Biomedical subjects

Tetsuo Akimoto

Publications and source records attributed to Tetsuo Akimoto.

At least 19 recordsLinked to original sources

PubMed2006

Rectal bleeding after high-dose-rate brachytherapy combined with hypofractionated external-beam radiotherapy for localized prostate cancer: impact of rectal dose in high-dose-rate brachytherapy on occurrence of grade 2 or worse rectal bleeding.

PURPOSE: To evaluate the incidence of Grade 2 or worse rectal bleeding after high-dose-rate (HDR) brachytherapy combined with hypofractionated external-beam radiotherapy (EBRT), with special emphasis on the relationship between the incidence of rectal bleeding and the rectal dose from HDR brachytherapy. METHODS AND MATERIALS: The records of 100 patients who were treated by HDR brachytherapy combined with EBRT for > or =12 months were analyzed. The fractionation schema for HDR brachytherapy was prospectively changed, and the total radiation dose for EBRT was fixed at 51 Gy. The distribution of the fractionation schema used in the patients was as follows: 5 Gy x 5 in 13 patients; 7 Gy x 3 in 19 patients; and 9 Gy x 2 in 68 patients. RESULTS: Ten patients (10%) developed Grade 2 or worse rectal bleeding. Regarding the correlation with dosimetric factors, no significant differences were found in the average percentage of the entire rectal volume receiving 30%, 50%, 80%, and 90% of the prescribed radiation dose from EBRT between those with bleeding and those without. The average percentage of the entire rectal volume receiving 10%, 30%, 50%, 80%, and 90% of the prescribed radiation dose from HDR brachytherapy in those who developed rectal bleeding was 77.9%, 28.6%, 9.0%, 1.5%, and 0.3%, respectively, and was 69.2%, 22.2%, 6.6%, 0.9%, and 0.4%, respectively, in those without bleeding. The differences in the percentages of the entire rectal volume receiving 10%, 30%, and 50% between those with and without bleeding were statistically significant. CONCLUSIONS: The rectal dose from HDR brachytherapy for patients with prostate cancer may have a significant impact on the incidence of Grade 2 or worse rectal bleeding.

Aged↗

PubMed2006

Radiation therapy for T2N0 laryngeal cancer: A retrospective analysis for the impact of concurrent chemotherapy on local control.

PURPOSE: The impact of concurrent chemotherapy on the local control in patients with T2N0 laryngeal cancer who receive radiation therapy (RT) was evaluated. METHODS AND MATERIALS: Sixty-three patients with T2N0 laryngeal cancer who were treated by definitive RT were analyzed. The primary site of the cancer was the glottis in 50 patients, the supraglottis in 9 patients, and the subglottis in 4 patients. Thirty-six patients were treated by RT alone and the remaining 27 patients received concurrent chemoradiotherapy (CRT). RESULTS: Complete response (CR) was obtained in 92% of the patients who received RT alone and 100% of the patients who received CRT. Voice preservation in the group who received CRT (89%) was significantly higher than that in the group treated by RT alone (61%). The 5-year disease-free survival rates in those who received concurrent CRT was significantly superior to that in the patients who received RT alone, although no significant difference was seen in the cause-specific survival rate between the 2 groups. The multivariate analysis revealed that the treatment method (RT alone vs. CRT) was the most significant risk factor that predicted recurrence after RT. CONCLUSION: Concurrent CRT had a positive impact on the local control of T2N0 laryngeal cancer.

Aged↗

PubMed2006

Anatomy-based inverse optimization in high-dose-rate brachytherapy combined with hypofractionated external beam radiotherapy for localized prostate cancer: comparison of incidence of acute genitourinary toxicity between anatomy-based inverse optimization and geometric optimization.

PURPOSE: To evaluate the advantages of anatomy-based inverse optimization (IO) in planning high-dose-rate (HDR) brachytherapy. METHODS AND MATERIALS: A total of 114 patients who received HDR brachytherapy (9 Gy in two fractions) combined with hypofractionated external beam radiotherapy (EBRT) were analyzed. The dose distributions of HDR brachytherapy were optimized using geometric optimization (GO) in 70 patients and by anatomy-based IO in the remaining 44 patients. The correlation between the dose-volume histogram parameters, including the urethral dose and the incidence of acute genitourinary (GU) toxicity, was evaluated. RESULTS: The averaged values of the percentage of volume receiving 80-150% of the prescribed minimal peripheral dose (V(80)-V(150)) of the urethra generated by anatomy-based IO were significantly lower than the corresponding values generated by GO. Similarly, the averaged values of the minimal dose received by 5-50% of the target volume (D(5)-D(50)) obtained using anatomy-based IO were significantly lower than those obtained using GO. Regarding acute toxicity, Grade 2 or worse acute GU toxicity developed in 23% of all patients, but was significantly lower in patients for whom anatomy-based IO (16%) was used than in those for whom GO was used (37%), consistent with the reduced urethral dose (p <0.01). CONCLUSION: The results of this study suggest that anatomy-based IO is superior to GO for dose optimization in HDR brachytherapy for prostate cancer.

Aged↗

PubMed2005

Acute toxicity and preliminary clinical outcomes of concurrent radiation therapy and weekly docetaxel and daily cisplatin for head and neck cancer.

OBJECTIVE: To examine the feasibility and efficacy of concurrent weekly docetaxel and radiation therapy as a definitive treatment for head and neck cancer (HNC). METHODS: Thirty-two patients with primary HNC, who were treated with concurrent weekly docetaxel and radiation therapy, were analysed. The distribution of the disease stage was as follows: Stage II, 18 patients; Stage III, 3 patients; Stage IVA, 7 patients; Stage IVB, 3 patients; the patient of cervical lymph node metastasis with unknown primary tumor was not assessable. The average total dose of radiotherapy was 67.5 Gy. Docetaxel (10 mg/m(2), intravenously, once a week) was given to all patients up to four cycles, and cisplatin (6 mg/m(2), intravenously, five times a week) was also administered to all patients for up to 3 weeks from the beginning of the radiation therapy. RESULTS: Only in two patients did the radiotherapy need to be temporarily interrupted due to the development of acute mucositis. Grade 3 toxicity was observed in six patients. Grade 4 acute mucositis was seen in one patient. The response rate was 100%, and complete response (CR) was observed in 30 patients (94%). At the time of the analysis, the 2 year local control and relapse-free rates in the 30 patients showing CR were 90 and 76%, respectively. CONCLUSIONS: Concurrent weekly docetaxel and radiation therapy did not affect the compliance of the patients for the radiation therapy, indicating that the acute toxicities were within acceptable limits.

Acute Disease↗

PubMed2005

Acute genitourinary toxicity after high-dose-rate (HDR) brachytherapy combined with hypofractionated external-beam radiation therapy for localized prostate cancer: correlation between the urethral dose in HDR brachytherapy and the severity of acute genitourinary toxicity.

PURPOSE: Several investigations have revealed that the alpha/beta ratio for prostate cancer is atypically low, and that hypofractionation or high-dose-rate (HDR) brachytherapy regimens using appropriate radiation doses may be expected to yield tumor control and late sequelae rates that are better or at least as favorable as those achieved with conventional radiation therapy. In this setting, we attempted treating localized prostate cancer patients with HDR brachytherapy combined with hypofractionated external beam radiation therapy (EBRT). The purpose of this study was to evaluate the feasibility of using this approach, with special emphasis on the relationship between the severity of acute genitourinary (GU) toxicity and the urethral dose calculated from the dose-volume histogram (DVH) of HDR brachytherapy. METHODS AND MATERIALS: Between September 2000 and December 2003, 70 patients with localized prostate cancer were treated by iridium-192 HDR brachytherapy combined with hypofractionated EBRT at the Gunma University Hospital. Hypofractionated EBRT was administered in fraction doses of 3 Gy, three times per week; a total dose of 51 Gy was delivered to the prostate gland and the seminal vesicles using the four-field technique. No elective pelvic irradiation was performed. After the completion of EBRT, all the patients additionally received transrectal ultrasonography (TRUS)-guided HDR brachytherapy. The fraction size and the number of fractions in HDR brachytherapy were prospectively changed, whereas the total radiation dose for EBRT was fixed at 51 Gy. The fractionation in HDR brachytherapy was as follows: 5 Gy x 5, 7 Gy x 3, 9 Gy x 2, administered twice per day, although the biologic effective dose (BED) for HDR brachytherapy combined with EBRT, assuming that the alpha/beta ratio is 3, was almost equal to 138 in each fractionation group. The planning target volume was defined as the prostate gland with 5-mm margin all around, and the planning was conducted based on computed tomography images. The number of patients in each fractionation group was as follows: 13 in the 5-Gy group; 19 in the 7-Gy group, and 38 in the 9-Gy group. The tumor stage was T1 in 10 patients, T2 in 36 patients, and T3 in 24 patients. The Gleason score was 2-6 in 11 patients, 7 in 34 patients, and 8-10 in 25 patients. Androgen ablation was performed in all the patients. The median follow-up duration was 14 months (range 3-42 months). The toxicities were graded based on the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer toxicity criteria. RESULTS: The main symptoms of acute GU toxicity were dysuria and increase in urinary frequency or nocturia. The grade distribution of acute GU toxicity in the patients was as follows: Grade 0-1, 39 patients (56%), and Grade 2-4, 31 patients (44%). One patient who developed acute urinary obstruction was classified as having Grade 4 toxicity. Comparison of the distribution of the grade of acute GU toxicity among the different fractionation groups revealed no statistically significant differences among the groups. The urethral dose in HDR brachytherapy was evaluated using the following DVH parameters: V30 (percentage of the urethral volume receiving 30% of the prescribed radiation dose), V80, V90, V100, V110, V120, V130, and V150. The V30-110 values in the patients with Grade 2-4 acute GU toxicity were significantly higher than those in patients with Grade 0-1 toxicity. On the other hand, there were no significant differences in the V120-150 values between patients with Grade 0-1 and Grade 2-4 toxicity. Regarding the influence of the number of needles implanted for the radiation therapy, patients with 11 needles or less showed a significantly higher incidence of Grade 2-4 acute GU toxicity compared with those with 12 needles or more (p < 0.05). CONCLUSIONS: It was concluded that HDR brachytherapy combined with hypofractionated EBRT is feasible for localized prostate cancer when considered from the viewpoint of acute toxicity. Increase in the fraction dose or reduction in the number of fractions in HDR brachytherapy did not affect the severity of acute GU toxicity, and the volume of urethra receiving an equal or lower radiation dose than the prescribed dose was more closely associated with the grade severity of acute GU toxicity than that receiving a higher than the prescribed dose.

Aged↗

PubMed2005

Acute genitourinary toxicity after high dose rate (HDR) brachytherapy combined with hypofractionated external-beam radiation therapy for localized prostate cancer: Second analysis to determine the correlation between the urethral dose in HDR brachytherapy and the severity of acute genitourinary toxicity.

PURPOSE: We have been treating localized prostate cancer with high-dose-rate (HDR) brachytherapy combined with hypofractionated external beam radiation therapy (EBRT) at our institution. We recently reported the existence of a correlation between the severity of acute genitourinary (GU) toxicity and the urethral radiation dose in HDR brachytherapy by using different fractionation schema. The purpose of this study was to evaluate the role of the urethral dose in the development of acute GU toxicity more closely than in previous studies. For this purpose, we conducted an analysis of patients who had undergone HDR brachytherapy with a fixed fractionation schema combined with hypofractionated EBRT. METHODS AND MATERIALS: Among the patients with localized prostate cancer who were treated by 192-iridium HDR brachytherapy combined with hypofractionated EBRT at Gunma University Hospital between August 2000 and November 2004, we analyzed 67 patients who were treated by HDR brachytherapy with the fractionation schema of 9 Gy x two times combined with hypofractionated EBRT. Hypofractionated EBRT was administered at a fraction dose of 3 Gy three times weekly, and a total dose of 51 Gy was delivered to the prostate gland and seminal vesicles using the four-field technique. No elective pelvic irradiation was performed. After the completion of EBRT, all the patients additionally received transrectal ultrasonography-guided HDR brachytherapy. The planning target volume was defined as the prostate gland with a 5-mm margin all around, and the planning was conducted based on computed tomography images. The tumor stage was T1c in 13 patients, T2 in 31 patients, and T3 in 23 patients. The Gleason score was 2-6 in 12 patients, 7 in 34 patients, and 8-10 in 21 patients. Androgen ablation was performed in all the patients. The median follow-up duration was 11 months (range 3-24 months). The toxicities were graded based on the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer toxicity criteria. RESULTS: The main symptoms of acute GU toxicity were dysuria and increase in the urinary frequency or nocturia. The grade distribution of acute GU toxicity in the patients was as follows: Grade 0-1, 42 patients (63%); Grade 2-3, 25 patients (37%). The urethral dose in HDR brachytherapy was determined using the following dose-volume histogram (DVH) parameters: V30 (percentage of the urethral volume receiving 30% of the prescribed radiation dose), V80, V90, V100, V110, V120, V130, and V150. In addition, the D5 (dose covering 5% of the urethral volume), D10, D20, and D50 of the urethra were also estimated. The V30-V150 values in the patients with Grade 2-3 acute GU toxicity were significantly higher than those in patients with Grade 0-1 toxicity. The D10 and D20, but not D5 and D50, values were also significantly higher in the patients with Grade 2-3 acute GU toxicity than in those with Grade 0-1 toxicity. Regarding the influence of the number of needles implanted, there was no correlation between the number of needles implanted and the severity of acute GU toxicity or the V30-V150 values and D5-D50 values. CONCLUSIONS: It was concluded that HDR brachytherapy combined with hypofractionated EBRT is feasible for localized prostate cancer, when considered from the viewpoint of acute toxicity. However, because the urethral dose was closely associated with the grade of severity of the acute GU toxicity, the urethral dose in HDR brachytherapy must be kept low to reduce the severity of acute GU toxicity.

Aged↗

PubMed2005

Attenuation of chronic thermotolerance by KNK437, a benzylidene lactam compound, enhances thermal radiosensitization in mild temperature hyperthermia combined with low dose-rate irradiation.

PURPOSE: We investigated whether the attenuation of chronic thermotolerance by KNK437, a heat shock protein inhibitor, can modify the effect of thermal radiosensitization in mild temperature hyperthermia (MTH) combined with low dose-rate irradiation (LDRI). MATERIALS AND METHODS: The human lung adenocarcinoma cell line A549 was simultaneously exposed to LDRI with MTH at 41 degrees C and KNK437 at a dose of 100 microM. Cell survival was estimated by a clonogenic assay. Cell cycle change during treatment was analyzed by flow cytometry. Expression levels of the heat shock proteins hsp72, hsp27 and heat shock factor 1 (HSF-1) were measured by Western blotting. RESULTS: KNK437 inhibited the expression of inducible hsp72 and hsp27, but produced no change in the mobility shift of HSF-1. The cytotoxicity of LDRI was enhanced by MTH. The survival curve for LDRI + MTH revealed no development of chronic thermotolerance up to 48 h. Simultaneous LDRI and KNK437 treatment also resulted in enhanced cell killing. The radiosensitizing effect of KNK437 was enhanced by simultaneous exposure of the cells to MTH. Flow cytometry analysis of cell cycle progression demonstrated marked G2 arrest and mild G1 arrest with LDRI alone, but mild G1 arrest with MTH alone, and mild G2-M, S-phase accumulation with KNK437 alone. The marked G2 arrest caused by LDRI was partially suppressed by the addition of MTH, and was also suppressed by KNK437 treatment. CONCLUSIONS: Exposure of A549 cells to KNK437 caused inhibition of hsp72 and hsp27 expression. The addition of KNK437 increased not only thermosensitivity to MTH, but also radiosensitivity to LDRI. KNK437 also enhanced the MTH-induced radiosensitization under these experimental conditions.

Adaptation, Physiological↗

PubMed2004

Rectal bleeding after hypofractionated radiotherapy for prostate cancer: correlation between clinical and dosimetric parameters and the incidence of grade 2 or worse rectal bleeding.

PURPOSE: To investigate the incidence and severity of rectal bleeding after high-dose hypofractionated radiotherapy (RT) for prostate cancer, and to explore the factors affecting the incidence of Grade 2 or worse rectal bleeding. METHODS AND MATERIALS: The data of 52 patients who had been treated by external beam RT for localized prostate cancer between 1999 and 2002 were analyzed. All the patients had received hypofractionated external beam RT to a total dose of 69 Gy in 3-Gy fractions, three fractions weekly. The clinical and dosimetric factors affecting the incidence of Grade 2 or worse late rectal bleeding were analyzed by univariate and multivariate analyses. The effect of the percentage of the whole rectal volume receiving 30%, 50%, 80%, and 90% of the prescribed radiation dose (V(30), V(50), V(80), and V(90), respectively) on the incidence of rectal bleeding was evaluated. RESULTS: Of the 52 patients, 13 (25%) developed Grade 2 or worse rectal bleeding. One patient who needed laser coagulation and blood transfusion for the treatment of rectal bleeding was classified as having Grade 3 rectal bleeding. The median time to the development of Grade 2 or worse rectal bleeding was 11 months. The results of the univariate analysis revealed that the presence of a history of diabetes mellitus (p < 0.001), and V(30) >/= 60%, V(50) >/= 40% (p < 0.05), V(80) >/= 25%, and V(90) >/= 15% (p < 0.001) were statistically significant risk factors for the occurrence of Grade 2 or worse rectal bleeding. The results of the multivariate analysis revealed that a history of diabetes mellitus was the most statistically significant risk factor for the occurrence of rectal bleeding after hypofractionated RT for prostate cancer (p < 0.05). CONCLUSION: A history of diabetes mellitus was the most statistically significant risk factor for the occurrence of Grade 2 or worse rectal bleeding after high-dose hypofractionated RT, although dosimetric factors were also closely associated with the risk of rectal bleeding.

Aged↗

PubMed2004

External beam radiotherapy for clinically node-negative, localized hormone-refractory prostate cancer: impact of pretreatment PSA value on radiotherapeutic outcomes.

PURPOSE: To analyze the results of clinically node-negative, localized hormone-refractory prostate cancer treated with external beam radiotherapy (EBRT) and to investigate the potential prognostic factors that influenced the therapeutic outcome. METHODS AND MATERIALS: Fifty-three patients who had developed localized hormone-refractory prostate cancer were treated with EBRT between 1994 and 2001. According to the 1992 American Joint Committee on Cancer clinical stage, 4 patients had T2 and 49 had T3 at the start of RT, and 14 patients had a Gleason score <7, 14 had a Gleason score of 7, and 23 had a Gleason score of 8-10. All patients were treated with EBRT using the unblocked oblique four-field technique, with a total dose of 69 Gy. The fraction dose was 3 Gy three times weekly. The median follow-up after RT was 35 months (range, 8-96 months) and after androgen ablation was 73 months (range, 42-156 months). RESULTS: Of 53 patients, 15 patients subsequently developed clinical relapse, including locoregional and/or distant metastases. The site of first relapse was bone metastasis in 10, lymph nodes in 3, and local failure in 2 patients; 3 patients died of prostate cancer during the analysis period. The 3-year and 5-year cause-specific survival rate was 94% and 87%, respectively, and the 3-year and 5-year clinical relapse-free survival rate was 78% and 56%, respectively. The univariate analysis revealed that a short prostate-specific antigen (PSA) doubling time and high PSA value at the start of RT and a high Gleason score were statistically significant factors for the risk of clinical relapse. Multivariate analysis demonstrated that the PSA value (PSA or=15 ng/mL) at the start of RT was an independent prognostic factor. CONCLUSION: EBRT could be a treatment of choice for clinically node-negative, localized, hormone-refractory prostate cancer.

Aged↗

PubMed2004

Molecular targets for potentiation of radiation-induced cell killing.

Molecular target-based drugs have been emerging as a cancer treatment. Clinical trials using the combined approach of radiation therapy and molecular target-based drugs have been performed to evaluate the feasibility of this approach, and improve the response of tumors to radiation. To achieve maximum radiotherapeutic gain, understanding of the interaction of radiation and drugs are indispensable. Preclinical data have already demonstrated synergistic enhancement of radiation-induced cell killing by several molecular target-based drugs. Among these, the effect of drugs that target receptor tyrosine kinase and its signal transduction pathways on radiosensitivity has been intensively investigated. In this review, established and potential molecular targets for potentiation of radiation-induced cell killing are summarized, and preclinical data regarding investigations of new molecular targets for radiosensitization will be introduced. In addition, the results and toxicities of clinical trials using combined radiation therapy and molecular target-based drugs are summarized.

Cell Death↗

PubMed2004

CT-fluoroscopy guided interstitial brachytherapy with image-based treatment planning for unresectable locally recurrent rectal carcinoma.

PURPOSE: The aim of the study is to develop high-dose-rate (HDR) conformal interstitial brachytherapy by means of combined CT-fluoroscopy guidance with CT-based treatment planning for locally recurrent rectal carcinoma. METHODS AND MATERIALS: Brachytherapy needle insertion was guided with a helical CT scanner providing continuous fluoroscopy reconstruction. A video monitor placed adjacent to the CT gantry simultaneously allowed the operator to see the process of needle insertion. Final CT images were transferred by an online system to the treatment-planning computer, which reconstructed the implant needles and organ contours. The doses in planning target volume were normalized and geometrically optimized. The patients received a brachytherapy dose at 5 Gy twice daily with a hypofractionated accelerated schedule at a total dose of 30-50 Gy with or without external radiation therapy. Eighteen patients were treated with this procedure. RESULTS: Ten to thirty-six needles (average, 17.3) were successfully placed to the planning target volume in each patient. The average time for CT fluoroscopy was 357 seconds for each procedure. No accident was seen at needle insertion, but 2 patients developed incomplete peroneal nerve palsy after needle removal, but gradually recovered. CT-based treatment planning was faster and more accurate than projection reconstruction with conventional radiograms. Analysis of the dose volume histogram showed conformal dose distribution to the target, while avoiding normal structures. CONCLUSION: CT fluoroscopy guidance ensures safety and increases the accuracy of needle placement in brachytherapy. Conformal high-dose-rate (HDR) interstitial brachytherapy with CT-based treatment planning is a method worth considering for locally recurrent rectal cancer.

Adenocarcinoma↗

PubMed2004

[Potentiation of radiation-induced cell killing by histone deacetylase inhibitor].

HDAC inhibitor has been focused as a molecular target agent for cancer treatment because of unique pharmacological activity. HDAC inhibitors induce cancer cells to undergo growth arrest, differentiation or induce apoptosis in vitro, and also inhibit the growth of transplanted tumors in vivo, but the enhancement effect or interaction of HDAC inhibitors with other chemotherapeutic agents or radiation has not yet been fully investigated. Biade et al examined the effect of trichostatin A (TSA), and reported synergistic enhancement of radiosensitivity in human cancer cell lines. We also confirmed the similar results in vitro by using TSA in combination with radiation. The main purpose of this paper is to review the current status of HDAC inhibitor in clinical use, and evaluate the potential possibility for the potentiation of radiation-induced cell killing including the results of our research.

Antineoplastic Agents↗

PubMed2003

Changes in the number of HSF1 positive granules in the nucleus reflects heat shock semiquantitatively.

PURPOSE: The purpose of this study is to examine the changes in the number of HSF1 granules in the nucleus caused by different degree of heat stress. MATERIALS AND METHODS: A human esophageal cancer cell line, TE-2, was used. HSF1 granules were examined in an immunofluorescence study, and the changes in the average number of HSF1 granules after heat alone or heat in combination with KNK437, Hsp inhibitor, were evaluated. A band shift of HSF1 was also determined by western blot. RESULTS: HSF1 granules appeared soon after the start of heating at 43 degrees C and reached a peak at 60 min and gradually disappeared after discontinuation of heat. In the fractionated heat treatment, preheating (43 degrees C, 30 min) suppressed the increase in the number of the granules during the second heating, but suppression of Hsp72 by KNK437 resulted in increase in the number of granules. Continued heating at 43 degrees C with or without KNK437 maintained the number of the granules at the peak level during heat treatment. The band shift of HSF1 examined by western blot correlated with the changes in the number of granules. The number of granules also reflected the degree of stress according to different temperature. CONCLUSION: The number of HSF1 granules in the nucleus well reflected heat stress, and was almost consistent with phosphorylation of HSF1. The number of HSF1 granules would be a useful tool for evaluating different degrees of heat stress semiquantitatively.

Benzhydryl Compounds↗

PubMed2003

Caffeine diminishes cytotoxic effects of paclitaxel on a human lung adenocarcinoma cell line.

This study was performed to investigate how caffeine modifies the cytotoxic effects of paclitaxel on a human lung carcinoma cell line. Caffeine doses up to 5mM had less effect on clonogenic survival. The cell killing effect, due to paclitaxel, increased in a dose-dependent manner up to 50 nM. For combined treatment with caffeine and paclitaxel, added caffeine reduced the cytotoxic effect of paclitaxel not only in dose-response but also in time-response curves. Caffeine combined with paclitaxel clearly suppressed cell proliferation in a dose-dependent manner. In the cell cycle analysis, caffeine alone caused early G1 accumulation, whereas paclitaxel alone caused an early increase in G2-M and a decrease in G1. As for the effect of caffeine on paclitaxel, caffeine suppressed the effect of paclitaxel on cell cycle distribution, where a dose-dependent early increase in G2-M and a decrease in G1 were not clear. We suggest that cell cycle modifying agents, such as caffeine, potentially diminish the cytotoxic activity of paclitaxel, and one should be careful when combining such agents.

Adenocarcinoma↗

PubMed2003

Comparable outcomes of radiation therapy without high-dose methotrexate for patients with primary central nervous system lymphoma.

BACKGROUND: The previous trials of radiotherapy conducted for primary central nervous system lymphoma (PCNSL) have not been successful. Therefore, we have investigated the clinical outcomes and the role of radiation therapy in the treatment of PCNSL. METHODS: Thirty-three consecutive patients with PCNSL treated with cranial radiotherapy (30-40 Gy whole brain plus 10-20 Gy boost) without administration of high-dose methotrexate were retrospectively analyzed. Nine patients received whole spinal irradiation (WSI) as an additional therapy. The median age of patients was 58 years (range: 28-78 years), and 70% showed a poor performance status (PS). RESULTS: The median survival time (MST) was 13 months, and the 5-year overall survival rate was 35%. The initial response and the number of tumors were significant prognostic factors, and WSI tended toward significance in a multivariate analysis. Four of five patients, who received prophylactic WSI, were 4-year survivors without a tumor relapse and none of them had tumor involvement in the vertebral canal. One patient developed radiation-induced brain necrosis, however, WSI did not seem to affect the late complications. CONCLUSIONS: We consider it important to reduce severe acute and late complications in patients qualified for receiving an aggressive therapy, and to explore the possible tolerable and curative treatment methods that can be used in order to improve the prognosis for PCNSL. Further modifications, including the application of WSI seem to be necessary in the management of PCNSL.

Adult↗

PubMed2002

Correlations between in vivo tumor weight, oxygen pressure, 31P NMR spectroscopy, hypoxic microenvironment marking by beta-D-iodinated azomycin galactopyranoside (beta-D-IAZGP), and radiation sensitivity.

PURPOSE: The purpose of this study is to evaluate the amount of hypoxic fraction in a rodent tumor by means of polarographic oxygen electrode, phosphorus-31 magnetic resonance spectroscopy (31P-MRS), and a newly synthesized hypoxic marker, beta-D-iodinated azomycin galactopyranoside (beta-D-IAZGP). We also investigated the radiosensitivity for tumors of different weights. METHODS AND MATERIALS: Murine mammary carcinoma cells, FM3A, were subcutaneously implanted into the back of 5-week-old male C3H/He mice. beta-D-IAZGP radiolabeled with 123I or with 125I was injected intravenously into tumor-bearing mice, and marker distribution was measured by nuclear medicine procedures. Radiosensitivity of the tumor was measured by the in vivo/in vitro clonogenic assay. Tumor oxygenation status was also measured directly by polarographic oxygen electrodes and indirectly estimated from 31P-MR spectra. RESULTS: Higher accumulation of 123I-beta-D-IAZGP was observed in the tumors than in normal tissues at 24 h after administration. As to biodistribution of 125I-beta-D-IAZGP, the tumor/blood ratio varied widely, but correlated significantly with tumor weight. Mean oxygen pressure (pO2) values and ratios of nucleoside triphosphate beta to inorganic phosphate (beta-ATP/Pi) and of phosphocreatine to inorganic phosphate (PCr/Pi) decreased significantly with the increase in tumor volume. As tumor volume increased, the surviving fraction of cells from tumors irradiated in vivo increased significantly. CONCLUSIONS: The increase in tumor volume was significantly correlated with a reduction in mean pO2, a decrease in the ratios of beta-ATP/Pi or PCr/Pi, an increase in uptake of beta-D-IAZGP, and an increase in radioresistance. Because the uptake of beta-D-IAZGP can be measured noninvasively by nuclear medicine techniques, it could be clinically useful for monitoring hypoxia in human tumors.

Animals↗

PubMed2002

Relationship between cyclin D1 expression and poor radioresponse of murine carcinomas.

PURPOSE: We recently reported that overexpression of epidermal growth factor receptor (EGFR) positively correlated with radioresistance of murine carcinomas. Because cyclin D1 is a downstream sensor of EGFR activation, the present study investigated whether a relationship exists between the extent of cyclin D1 expression and in vivo radiocurability of murine tumors. We further investigated the influence of radiation on cyclin D1 expression and the expression of p27, an inhibitor of the cyclin D1 downstream pathway, as well as the relationship of these molecular determinants to cell proliferation and induced apoptosis in tumors exposed to radiation. METHODS AND MATERIALS: Cyclin D1 expression was assayed in nine carcinomas syngeneic to C3Hf/Kam mice using Western blot analysis. These tumors greatly differed in their radioresponse as assessed by TCD(50). The expression of cyclin D1 and p27 proteins was determined by Western blotting. Cell proliferative activity in tumors was determined by proliferating cell nuclear antigen (PCNA) immunochemistry. The effect of irradiation on the expression of cyclin D1 or p27 proteins and on PCNA positivity was determined in the radiosensitive OCa-I and in the radioresistant SCC-VII tumors. RESULTS: Cyclin D1 expression varied among tumors by 40-fold, and its magnitude positively correlated with poorer tumor radioresponse (higher TCD(50) values). The level of cyclin D1 expression paralleled that of EGFR. A 15-Gy dose reduced constitutive expression of cyclin D1 in the radiosensitive OCa-I tumors, but had no influence on expression of cyclin D1 in the radioresistant SCC-VII tumors. In contrast, 15 Gy increased the expression of p27 in radiosensitive tumors and reduced it in radioresistant tumors. Radiation induced no significant apoptosis or change in the percentage of PCNA-positive (proliferating) cells in SCC-VII tumors with high cyclin D1 levels, but it induced significant apoptosis and a decrease in the percentage of proliferating cells in OCa-I tumors with low cyclin D1 expression. CONCLUSION: Our findings show a positive correlation between cyclin D1 expression and tumor radioresistance. The expression of cyclin D1 and p27 was modified by radiation and was associated with cellular response to radiation, but this depended on the pretreatment level of cyclin D1 expression. These findings may have important clinical implications: The pretreatment assessment of cyclin D1 expression could serve as a useful predictor of radiotherapy outcome and assist in selecting an effective treatment modality.

Animals↗

PubMed2002

Salvage external beam radiotherapy for local recurrence without systemic progression or prostate specific antigen recurrence of prostate cancer after initial hormonal therapy: is it possible to identify patients likely to have good treatment outcomes?

BACKGROUND: We attempted to identify factors that predict the outcomes of salvage external beam radiotherapy (sEBRT) in patients who showed local recurrence without systemic progression or isolated prostate specific antigen (PSA) recurrence after initial hormonal therapy. METHODS: The subjects were 33 patients who were diagnosed as having local recurrence without systemic progression (30 cases) or isolated PSA recurrence (three cases). Of these patients, those with continuously decreasing PSA levels, which were 1.0 ng/ml or less 1-1.5 years after sEBRT, were regarded as good responders (GR) whereas the remaining patients were regarded as poor responders (nGR). Survival rates in these patients and factors that distinguish GR from nGR were evaluated retrospectively. RESULTS: The cancer-specific 10-year survival rate was 82.4% in the 33 patients, 100% in the 21 GR patients and 55% in the 12 nGR patients (P < 0.0001). Stepwise variable selection to discriminate between GR and nGR revealed that the time from sEBRT initiation to the nadir PSA was the most significant factor (P = 0.000097). Before sEBRT, GR can be predicted in patients with pre-sEBRT PSA <30.0 ng/ml and PSA doubling time (PSADT) >7.0 months, with a sensitivity of 95.2% (20/21), a specificity of 100% and an accuracy of 97.0%. CONCLUSION: Good responses to sEBRT can be expected in patients with local recurrence without systemic progression or isolated PSA recurrence after initial hormonal therapy when the patients show both pre-sEBRT PSA <30.0 ng/ml and PSADT >7.0 months.

Aged↗