Examining electrometer performance checks with direct-current generator in a clinic: Assessment of generated charges and implementation of electrometer checks.

PURPOSE: Medical physicists use a suitable detector connected to an electrometer to measure radiotherapy beams. Each detector and electrometer has a lifetime (due to physical deterioration of detector components and electrical characteristic deterioration in electronic electrometer components), long-term stability [according to IEC 60731:2011, ≤0.5% (reference-class dosimeter)], and calibration frequency [according to Muir et al. (J Appl Clin Med Phys. 2017; 18:182-190), generally 2 years]; thus, physicists should check the electrometer and detector separately. However, to the best of our knowledge, only one study (Blad et al., Phys Med Biol. 1998; 43:2385-2391) has reported checking the electrometer independently from the detector. The present study conducts performance checks on electrometers separately from the detector in clinical settings, using an electrometer equipped with a direct current (DC) generator (EMF 521R) capable of injecting DC (effective range: ±20 pA to ±20 nA) into itself or another electrometer. METHODS: First, to check the nonlinearity of the generated currents from ±20 pA to ±20 nA, charges generated from the DC generator were measured with the EMF 521R electrometer. Next, six reference-class electrometers classified according to IEC 60731:2011 were checked for repeatability at a current of ±20 pA or a minimum effective indicated value meeting IEC 60731:2011, as well as for nonlinearity within the current range from ±20 pA to ±20 nA. RESULTS: The nonlinearities for the measured currents were less than ±0.05%. The repeatability for the six electrometers was < 0.1%. While the nonlinearity of one electrometer reached up to 0.22% at a current of -20 pA, all six electrometers displayed nonlinearities of less than ±0.1% at currents of ±100 pA or higher. CONCLUSIONS: This work suggests that it is possible to check the nonlinearity and repeatability of clinical electrometers with DCs above the ±30 pA level using a DC generator in a clinic.

Uncertainty in positioning ion chamber at reference depth for various water phantoms.

BACKGROUND: Uncertainty in the calibration of high-energy radiation sources is dependent on user and equipment type. AIM: We evaluated the uncertainty in the positioning of a cylindrical chamber at a reference depth for reference dosimetry of high-energy photon beams and the resulting uncertainty in the chamber readings for 6- and 10-MV photon beams. The aim was to investigate major contributions to the positioning uncertainty to reduce the uncertainty in calibration for external photon beam radiotherapy. MATERIALS AND METHODS: The following phantoms were used: DoseView 1D, WP1D, 1D SCANNER, and QWP-07 as one-dimensional (1D) phantoms for a vertical-beam geometry; GRI-7632 as a phantom for a fixed waterproofing sleeve; and PTW type 41023 and QWP-04 as 1D phantoms for a horizontal-beam geometry. The uncertainties were analyzed as per the Guide to the Expression of Uncertainty in Measurement. RESULTS: The positioning and resultant uncertainties in chamber readings ranged from 0.22 to 0.35 mm and 0.12-0.25%, respectively, among the phantoms (using a coverage factor k = 1 in both cases). The major contributions to positioning uncertainty are: definition of the origin for phantoms among users for the 1D phantoms for a vertical-beam geometry, water level adjustment among users for the phantom for a fixed waterproofing sleeve, phantom window deformation, and non-water material of the window for the 1D phantoms for a horizontal-beam geometry. CONCLUSION: The positioning and resultant uncertainties in chamber readings exhibited minor differences among the seven phantoms. The major components of these uncertainties differed among the phantom types investigated.

Comparison of AAPM Addendum to TG-51, IAEA TRS-398, and JSMP 12: Calibration of photon beams in water.

The American Association of Physicists in Medicine (AAPM) Working Group on TG-51 published an Addendum to the AAPM's TG-51 protocol (Addendum to TG-51) in 2014, and the Japan Society of Medical Physics (JSMP) published a new dosimetry protocol JSMP 12 in 2012. In this study, we compared the absorbed dose to water determined at the reference depth for high-energy photon beams following the recommendations given in AAPM TG-51 and the Addendum to TG-51, IAEA TRS-398, and JSMP 12. This study was performed using measurements with flattened photon beams with nominal energies of 6 and 10 MV. Three widely used ionization chambers with different compositions, Exradin A12, PTW 30013, and IBA FC65-P, were employed. Fully corrected charge readings obtained for the three chambers according to AAPM TG-51 and the Addendum to TG-51, which included the correction for the radiation beam profile (Prp ), showed variations of 0.2% and 0.3% at 6 and 10 MV, respectively, from the readings corresponding to IAEA TRS-398 and JSMP 12. The values for the beam quality conversion factor kQ obtained according to the three protocols agreed within 0.5%; the only exception was a 0.6% difference between the results obtained at 10 MV for Exradin A12 according to IAEA TRS-398 and AAPM TG-51 and the Addendum to TG-51. Consequently, the values for the absorbed dose to water obtained for the three protocols agreed within 0.4%; the only exception was a 0.6% difference between the values obtained at 10 MV for PTW 30013 according to AAPM TG-51 and the Addendum to TG-51, and JSMP 12. While the difference in the absorbed dose to water determined by the three protocols depends on the kQ and Prp values, the absorbed dose to water obtained according to the three protocols agrees within the relative uncertainties for the three protocols.

Evaluation of obliteration of arteriovenous malformations after stereotactic radiosurgery with arterial spin labeling MR imaging.

PURPOSE: Complete obliteration of treated arteriovenous malformations (AVMs) can be diagnosed only by confirming the disappearance of arterio-venous (A-V) shunts with invasive catheter angiography. The authors evaluated whether non-invasive arterial spin labeling (ASL) magnetic resonance (MR) imaging can be used to diagnose the obliteration of AVMs facilitate the diagnosis of AVM obliteration after treatment with stereotactic radiosurgery (SRS). MATERIAL AND METHODS: Seven patients with a cerebral AVM treated by SRS were followed up with ASL images taken with a 3T-MR unit, and received digital subtraction angiography (DSA) after the AVM had disappeared on ASL images. Three patients among the seven received DSA also after the postradiosurgical AVM had disappeared on conventional MR images but A-V shunt was residual on ASL images. Four patients among the seven received contrast-enhanced (CE) MR imaging around the same period as DSA. RESULTS: ASL images could visualize postradiosurgical residual A-V shunts clearly. In all seven patients, DSA after the disappearance of A-V shunts on ASL images demonstrated no evidence of A-V shunts. In all three patients, DSA after the AVM had disappeared on conventional MR images but not on ASL images demonstrated residual A-V shunt. CE MR findings of AVMs treated by SRS did not correspond with DSA findings in three out of four patients. CONCLUSIONS: Findings of radiosurgically treated AVMs on ASL images corresponded with those on DSA. The results of this study suggest that ASL imaging can be utilized to follow up AVMs after SRS and to decide their obliteration facilitate to decide the precise timing of catheter angiography for the final diagnosis of AVM obliteration after SRS.

Thermosensitization by parthenolide in human lung adenocarcinoma A549 cells and p53- and hsp72-independent apoptosis induction via the nuclear factor-kappaB signal pathway.

The thermo-enhancement effects of the sesquiterpene lactone parthenolide (PTL), which targets the transcription factor nuclear factor-kappaB (NF-kappaB), and hyperthermia at 40, 42 and 44 degrees C on the human lung adenocarcinoma A549 cell line were investigated in vitro. Thermotherapy using a combined treatment with PTL (0.02 microM) prior to hyperthermia showed synergistic thermo-enhancement effects towards A549 cells. The expression of p53 and hsp72 proteins following the application of PTL and hyperthermia at 44 degrees C, both alone and in combination, were examined to investigate whether p53 and hsp72 participated in apoptosis induction via the NF-kappaB signal pathway. After treatment with PTL alone, Hsp72 was only slightly induced, which was the same as for the control, while the level following the combination treatment was not significantly different as compared with hyperthermia alone. In addition, the level of p53 after the combination treatment was only slightly increased in comparison with hyperthermia alone. The kinetics of apoptosis and necrosis induction during the incubation periods following PTL exposure and hyperthermia, and the combination of both were also determined. The incidence of apoptosis following hyperthermia alone was approximately 0.6% on average after 12, 24 and 48 h of incubation, while that of PTL alone was approximately 1.7%, and that with the combination treatment was around 2.3%. Thus, induction of apoptosis following the combination treatment was increased as compared to each treatment alone. With regard to the kinetics of necrosis, the incidence of necrosis after treatment with hyperthermia alone was approximately 2.7%, while that with the combination treatment was lower, at around 2.2%. We hypothesized that cells treated with PTL had an altered arrangement of stressed cells undergoing the transformation from necrotic cell death to apoptotic cell death via another mechanism. Our results suggested that the PTL-induced apoptosis of A549 cells was due to the direct suppression of NF-kappaB activity in a p53- and hsp72-independent manner based on NF-kappaB signaling.

Neurocognitive function of patients with brain metastasis who received either whole brain radiotherapy plus stereotactic radiosurgery or radiosurgery alone.

PURPOSE: To determine how the omission of whole brain radiotherapy (WBRT) affects the neurocognitive function of patients with one to four brain metastases who have been treated with stereotactic radiosurgery (SRS). METHODS AND MATERIALS: In a prospective randomized trial between WBRT+SRS and SRS alone for patients with one to four brain metastases, we assessed the neurocognitive function using the Mini-Mental State Examination (MMSE). Of the 132 enrolled patients, MMSE scores were available for 110. RESULTS: In the baseline MMSE analyses, statistically significant differences were observed for total tumor volume, extent of tumor edema, age, and Karnofsky performance status. Of the 92 patients who underwent the follow-up MMSE, 39 had a baseline MMSE score of < or =27 (17 in the WBRT+SRS group and 22 in the SRS-alone group). Improvements of > or =3 points in the MMSEs of 9 WBRT+SRS patients and 11 SRS-alone patients (p = 0.85) were observed. Of the 82 patients with a baseline MMSE score of > or =27 or whose baseline MMSE score was < or =26 but had improved to > or =27 after the initial brain treatment, the 12-, 24-, and 36-month actuarial free rate of the 3-point drop in the MMSE was 76.1%, 68.5%, and 14.7% in the WBRT+SRS group and 59.3%, 51.9%, and 51.9% in the SRS-alone group, respectively. The average duration until deterioration was 16.5 months in the WBRT+SRS group and 7.6 months in the SRS-alone group (p = 0.05). CONCLUSION: The results of the present study have revealed that, for most brain metastatic patients, control of the brain tumor is the most important factor for stabilizing neurocognitive function. However, the long-term adverse effects of WBRT on neurocognitive function might not be negligible.

Enhancement of radiosensitivity by topoisomerase II inhibitor, amrubicin and amrubicinol, in human lung adenocarcinoma A549 cells and kinetics of apoptosis and necrosis induction.

The effects of amrubicin (AMR) and its active metabolite, amrubicinol (AMROH), on the sensitivity of human lung adenocarcinoma A549 cells to ionizing radiation were investigated in vitro. Further, the kinetics of apoptosis and necrosis induction were also analyzed. The cytocidal effects of X-ray irradiation on A549 cells resulted in a low level of radiosensitivity with a D0 value of 12 Gy. The slopes of the survival curves in the exponential phase were plotted on semilogarithmic paper for radiation combined with AMR (2.5 microg/ml) and AMROH (0.02 microg/ml) treatment, and were shown to be approximately parallel to treatment with irradiation alone. The initial shoulder-shape portion of the survival curve for radiation alone, indicating the repair of sublethal damage, was reduced as compared to that for sequential combined treatment with AMR or AMROH. Sequential treatments with AMR or AMROH prior to ionizing radiation resulted in an additive radio-enhancement effect that reduced not only survival, but also the shoulder width. Fractionated irradiation with 2 Gy per fraction of A549 cells was carried out in vitro similar to that commonly performed in clinical radiotherapy and the radio-resistance of the cells was shown to be inhibited by AMR and AMROH. Similar to AMR and AMROH, adriamycin and etoposide (VP-16) are DNA topoisomerase II inhibitors. The effects of these 4 agents on cells that received X-ray irradiation were compared and all of the agents exhibited comparable radio-enhancement effects. The induction of apoptosis was investigated at 48 and 72 h after administration of AMROH, radiation or combined treatment, and apoptosis was not significantly induced after any of the treatments. We also examined the induction of necrosis, and found that the incidence of necrosis following combined treatment was approximately 2 times higher than that with either of the single treatments.

Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial.

CONTEXT: In patients with brain metastases, it is unclear whether adding up-front whole-brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) has beneficial effects on mortality or neurologic function compared with SRS alone. OBJECTIVE: To determine if WBRT combined with SRS results in improvements in survival, brain tumor control, functional preservation rate, and frequency of neurologic death. DESIGN, SETTING, AND PATIENTS: Randomized controlled trial of 132 patients with 1 to 4 brain metastases, each less than 3 cm in diameter, enrolled at 11 hospitals in Japan between October 1999 and December 2003. INTERVENTIONS: Patients were randomly assigned to receive WBRT plus SRS (65 patients) or SRS alone (67 patients). MAIN OUTCOME MEASURES: The primary end point was overall survival; secondary end points were brain tumor recurrence, salvage brain treatment, functional preservation, toxic effects of radiation, and cause of death. RESULTS: The median survival time and the 1-year actuarial survival rate were 7.5 months and 38.5% (95% confidence interval, 26.7%-50.3%) in the WBRT + SRS group and 8.0 months and 28.4% (95% confidence interval, 17.6%-39.2%) for SRS alone (P = .42). The 12-month brain tumor recurrence rate was 46.8% in the WBRT + SRS group and 76.4% for SRS alone group (P<.001). Salvage brain treatment was less frequently required in the WBRT + SRS group (n = 10) than with SRS alone (n = 29) (P<.001). Death was attributed to neurologic causes in 22.8% of patients in the WBRT + SRS group and in 19.3% of those treated with SRS alone (P = .64). There were no significant differences in systemic and neurologic functional preservation and toxic effects of radiation. CONCLUSIONS: Compared with SRS alone, the use of WBRT plus SRS did not improve survival for patients with 1 to 4 brain metastases, but intracranial relapse occurred considerably more frequently in those who did not receive WBRT. Consequently, salvage treatment is frequently required when up-front WBRT is not used. TRIAL REGISTRATION: umin.ac.jp/ctr Identifier: C000000412.

Long-Term Endoscopic Follow-Up of Patients with Chronic Radiation Proctopathy after Brachytherapy for Prostate Cancer.

Background. Chronic radiation proctopathy (CRP) is late toxicity and associated with morbidity. Aim. To investigate the predictors of prognosis in patients with CRP after brachytherapy (BT). Methods. One hundred four patients with prostate cancer were treated with BT or BT followed by external-beam radiotherapy (BT + EBRT). We retrospectively investigated the 5-year incidence of rectal bleeding and endoscopic findings of CRP using the Vienna Rectoscopy Score (VRS). Twenty patients with VRS ≥ 1 were divided into the improved VRS group without treatment, unchanged VRS group, and treated group. The parameters associated with alteration of VRS were analyzed. Results. The incidence of rectal bleeding was 24%. The risk of rectal bleeding was higher in patients treated with BT + EBRT compared to those treated with BT (p < 0.0001). The incidence of superficial microulceration was higher in the improved VRS group than in the unchanged VRS group (p < 0.05). The incidence of multiple confluent telangiectasia or superficial ulcers > 1 cm(2) was higher in the treated group than in both the improved and unchanged VRS groups (p < 0.05). Conclusions. Patients treated with BT + EBRT have a high risk of CRP. Endoscopic findings were useful for prognostic prediction of CRP.

Modification of thermosensitivity by amrubicin or amrubicinol in human lung adenocarcinoma A549 cells and the kinetics of apoptosis and necrosis induction.

The effects of amrubicin (AMR) and its active metabolite, amrubicinol (AMROH), on the sensitivity of human lung adenocarcinoma A549 cell line to hyperthermia at 44 degrees C were investigated. The cell phase response as well as the kinetics of apoptosis and necrosis induction were also analyzed. The cytocidal effects of 44 degrees C hyperthermia on A549 cells exhibited low thermosensitivity with a T(0) value of 12 min. The slope of the survival curve in the exponential phase, described semilogarithmically, in 44 degrees C hyperthermia combined treatment with AMROH (0.02 microg/ml) was approximately parallel to 44 degrees C hyperthermia alone. The initial shoulder shape portion of the survival curve from 44 degrees C hyperthermia alone, indicating the repair of sublethal thermal damage (SLTDR), was reduced with the sequential combined treatment of AMR or AMROH. Sequential treatments with AMR or AMROH prior to 44 degrees C hyperthermia resulted in additive thermo-enhancement effect by reducing not only survival but was shoulder wide. Furthermore, like AMR and AMROH, adriamycin (ADM) and etoposide (VP-16) are DNA topoisomerase II inhibitors, and the effects of these 4 agents on 44 degrees C hyperthermia were compared. All 4 agents exhibited comparable thermo-enhancement effects. Using synchronized A549 cells, AMR or AMROH did not elicit cell phase responses, irrespective of the concentration. The induction of apoptosis was investigated at 48 and 72 h after AMROH treatment, 44 degrees C hyperthermia or the combined treatment, in which apoptosis was not significantly induced after any treatment. Furthermore, the incidence of necrosis was examined as well as apoptosis. The incidence of necrosis at 48 and 72 h after AMROH was 2.4 and 4.3%, respectively; after 44 degrees C hyperthermia was 3.3 and 4.0%, respectively; and after the combined treatment it was 10.7 and 8.7%, respectively. The necrosis induced after the combined treatment was circa 3 times higher than that in either of the single treatments.

P53-independent thermosensitization by mitomycin C in human non-small-cell lung cancer cells.

PURPOSE: To elucidate the relationship between p53 functions and the interactive effects of the combined treatment with mild hyperthermia and mitomycin C. METHODS AND MATERIALS: p53-deficient human non-small-cell lung cancer H1299 cells were transfected with a vector carrying a neomycin-resistant gene (neo) or together with a wild-type or mutant p53 gene. Sensitivities of these transfectants to mild hyperthermia at 42 degrees C, mitomycin C (0.05 microg/mL) at 37 degrees C, or the combination treatment were determined by colony formation assay. After these treatments, the induction of apoptosis, the changes in cell cycle distribution, and the accumulation of Hsp72 were examined. RESULTS: The combined treatment resulted in an enhanced cell killing effect in H1299 cells in a p53-independent manner, which was partially the result of an enhancement of heat-induced apoptosis. The treatment also caused a marked G(2)/M arrest in the neo and the mutant p53 cells, but not in the wild-type p53 cells. The subsequent release of G(2)/M arrest was accompanied with an increase in the sub-G(1) fractions. Mitomycin C did not affect the accumulation of Hsp72 induced by hyperthermia in H1299 cells regardless of their p53 gene status. CONCLUSION: Our findings demonstrate a p53-independent mechanism for an interactively cytotoxic enhancement by combined treatment with mild hyperthermia and mitomycin C.

Effects of combined treatment with 40 degrees C hyperthermia and bleomycin on the accumulation of heat shock protein in murine L cells.

Our research group has reported the enhanced cytotoxicity of combined treatment with bleomycin (BLM) and low hyperthermia at 40 degrees C, using murine L cells, and suggested that post-heating could inhibit BLM-induced sublethal damage repair. For further understanding of the involved mechanisms, we subsequently investigated the kinetics of the cellular accumulations of inducible 72-kDa heat shock protein (hsp72) after 40 degrees C hyperthermia and/or BLM treatment using the same cell line. Western blot analysis showed significantly enhanced accumulation of hsp72 after a low hyperthermia at 40 degrees C for 40, 105 or 180 min, and no significant enhancement of it after exposure to 10 microg/ml BLM at 37 degrees C for either 40 or 105 min. When the cells were heated in the presence of BLM, the accumulations of hsp72 were markedly suppressed, with the maxima of hsp72 accumulation decreasing to 38% and 63% of those induced by hyperthermia alone for 40 or 105 min, respectively. On the other hand, sequential treatment with hyperthermia either before or after BLM treatment did not show significant alteration of the heat-induced accumulations of hsp72. It was demonstrated that BLM was necessary during heating to effectively suppress the heat-induced accumulation of hsp72. This study indicates that the suppression of heat-induced accumulation of hsp72 by BLM may partially contribute to enhance cytotoxicity of the simultaneous treatment of 40 degrees C hyperthermia and BLM.

Arterial spin labeling perfusion-weighted MRI for long-term follow-up of a cerebral arteriovenous malformation after stereotactic radiosurgery.

We present a longitudinal series of arterial spin-labeling magnetic resonance imaging (ASL-MRI) in a patient with cerebral arteriovenous malformations (AVMs) treated by stereotactic radiosurgery (SRS). Pretreatment ASL-MRI showed high signal intensity in both the nidus and draining veins, and the latter signal abnormality gradually moved proximally by 14 months after SRS. At 24 months, the signal abnormalities finally disappeared, indicating complete obliteration of the nidus. The hemodynamic changes in the AVM were clearly visualized in the longitudinal ASL-MRI series, thus this non-invasive MR method may be useful not only for detecting AVMs but also for assessment of their response after SRS.

Alpha 1-adrenoceptor blocker may improve not only voiding but also storage lower urinary tract symptoms caused by (125) I brachytherapy for prostate cancer.

Purpose. To assess changes in lower urinary tract symptoms (LUTS) within 1 year after brachytherapy in patients receiving alpha 1-adrenoceptor antagonists. Methods. We retrospectively evaluated 116 patients who underwent (125)I prostate brachytherapy in our institute. Seventy-one patients were treated with a combination of external beam radiation therapy and brachytherapy. Alpha 1-adrenoceptor antagonists were prescribed to all patients after brachytherapy. International Prostate Symptom Score (IPSS) forms and postvoid residual urine volume were recorded at all follow-up visits. Results. Forty-nine patients were given tamsulosin hydrochloride, 32 were given silodosin hydrochloride, and 35 were given naftopidil for up to 6 months after seed implantation. Patients given tamsulosin or naftopidil tended to show a higher peak IPSS and slower recovery to baseline values than those given silodosin. The patients given naftopidil showed an insufficient recovery in storage symptoms in naftopidil group in comparison with tamsulosin group at 3 months and with silodosin group at 6 and 9 months. Conclusions. In the management of LUT after brachytherapy, silodosin may provide a more favorable improvement. Silodosin and tamsulosin may have an advantage in improving not only voiding but also storage lower urinary tract symptoms after brachytherapy.

Monitoring of extra-axial brain tumor response to radiotherapy using pseudo-continuous arterial spin labeling images: preliminary results.

INTRODUCTION: Technological developments have increased the ease of performing perfusion MRI by arterial spin labeling (ASL) in clinical settings. The objective of this study was to evaluate the effects of radiotherapy on extra-axial brain tumors by using MR perfusion images obtained using the pseudo-continuous arterial spin labeling (pcASL) method. MATERIALS AND METHODS: Six consecutive patients (nine lesions) with extra-axial brain tumors treated only with radiotherapy were enrolled in this study. MR examinations, including pcASL imaging, were performed before and after radiotherapy. Cerebral blood flow, maximum tumor blood flow (mTBF), tumor volume and the ratio of signal enhancement by contrast material (enhancement ratio) were evaluated in serial examinations during the course of radiotherapy. Both the percentage change in mTBF (mTBF ratio) and the percentage change in volume (volume ratio) were calculated using values obtained before and after radiotherapy. The correlation between the volume ratio and the mTBF ratio was assessed using linear regression analysis and Spearman's rank correlation coefficient (rs). RESULTS: A strong correlation was demonstrated between the tumor volume ratio and the mTBF ratio before and after radiotherapy (rs=0.93, P<.01). However, no significant correlation was identified between changes in enhancement and volume ratio (rs=0.20) or between changes in enhancement and mTBF ratio (rs=0.30) before and after radiotherapy. CONCLUSION: The mTBF measured using pcASL may serve as an additive index for tumor volume when determining tumor response to radiotherapy even in the absence of contrast material.

Thermosensitization and induction of apoptosis or cell-cycle arrest via the MAPK cascade by parthenolide, an NF-κB inhibitor, in human prostate cancer androgen-independent cell lines.

Parthenolide (PTL), a nuclear factor-κB (NF-κB) inhibitor, has a significant thermo-enhancement effect. Modification of thermosensitivity by treatment with PTL prior to hyperthermia was investigated in the human prostate cancer androgen-independent cell lines PC3 and DU145. In addition, we analyzed the mechanisms related to induction of apoptosis or G2/M cell-cycle arrest via the effects of ERK1/2, p38 and SAPK/JNK signaling on mitogen-activated protein kinase (MAPK). Lethal damage caused by mild hyperthermia at 41.0˚C or 42.0˚C in both cell lines resulted in a low level of thermosensitivity, while sequential combination with PTL showed significant thermosensitization. Step-up hyperthermia (SUH) (42˚C for 30 min, 43.0˚C or 43.5˚C for various periods) reduced the thermosensitivity of the cells to second heating. However, PTL given as pre-treatment prior to SUH prevented SUH-induced thermal tolerance and resulted in significant thermosensitization. Induction of apoptosis by the combination of PTL and hyperthermia at 44.0˚C was determined by the ratio of sub-G1 division cells using flow cytometry, which was increased significantly in comparison with single treatment, and was more effective in PC3 than DU145 cells. The behavior of ERK1/2, p38, and SAPK/JNK signaling in the MAPK cascade by treatment with PTL and hyperthermia were examined by Western blotting. As for PC3 cells, ras-downstream p-ERK1/2 was activated and p-p38 slightly activated by combined treatment with PTL and hyperthermia in comparison with each alone. As for DU145 cells, ERK1/2 was not changed, while p38 and SAPK/JNK were slightly activated by combination treatment. These results were related to increases in the induction of apoptosis, G2/M cell cycle arrest, and lethal damage of cells via the MAPK cascade. Together, our findings demonstrate that PTL is an effective thermosensitizing agent for multidisciplinary therapy for human prostate cancer.

Inhibition of NF-kappaB by combination therapy with parthenolide and hyperthermia and kinetics of apoptosis induction and cell cycle arrest in human lung adenocarcinoma cells.

We investigated the mechanisms of thermosensitization related to combination therapy with sesquiterpene lactone parthenolide (PTL), a nuclear factor-kappaB (NF-kappaB) inhibitor, and hyperthermia using human lung adenocarcinoma cells A549. The kinetics of apoptosis induction and cell cycle of cells treated with PTL, heating, and combined treatment were examined by flow cytometric analysis. The flow cytometric distribution was calculated and expressed as a percentage. The ratios of the sub-G1 division, used to determine the induction of apoptosis, increased significantly with the combination therapy. Furthermore, the ratios of G2/M division increased and the ratios of G0/G1 division decreased, indicating cell cycle arrest in G2/M. The cell phase response to PTL by A549 cells synchronized in the G1/S border with hydroxyurea was also analyzed. PTL showed remarkable cytotoxicity at the S phase of the cell cycle in A549 cells at all concentrations as well as with hyperthermia, thus PTL reduced the number of cells in the proliferation phase. Inhibition of intracellular transcription factor NF-kappaB activation in A549 cells with various incubation periods after treatments with PTL, heating and combined treatment was examined by Western blot analysis. Unexpectedly, PTL alone did not inhibit NF-kappaB activation in cells stimulated with TNF-alpha, while heating alone inhibited NF-kappaB early after treatment and that effect faded over time. In contrast, PTL combined with heating completely inhibited NF-kappaB activation. Our results demonstrated that PTL and heating in combination cause significant thermosensitization of A549 cells via induction of apoptosis or cell cycle arrest in G2/M by inhibiting NF-kappaB activation in a synergistic manner.

[Clinical results of LINAC-based stereotactic radiosurgery for pituitary adenoma].

PURPOSE: We retrospectively evaluated our clinical results of stereotactic radiosurgery (SRS) for pituitary adenoma. MATERIALS AND METHODS: Between 1995 and 2000, 13 patients were treated with SRS for pituitary adenoma. In all cases, the tumors had already been surgically resected. The adenomas were functional in 5 and non-functional in 8 patients. The median follow-up period was 30 months. SRS was performed with the use of a dedicated stereotactic 10-MV linear accelerator (LINAC). The median dose to the tumor margin was 15 Gy. The dose to the optic apparatus was limited to less than 8 Gy. RESULTS: MR images of 12 patients revealed tumor CR in one case and PR in 9 cases; in the remaining two patients, tumor size decreased by less than 50%. There was no recognizable regrowth of any of the tumors. In two of four GH-secreting adenomas, hormonal overproduction normalized, while the other two showed reduced hormonal production. One PRL-secreting adenoma did not respond. Reduction of visual acuity and field was seen in one patient. This patient also had a brain infarction. None of the patients developed brain radionecrosis or radiation-induced hypopituitarism. CONCLUSION: Although further studies based on greater numbers of cases and longer follow-up periods are needed, our results suggest that SRS seems to be a safe, effective treatment for pituitary adenoma.