsevier Inc.)

Purpose: Extramammary Paget's 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., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: Loss of the cell-cycle regulatory protein p53 or overexpression of the antiapoptotic protein Bcl-2 is associated with resistance to radiation in several types of cancer cells. Flavopiridol, a synthetic flavone, inhibits the growth of malignant tumors cells in vitro and in vivo through multiple mechanisms. The purpose of the present study is to clarify whether flavopiridol enhances the cytotoxic effects of radiation in tumor cells that contain dysfunction p53 or that overexpress Bcl-2., Methods and Materials: A human glioma cell line (A172/mp53) stably transfected with a plasmid containing mutated p53 and a human cervical cancer cell line (HeLa/bcl-2) transfected with a bcl-2 expression plasmid were used. Cells were incubated with flavopiridol for 24 h after radiation, and then cell viability was determined by a colony formation assay. Foci of phosphorylated histone H2AX were also evaluated as a sensitive indicator of DNA double-strand breaks., Results: Compared with the parental wild-type cells, both transfected cell lines were more resistant to radiation. Post-treatment with flavopiridol increased the cytotoxic effects of radiation in both transfected cell lines, but not in their parental wild-type cell lines. Post-treatment with flavopiridol inhibited sublethal damage repair as well as the repair of DNA double-strand breaks in response to radiation., Conclusions: Flavopiridol enhanced the cytotoxic effect of radiation in radioresistant tumor cells that harbor p53 dysfunction or Bcl-2 overexpression. A combination treatment of flavopiridol with radiation has the potential to conquer the radioresistance of malignant tumors induced by the genetic alteration of p53 or bcl-2.

Purpose: To identify haplotypes of single nucleotide polymorphism markers associated with the risk of early adverse skin reactions (EASRs) after radiotherapy in breast cancer patients., Methods and Materials: DNA was sampled from 399 Japanese breast cancer patients who qualified for breast-conserving radiotherapy. Using the National Cancer Institute-Common Toxicity Criteria scoring system, version 2, the patients were grouped according to EASRs, defined as those occurring within 3 months of starting radiotherapy (Grade 1 or less, n = 290; Grade 2 or greater, n = 109). A total of 999 single nucleotide polymorphisms from 137 candidate genes for radiation susceptibility were genotyped, and the haplotype associations between groups were assessed., Results: The global haplotype association analysis (p < 0.05 and false discovery rate < 0.05) indicated that estimated haplotypes in six loci were associated with EASR risk. A comparison of the risk haplotype with the most frequent haplotype in each locus showed haplotype GGTT in CD44 (odds ratio [OR] = 2.17; 95% confidence interval [CI], 1.07-4.43) resulted in a significantly greater EASR risk. Five haplotypes, CG in MAD2L2 (OR = 0.55; 95% CI, 0.35-0.87), GTTG in PTTG1 (OR = 0.48; 95% CI, 0.24-0.96), TCC (OR = 0.48; 95% CI, 0.26-0.89) and CCG (OR = 0.50; 95% CI, 0.27-0.92) in RAD9A, and GCT in LIG3 (OR = 0.46; 95% CI, 0.22-0.93) were associated with a reduced EASR risk. No significant risk haplotype was observed in REV3L., Conclusion: Individual radiosensitivity can be partly determined by these haplotypes in multiple loci. Our findings may lead to a better understanding of the mechanisms underlying the genetic variation in radiation sensitivity and resistance among breast cancer patients.

Purpose: Bcl-2, an inhibitor of apoptosis frequently shows elevated expression in human tumors, thus resulting in resistance to radiation therapy. Therefore, inhibiting Bcl-2 function may enhance the radiosensitivity of tumor cells. Tetrocarcin A (TC-A) and bcl-2 antisense oligonucleotides exhibit antitumor activity by inhibiting Bcl-2 function and transcription, respectively. We investigated whether these antitumor agents would enhance the cytotoxic effects of radiation in tumor cells overexpressing Bcl-2., Methods and Materials: We used HeLa/bcl-2 cells, a stable Bcl-2-expressing cell line derived from wild-type HeLa (HeLa/wt) cells. Cells were incubated with TC-A and bcl-2 antisense oligonucleotides for 24 h after irradiation, and cell viability was then determined. Apoptotic cells were quantified by flow cytometric assay., Results: The HeLa/bcl-2 cells were more resistant to radiation than HeLa/wt cells. At concentrations that are not inherently cytotoxic, both TC-A and bcl-2 antisense oligonucleotides increased the cytotoxic effects of radiation in HeLa/bcl-2 cells, but not in HeLa/wt cells. However, in HeLa/bcl-2 cells, additional treatment with TC-A in combination with radiation did not significantly increase apoptosis., Conclusions: The present results suggest that TC-A and bcl-2 antisense oligonucleotides reduce radioresistance of tumor cells overexpressing Bcl-2. Therefore, a combination of radiotherapy and Bcl-2 inhibitors may prove to be a useful therapeutic approach for treating tumors that overexpress Bcl-2.

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 Children's 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.