Stereotactic ablative radiotherapy with CyberKnife for advanced thymic carcinoma: a case report.

Thymic carcinoma is a rare but lethal mediastinal cancer. The optimal treatment for advanced thymic carcinoma is not yet established. This report is the first known of stereotactic ablative radiotherapy (sabr) with CyberKnife (Accuray, Sunnyvale, CA, U.S.A.) as definitive therapy for thymic carcinoma. The patient, a 70-year-old woman with thymic carcinoma, invasion into neighboring organs, and pleural metastases-underwent CyberKnife sabr at 40 Gy in 5 fractions for two lesions, one in the thymus and one in the right paraspinal pleura. After 61 months of observation, a partial response was observed in the irradiated fields. However, disease progression in the non-irradiated pleura was noted. The patient underwent salvage CyberKnife sabr for the four initially nonirradiated pleural lesions. Computed tomography images obtained 10 months after the salvage therapy revealed a partial response. The patient is living, with progression-free irradiated lesions and no radiation-related toxicity. CyberKnife sabr is feasible for patients who are unable to undergo either surgery or conventionally fractionated radiation therapy.

Survival outcome of patients with nasopharyngeal carcinoma: a nationwide analysis of 13 407 patients in Taiwan.

OBJECTIVES: We reported the contemporary survival outcome of patients with nasopharyngeal carcinoma (NPC) and analysed the factors affecting survival. DESIGN: A retrospective cohort study. SETTING: A nationwide population-based study in Taiwan. PARTICIPANTS: We identified 13 407 patients with newly diagnosed NPC from 2002 to 2010. MATERIAL AND METHODS: The multivariate Cox proportional hazards model was performed to measure the mortality-association risk factor in patients with NPC after adjusting for NPC treatment and socio-demographic characteristics. RESULTS: The 1-, 2-, 5- and 8-year overall survival (OS) rates were 89.6%, 80.4%, 65.2% and 56.5%, respectively. The factors associated with mortality risk were sex (men versus women, HR = 1.45), age (>60 versus ≤ 40 years, HR = 3.61), geographic region of residence (eastern Taiwan versus northern Taiwan HR = 1.39), income (<15 840 versus >25 000, HR = 1.87) and treatment modality (chemotherapy alone versus radiotherapy alone, HR = 2.25). CONCLUSION: The contemporary 5-year OS rate was 65.2% in Taiwan. Male patients, old age, residing in eastern Taiwan, low income and receiving chemotherapy alone were independent predictors for poor OS.

Paediatric head CT scan and subsequent risk of malignancy and benign brain tumour: a nation-wide population-based cohort study.

BACKGROUND: To evaluate the possible association between paediatric head computed tomography (CT) examination and increased subsequent risk of malignancy and benign brain tumour. METHODS: In the exposed cohort, 24 418 participants under 18 years of age, who underwent head CT examination between 1998 and 2006, were identified from the Taiwan National Health Insurance Research Database (NHIRD). Patients were followed up until a diagnosis of malignant disease or benign brain tumour, withdrawal from the National Health Insurance (NHI) system, or at the end of 2008. RESULTS: The overall risk was not significantly different in the two cohorts (incidence rate=36.72 per 100 000 person-years in the exposed cohort, 28.48 per 100 000 person-years in the unexposed cohort, hazard ratio (HR)=1.29, 95% confidence interval (CI)=0.90-1.85). The risk of benign brain tumour was significantly higher in the exposed cohort than in the unexposed cohort (HR=2.97, 95% CI=1.49-5.93). The frequency of CT examination showed strong correlation with the subsequent overall risk of malignancy and benign brain tumour. CONCLUSIONS: We found that paediatric head CT examination was associated with an increased incidence of benign brain tumour. A large-scale study with longer follow-up is necessary to confirm this result.

Dosimetric and efficiency comparison of high-dose radiotherapy for esophageal cancer: volumetric modulated arc therapy versus fixed-field intensity-modulated radiotherapy.

The aim of this study was to compare high-dose volumetric modulated arc therapy (VMAT) and fixed-field intensity-modulated radiotherapy (ff-IMRT) plans for the treatment of patients with middle-thoracic esophageal cancer. Eight patients with cT2-3N0M0 middle-thoracic esophageal cancer were enrolled. The treatment planning system was the version 9 of the Pinnacle(3) with SmartArc (Philips Healthcare, Fitchburg, WI, USA). VMAT and ff-IMRT treatment plans were generated for each case, and both techniques were used to deliver 50 Gy to the planning target volume (PTV(50)) and then provided a 16-Gy boost (PTV(66)). The VMAT plans provided superior PTV(66) coverage compared with the ff-IMRT plans (P = 0.034), whereas the ff-IMRT plans provided more appropriate dose homogeneity to the PTV(50) (P = 0.017). In the lung, the V(5) and V(10) were lower for the ff-IMRT plans than for the VMAT plans, whereas the V(20) was lower for the VMAT plans. The delivery time was significantly shorter for the VMAT plans than for the ff-IMRT plans (P = 0.012). In addition, the VMAT plans delivered fewer monitor units. The VMAT technique required a shorter planning time than the ff-IMRT technique (3.8 ± 0.8 hours vs. 5.4 ± 0.6 hours, P = 0.011). The major advantages of VMAT plans are higher efficiency and an approximately 50% reduction in delivery time compared with the ff-IMRT plans, with comparable plan quality. Further clinical investigations to evaluate the use of high-dose VMAT for the treatment of esophageal cancer are warranted.

Studies on anthracenes. 2. Synthesis and cytotoxic evaluation of 9-acyloxy 1,8-dichloroanthracene derivatives.

The synthesis and cytotoxic evaluation of 9-acyloxy 1,8-dichloroanthracene derivatives are described. The system selectively reduces the carbonyl group flanked by the peri substituents of the anthracenediones to give the corresponding 1,8-dichloro-9(10H)-anthracenone. Simple acylation of anthracenone occurred with appropriate acyl chlorides in CH2Cl2 with a catalytic amount of pyridine to give the 9-acyloxy-1,8-dichloroanthracene derivatives. Considerable interest has developed in the mechanism of how anthracenones achieve this desirable selectivity. These compounds were evaluated in vitro for their ability to inhibit the growth of human oral epidermoid carcinoma cells (KB cell line), human cervical carcinoma cells of ME 180 (GBM 8401) and Chinese hamster ovary (CHO) cells, respectively, as compared to mitoxantrone. The in vitro cytotoxicity evaluation of 9-acyloxy 1,8-dichloroanthracenes against these above cell lines revealed for most of the compounds a cytotoxic potency lower than that of mitoxantrone. The most active compounds were thus selected for further in vitro biological evaluation and structural modification.

Lamivudine treatment for hepatitis B reactivation in HBsAg carriers after organ transplantation: a 4-year experience.

BACKGROUND: Reactivation of hepatitis B after organ transplantation in hepatitis B surface antigen (HBsAg) carriers may be fatal. In this study, we reported our experience of lamivudine treatment in HBsAg carriers who had post-transplant reactivation of hepatitis B. METHODS: The patients were 15 men and one woman. Nine received kidney transplants, six received heart transplants, and one received a lung transplant. They developed a reactivation of hepatitis B 1-101 months (median, 14 months) after transplantation. They received lamivudine 100 mg daily on a compassionate-use basis, and had regular follow ups. The median pretreatment total serum bilirubin level was 3.0 mg/dL, and the alanine aminotransferase level was 357 U/L. Four of the 16 patients were positive for HBeAg. The serum hepatitis B virus (HBV) DNA levels were > 3000 pg/mL in 13 (81%) patients. Three were coinfected with hepatitis C virus. RESULTS: The overall survival rate was 75%. All four fatal cases had a pretreatment total serum bilirubin level of > or = 3 mg/dL. Serum HBV-DNA soon became undetectable in 12 survivors. Of the 12 survivors, after a median treatment period of 101 weeks, a lamivudine-resistant strain with variation in the YMDD motif of the HBV polymerase gene developed in three (25%). None had significant adverse reactions to lamivudine treatment. CONCLUSIONS: These results indicated that lamivudine is effective in the treatment of post-transplant hepatitis B reactivation, including patients with dual chronic hepatitis B and C. Early recognition of HBV reactivation and prompt lamivudine treatment are important to prevent mortality.

Different risks of symptomatic brain necrosis in NPC patients treated with different altered fractionated radiotherapy techniques.

PURPOSE: To report our observation of excessive temporal lobe necrosis in nasopharyngeal carcinoma (NPC) patients treated with 160 cGy b.i.d. radiotherapy technique. During the same period, patients treated with 120 cGy b.i.d. have not shown a similar tendency. Our experience may be useful for designing unconventional radiotherapy regimens for NPC patients. METHODS AND MATERIALS: During the period from October 1991 to January 1998, 81 M0, previously untreated NPC patients completed altered fractionated radiotherapy. Seventy patients were treated with the hyperfractionated technique, and 11 were treated using the accelerated-hyperfractionated scheme. Hyperfractionated radiotherapy was delivered using 120 cGy b.i.d. separated by 6-h intervals throughout the course. A minimum tumor dose of 8000 cGy was the standard dose over an 8-week period. With the accelerated-hyperfractionated scheme, 160 cGy was given twice daily, also with an interval of 6 h. The minimum tumor dose ranged between 6840 and 7640 cGy, with 7 of the 11 patients receiving 7000 cGy. The arrangement of portals was the same for both regimens. The follow-up period for patients alive was from 32 to 102 months with a median of 61 months for the hyperfractionated patients. For the accelerated-hyperfractionated group, it ranged from 67 to 82 months with a median of 72 months. No patient was lost to follow-up. RESULTS: At the time of analysis, 49 of the 70 patients in the hyperfractionated group were alive. In the accelerated group, 8 of the 11 patients were alive. The estimated radiation dose to the temporal lobe for the hyperfractionated group was 6000-7440 cGy with a median of 7080 cGy. For the accelerated-hyperfractionated group, the dose range was 4480-6700 cGy with a median of 6400 cGy. Of the 70 patients treated with hyperfractionated radiotherapy, none developed symptomatic brain necrosis, despite the higher total dose to the temporal lobe in general. In contrast, 3 of the 11 (27%) patients irradiated using the accelerated-hyperfractionated regimen suffered from temporal lobe necrosis at 16, 19, and 40 months after completion of radiotherapy. CONCLUSION: An excessive incidence of temporal lobe necrosis was noted when an accelerated-hyperfractionated regimen with 160 cGy b.i.d. was used in NPC patients with a median brain dose of 6400 cGy. There has been no such event in patients treated using a hyperfractionated regimen with 120 cGy and a median brain dose of 7000 cGy. The real causes of this discrepancy are not known. However, a high sensitivity of the human brain to a change in fraction size may play a role.

Studies on anthracenes. 1. Human telomerase inhibition and lipid peroxidation of 9-acyloxy 1,5-dichloroanthracene derivatives.

The synthetically useful approaches to 9-acyloxy 1,5-dichloroanthracene derivatives are reported. The system selectively reduces the carbonyl group flanked by the peri substituents of the anthracenediones to give the corresponding 1,5-dichloro-9(10H)-anthracenone. Simple regioselective acylation of anthracenone is applied with appropriate acyl chlorides in CH2Cl2 with catalytic amount of pyridine to give the novel 9-acyloxy 1,5-dichloroanthracene derivatives. Considerable interest has developed in the mechanism of how anthracenone achieves this desirable selectivity. In an attempt to understand the mechanism of this reaction, solid-state structures of anthracene derivatives have been obtained. In addition, the inhibition of lipid peroxidation in model membranes was determined as was their ability to inhibit the telomere-addition function of the human telomerase enzyme together with their inhibition of the Taq polymerase enzyme. In contrast to (+)-alpha-tocopherol, 3b, 3c, 3d, 3g, and 3i do not enhance lipid peroxidation in model membranes. Implications for 9-acyloxy 1,5-dichloroanthracene analogues as potential anticancer agents are discussed.

Neoadjuvant chemotherapy followed by radiotherapy should not be a standard approach for locally advanced cervical cancer.

PURPOSE: To investigate the role of neoadjuvant chemotherapy followed by radiotherapy in locally advanced cervical cancer. METHODS AND MATERIALS: This study cites all known literature on the subject in the English language. Articles were selected for analysis by MEDLINE and CANCERLINE computer searches. In Phase II trials, the response rates of some selective series were analyzed. However, This article will specially emphasize the result of all Phase III randomized trials. RESULTS: Several investigators did obtain promising results from Phase II trials of neoadjuvant chemotherapy, mostly cisplatin-based combinations, followed by radiotherapy. However, most Phase III trials failed to demonstrate any benefit in terms of loco-regional relapse and/or survival by up-front chemotherapy. CONCLUSION: The role of neoadjuvant chemotherapy remains to be defined, and the search for more active new agents must be continued. The neoadjuvant setting is still experimental and could not be recommended as a standard treatment at the present.

Concurrent 5-fluorouracil, daily low-dose cisplatin, and radiotherapy in stage IIIB cervical cancer. A phase II prospective study.

Between June 1987 and May 1991, 30 patients with Stage IIIB cervical cancers were treated using synchronous radiotherapy, 5-fluorouracil (5-FU), and daily low-dose cisplatin. External radiotherapy (3,600-3,960 cGy) was given to the whole pelvis in 4 weeks. Two courses of intracavitary brachytherapy were given 2 weeks later. Parametrial boost was then given. Continuous infusion of 5-FU 750 mg/m2 was given for 5 days during the first and third week of pelvic irradiation. Cisplatin (6 mg/m2) was given 30 min before every irradiation in the second and fourth week. The complete response rate was 87%. The 3-year local control rate was 77%. The 3-year overall and disease-free survival rate was 66% and 56%, respectively. Distant metastases were the major causes of treatment failure. Toxicities were acceptable. Our preliminary results indicate that this synchronous combination treatment is feasible. Further follow-up is required to determine whether this regimen has a genuine favorable impact on survival and chronic toxicity.

Twice-per-day fractionated high versus continuous low dose rate intracavitary therapy in the radical treatment of cervical cancer: a nonrandomized comparison of treatment results.

PURPOSE: To compare the efficacy of two twice-per-day fractionated high dose rate (HDR) brachytherapies with a historical control group treated with low dose rate (LDR) brachytherapy for cervical cancer patients. METHODS AND MATERIALS: From 1985 to 1988, 92 patients with cancer of the cervic were treated by remote-controlled, HDR brachytherapy, six fractions of 7 Gy per fraction (42 Gy) at point A (HDR-6). Fifty-seven patients were treated with four fractions of 8 Gy per fraction (32 Gy) at point A (HDR-4). A twice-per-day program was used for all HDR patients by two split courses. As a historical control, treatment results of 259 patients treated with LDR brachytherapy (40 Gy in two split courses) were compared with those of the two HDR regimens. All patients received whole pelvic external irradiation, 36-45 Gy (mostly 40 Gy) before brachytherapy. RESULTS: Five-year local control rates were not significantly different for the three groups (HDR-6 = 82.0%, HDR-4 = 85.5%, and LDR = 89.5%, respectively). Five-year survival rates were also comparable (67.7%, 77.9%, and 74.1%, respectively). However, late complications were lower in HDR-4 than HDR-6 (11.0% vs. 25.6%). CONCLUSIONS: Both 5-year local control and survival rates were comparable among the three groups. However, HDR-4, which was more biologically equivalent to our LDR regimen, showed fewer complications compared to HDR-6. In addition, our twice-per-day schedule shortened the hospital stay.

Two components of repair in irradiated kidney colony forming cells.

Data describing the response of mouse kidney colony-forming cells to fractionated X-irradiation using different interfraction intervals were analysed in order to detect the presence of one or more components of repair. A two-component repair model gave a superior fit, with reference to a single-repair rate model, giving distinct repair halftimes of 0.15 (approximate 95% confidence limits: 0.0, 0.40) and 5.03 (1.23, 8.84) h. These values are the first reported for normal cells in vivo, and they are similar to values calculated for tissue responses in skin, lung and the spinal cord. The slow component of repair is important in radiotherapy, in particular regarding novel hyperfractionation regimens when interfraction intervals much less than 1 day are employed.

Intrathoracic extraskeletal Ewing's sarcoma: a case report and review of literature.

Extraskeletal Ewing's sarcoma (EES) is a rare tumor of soft tissue. As an uncommon clinical entity with histologic features similar to those of other small round-cell tumors, EES occasionally produces difficulty in diagnosis. Hence, diagnosis should be confirmed by histochemical, immunohistochemical and clinical findings. Here, we describe a man aged 29 years who had intrathoracic mass was diagnosed as EES after incisional biopsy of the tumor. The presence of glycogen in the tumor cells was demonstrated by periodic acid-Schiff (PAS) stain but immunoreactivity for cytokeratin, epithelial membrane antigen, leukocyte common antigen, desmin, actin and neuron-specific enolase were absent; vimentin was present. The patient was successfully treated with VIP regimen (etoposide, ifosfamide and cisplatin) followed by local irradiation. He remained alive without recurrence after one year. A review of the literature and recent advances in the treatment of EES are reported.

The distribution of colony-forming cells in the kidney.

A method is described for producing outgrowths of small nephron segments (average 24 cells) in culture. The method was used to estimate an overall colony-forming efficiency of 4.6% for cells constituting the segments. Efficiency was found to be lower for thick segments (1%) than for thin segments (6%) from Henle's loop. The latter higher level indicates that precursor cells are concentrated near the middle of the nephron. For comparison, a two-dose irradiation technique was used to calculate a mean number of 5 +/- 2 (SE) clonogens per segment producing outgrowths. This tended to be higher than the value of about 1 calculated from the 65% of segments producing outgrowths, as expected if the remaining segments contained no clonogens.

The dose-fractionation sensitivity of the kidney; assessment of viable tubule cross-sections at 19 months after X irradiation.

The formation of viable tubule cross-sections was assessed in histological sections of murine kidneys at 19 months after fractionated bilateral X-ray doses with 12 h intervals between fractions. The data were analysed using the linear-quadratic model which provides values of alpha and beta characterizing the slope of the dose-response curve, and the ratio of alpha and beta indicative of the sparing effect of dose fractionation. The tubule data were characterized by alpha = 0.057 +/- 0.009 Gy-1, beta = 0.011 +/- 0.001 Gy-2, alpha/beta = 5.0 +/- 0.9 Gy. Also, the number of cells (per focus region of the nephron) calculated as being capable of producing a viable focus was 2.5 +/- 0.5, which was confirmed using a separate two-dose approach (2.1 +/- 0.3). Together with other data, of the order of 1000 regenerative cells per nephron (10(4) total cells) can be deduced. The values of the fractionation sensitivity parameters are similar to values measured previously for cells taken from irradiated kidneys up to a year after irradiation and forming colonies in primary culture, and also similar to values assessed using various functional measures of kidney injury.

Dose-fractionation sensitivity of mouse kidney clonogens measured using different interfraction intervals and postirradiation assay times.

The fractionation sensitivity of kidney clonogenic epithelial cells (X-irradiation in vivo, assay in vitro) was quantified using the linear-quadratic model. The cells were assayed either immediately after the fractionation schedule or after a time delay in order to compare the relative amounts of dose sparing due to fractionation (conventionally sublethal damage repair) and to post-irradiation delay intervals before assay (conventionally potentially-lethal damage repair). As the delay before assay was increased, there was a tendency for both alpha and beta to decrease, and as a consequence the alpha/beta ratio stayed virtually unchanged (3.3-4.4 Gy) regardless of delay time before assay. No change in survival was observed from 12 h to 6 weeks after neutron irradiation (62 MeVp-->Be), suggesting that the change observed after X-rays was due to repair rather than repopulation. As the interfraction intervals in an 8-fraction X-irradiation schedule were increased in steps from 6 h to 5 days, there was improved survival, consistent with the presence of long-term repair. These studies provide further evidence for the potential importance of long-term repair in late reacting tissues not only during but also after multifraction irradiation schedules.

The lower radiosensitivity of mouse kidney cells irradiated in vivo than in vitro: a cell contact effect phenomenon.

For mouse kidney cells assayed in primary culture, the Do and n values were 1.1 +/- 0.06 Gy and 7 +/- 2 for single cells irradiated in vitro, and 1.3 +/- 0.08 Gy and 25 +/- 11 for in vivo irradiation. The lower radiosensitivity in vivo was shown not to be caused by natural hypoxia, as the average oxygen enhancement ratios were 2.6 +/- 0.3 for in vitro and 2.8 +/- 0.4 for in vivo irradiation. Irradiations of fragments of kidney tubules produced similar survivals as irradiations of kidneys in situ, even for irradiation immediately before the fragments were disaggregated into single cells. The critical point of change in radiosensitivity from in vivo to in vitro values due to this contact effect was the time that the kidney cells were monodispersed.

Acute response of mouse kidney clonogens to fractionated irradiation in situ and then assayed in primary culture.

Although the difference in sensitivity to the changes in dose fraction size between early-responding and late-responding tissues is well established, the underlying mechanisms in terms of target-cell responses are not yet clearly identified for any tissue. The radiosensitivity of mouse kidney cells after in situ single-dose, 2, 8, and 16 fraction X-irradiations was measured in primary culture using a clonogenic assay. The assay was made 12 h after single doses or 12 h after the last dose of the multifraction regimens. When analysed using the linear-quadratic model, as predicted the individual alpha components for all the different fractionation schedules were not significantly different, and the changes in the beta values were consistent with those expected on the basis of the reciprocal fraction numbers. When all four data sets were integrated to derive a common alpha/beta ratio, the result was 4.4 +/- 1.3 (1SE) Gy, or 2.8 +/- 0.9 Gy (a better fit) if the single-dose data set was excluded. These values fall into the range reported for kidney using assays of tissue function at long times after irradiation. Hence, it has been shown for the first time that the fractionation sensitivity of a late-responding organ is mimicked by that of a clonogenic cell population in that organ. The evidence also suggests that the time available prior to fixation of potentially lethal damage does not influence the low alpha/beta ratio observed for the kidney.