A new method for assessing lung tumor motion in radiotherapy using dynamic chest radiography.

Dynamic chest radiography (DCR) is a recent advanced modality to acquire dynamic and functional images. We developed a new method using DCR and the free analysis software, Kinovea, to assess lung tumor motion. This study aimed to demonstrate the usefulness of our method. Phantom and clinical studies were performed. In the phantom study, dynamic images of a moving lead sphere were acquired using DCR, and the motion of the phantom was tracked using Kinovea in a DCR video. The amplitude of phantom motion was measured and compared with a predetermined baseline amplitude. In a clinical study, DCR and respiratory-gated four-dimensional computed tomography (4D-CT) were performed on 15 patients who underwent stereotactic body radiation therapy for lung tumors. The amplitudes of tumor motion in DCR and 4D-CT were measured in the superior-inferior (SI), left-right (LR), and anterior-posterior (AP) directions, and the square root of the sum of squares (SRSS) of the amplitude was calculated in all directions. Spearman's rank correlation and the Wilcoxon signed-rank test were performed to determine the correlations of the amplitudes of tumor motion obtained using DCR and 4D-CT. In the phantom study, the absolute mean error between the measured and predetermined amplitudes was 0.60 mm (range: 0.061.53 mm). In the clinical study, the amplitudes of tumor motion obtained using DCR correlated significantly with those of 4D-CT in the SI and LR directions, as did the SRSS values. The median amplitudes for DCR were significantly higher than those for 4D-CT in all (SI, LR, and AP) directions, as were the SRSS values. Our proposed method based on DCR and Kinovea is useful for assessing lung tumor motion, visually and quantitatively. Therefore, DCR has potential as a new modality for evaluating lung tumor motion in radiotherapy.

Long-term clinical outcomes of external beam radiation therapy for oligometastatic prostate cancer: A combination of prostate-targeted treatment and metastasis-directed therapy.

OBJECTIVE: To assess the efficacy of combination of prostate-targeted treatment and metastasis-directed therapy for oligometastatic prostate cancer. METHODS: We retrospectively evaluated the clinical outcomes of synchronously diagnosed oligometastatic prostate cancer patients treated with external beam radiation therapy for the prostate and all metastatic lesions (≤3 lesions) at Kyoto University Hospital between January 2004 and April 2019. The prescribed dose was basically ≥70 Gy for the prostate with or without whole pelvic irradiation, and ≥45 Gy for the metastatic lesions. Clinical outcomes were compared with a contemporary cohort of 55 synchronous oligometastatic prostate cancer patients treated with the standard of care. RESULTS: In total, 16 consecutive patients with synchronous oligometastatic prostate cancer were analyzed. The median follow-up period was 7.4 years. The 8-year overall survival, prostate cancer-specific survival, biochemical failure-free, clinical failure-free and castration-resistant prostate cancer-free rates were 64.8%, 71.3%, 38.5%, 47.3% and 67.3%, respectively. No grade 3 or higher radiation-induced late toxicities occurred. Patients with prostate-targeted treatment plus metastasis-directed therapy had a significantly higher castration-resistant prostate cancer-free rate than those without prostate-targeted treatment plus metastasis-directed therapy (P = 0.00741). CONCLUSIONS: Prostate-targeted treatment plus metastasis-directed therapy through external beam radiation therapy can result in favorable long-term disease-free and survival outcomes with acceptable morbidities among synchronous oligometastatic prostate cancer patients. Therefore, this approach may represent a promising treatment strategy for this population. Further investigation is required.

National survey of radiation oncologists' practice patterns regarding hormone-naïve prostate cancer with bone metastases.

OBJECTIVE: To explore radiation oncologists' attitudes and practice patterns of radiotherapy for hormone-naïve prostate cancer with bone metastases in Japan. METHODS: An internet-based survey was distributed to board-certified radiation oncologists of the Japanese Society of Radiation Oncology. Three hypothetical cases were assumed: hormone-naïve prostate cancer with single, three or multiple non-symptomatic bone metastases. The respondents described their attitude regarding such cases, treatment methods and the radiotherapy dose fractionation that they would recommend. RESULTS: Among the 1013 board-certified radiation oncologists in Japan, 373 (36.8%) responded to the questionnaire. Most of the respondents (85.0%) believed that radiotherapy may be applicable as a primary treatment for hormone-naïve prostate cancer with bone metastases in some circumstances. For Case 1 (single bone metastasis), 55.0% of the respondents recommended radiotherapy for the prostate and bone metastasis. For Case 2 (three bone metastases), only 24.4% recommended radiotherapy for all lesions, and 31.4% recommended radiotherapy for the prostate only. For Case 3 (multiple bone metastases), 49.1% of the respondents stated that there was no indication for radiotherapy. However, 34% of the respondents still preferred to administer radiotherapy for the prostate. The radiotherapy techniques and dose fractionations varied widely among the respondents. CONCLUSION: Most of the respondent radiation oncologists believed that radiotherapy may be beneficial for hormone-naïve prostate cancer with bone metastases.

Low incidence of late recurrence in patients with intermediate-risk prostate cancer treated by intensity-modulated radiation therapy plus short-term androgen deprivation therapy.

OBJECTIVES: This study evaluated the long-term outcomes of intensity-modulated radiation therapy (IMRT) combined with short-term neoadjuvant androgen deprivation therapy (ADT) in patients with intermediate-risk (IR) prostate cancer (PCa). MATERIALS AND METHODS: Patients with IR PCa treated with IMRT at our institution between September 2000 and November 2010 were analyzed retrospectively. The treatment consisted of IMRT (70-78 Gy in 35-39 fractions) combined with 6 months of neoadjuvant ADT. Salvage ADT was initiated when the prostate-specific antigen level was > 4.0 ng/mL RESULTS: In total, 106 consecutive patients with IR PCa (median age: 70 years old) were analyzed. The median follow-up period was 8.0 years. The overall survival, PCa-specific survival, biochemical failure, and clinical failure rates were 99.0%, 100.0%, 6.8%, and 1.9% at 5 years and 89.1%, 100.0%, 11.3%, and 2.9% at 10 years, respectively. Late recurrence (> 5 years) was observed in three cases (2.8%). The cumulative incidence rates of genitourinary (GU) and gastrointestinal (GI) toxicities (grade 2/3) were 10.5% and 5.8% at 5 years, and 14.7% and 5.8% at 10 years, respectively. No patient developed grade 4/5 GU toxicities or grade 3-5 GI toxicities. CONCLUSION: IMRT at a dose up to 78 Gy combined with short-term neoadjuvant ADT resulted in excellent long-term disease-free outcomes with acceptable morbidities among patients with IR PCa. In addition, the incidence of late recurrence was very low. Further investigation is warranted to confirm our findings.

Ten-year outcomes of high-dose intensity-modulated radiation therapy for nonmetastatic prostate cancer with unfavorable risk: early initiation of salvage therapy may replace long-term adjuvant androgen deprivation.

BACKGROUND: The optimal timing of salvage androgen deprivation therapy (ADT) following definitive radiation therapy for prostate cancer (PCa) is unknown. This study evaluated the efficacy of early initiation of salvage-ADT (S-ADT) based on predetermined timing among patients with unfavorable PCa treated with high-dose intensity-modulated radiation therapy (IMRT). MATERIALS AND METHODS: High-risk (HR) and very-high-risk (VHR) PCa patients treated with IMRT at our institution between September 2000 and December 2010 were analyzed retrospectively. Treatment consisted of high-dose IMRT (78 Gy/39 fractions) combined with 6 months of neoadjuvant-ADT (NA-ADT). S-ADT was initiated when prostate-specific antigen levels exceeded 4.0 ng/mL. RESULTS: In total, 268 (184 HR and 84 VHR) patients were analyzed. The median follow-up period was 114.4 months. The 10-year overall survival (OS), PCa-specific survival (PCSS), biochemical failure (BF), and clinical failure (CF) rates were 82.8%, 97.1%, 27.3%, and 12.8% among the HR PCa patients and 79.4%, 87.9%, 56.2%, and 26.7% among the VHR PCa patients (p = 0.839, = 0.0377, < 0.001, and < 0.001), respectively. The 10-year cumulative incidence rates of urinary and rectal (grades 2-3) toxicities were 22.6% and 5.8%, respectively. No grade 4 or higher toxicities were observed. CONCLUSION: High-dose IMRT combined with short-term NA-ADT resulted in long-term disease-free status, with acceptable morbidity among approximately three-fourths of the HR PCa patients and nearly half of the VHR PCa patients. Moreover, excellent survival outcomes were achieved by the early S-ADT initiation. This approach may be a promising alternative to uniform provision of long-term ADT.

Long-term outcomes of definitive external-beam radiotherapy for non-metastatic castration-resistant prostate cancer.

BACKGROUND: Although definitive external-beam radiotherapy (EBRT) is one of the treatment options for non-metastatic castration-resistant prostate cancer (NM-CRPC), there are limited data on the long-term outcomes of this treatment. METHODS: We retrospectively evaluated 31 NM-CRPC patients consecutively treated with definitive EBRT. The median age was 74 years upon EBRT initiation. The initial T stage distribution was as follows: T1c in 3, T2 in 11, T3 in 14, and T4 in 3 cases, respectively. The median prostate dose was 70.4 Gy. A castration-resistant status was defined as continuously increasing serum prostate-specific antigen levels despite ongoing hormonal therapy (HT). RESULTS: The median follow-up duration after EBRT was 66.6 months. The median period of primary HT was 18.0 months. The 5- and 8-year overall survival rates were 74.6 and 49.8%, respectively. The 5- and 8-year prostate cancer-specific survival rates were 77.4 and 51.7%, respectively. Fourteen patients died, and prostate cancer was the cause of death in 12 of these patients. The 5- and 8-year relapse-free survival rates were 32.3 and 25.8%, respectively. Among 23 patients who experienced biochemical or clinical failure, the median duration to recurrence after EBRT was 19.3 months. The 5- and 8-year clinical failure-free survival rates were 56.0 and 51.4%, respectively. Among the 14 patients who experienced clinical failure, the median duration after EBRT was 16.0 months. The local relapse-free rates at 5 and 8 years were 91.0 and 91.0%, respectively. Grade 3 or higher adverse events were observed in four patients. CONCLUSION: Definitive EBRT achieved a long-term disease-free and clinical failure-free status in approximately one-third of and half of the treated NM-CRPC patients, respectively. This approach was also associated with favorable local relapse-free rates and overall survival outcomes. Definitive EBRT is a promising approach for NM-CRPC patients.

Phase I study of stereotactic body radiation therapy for centrally located stage IA non-small cell lung cancer (JROSG10-1).

BACKGROUND: To investigate the maximum tolerated dose (MTD) and recommended dose (RD) of stereotactic body radiation therapy (SBRT) for centrally located stage IA non-small cell lung cancer (NSCLC). METHODS: Five dose levels, ranging from of 52 to 68 Gy in eight fractions, were determined; the treatment protocol began at 60 Gy (level 3). Each dose level included 10 patients. Levels 1-2 were indicated if more than four patients exhibited dose-limiting toxicity (DLT), which was defined as an occurrence of a grade 3 (or worse) adverse effect within 12 months after SBRT initiation. MTD was defined as the lowest dose level at which more than four patients exhibited DLT. RESULTS: Ten patients were enrolled in the level 3 study. One patient was considered unsuitable because of severe emphysema. Therefore, nine patients were evaluated and no patient exhibited DLT. The level 3 results indicated that we should proceed to level 4 (64 Gy). However, due to the difficulty involved in meeting the dose constraints, further dose escalation was not feasible and the MTD was found to be 60 Gy. CONCLUSIONS: The RD of SBRT for centrally located stage IA NSCLC was 60 Gy in eight fractions.

Clinical effect of multileaf collimator width on the incidence of late rectal bleeding after high-dose intensity-modulated radiotherapy for localized prostate carcinoma.

BACKGROUND: Several studies have confirmed a dosimetric advantage associated with use of a smaller leaf in intensity-modulated radiation therapy (IMRT). However, no studies have identified any clinical benefits. We investigated the effect of a smaller multileaf collimator (MLC) width on the onset of late rectal bleeding after high-dose prostate IMRT. MATERIALS AND METHODS: Two hundred and five prostate cancer patients were treated with a total dose of 78 Gy in 39 fractions by use of a dynamic MLC technique; however, two different MLC were used: a 10-mm-wide device and a 5-mm-wide device. Gastrointestinal toxicity and several clinical factors were assessed. RESULTS: The 5-year actuarial risk of grade 2 or higher rectal bleeding was 6.9 % for the 10-mm-wide group (n = 132) and 1.8 % for the 5-mm-wide group (n = 73) (p = 0.04). The median estimated rectal doses for the two groups were 55.1 and 50.6 Gy (p < 0.001), respectively. Univariate analysis showed that acute toxicity, rectal V30-60, median rectal dose, normal tissue complication probability (NTCP), and MLC type were significant predictive factors for late rectal toxicity. In multivariate analysis, acute toxicity and NTCP remained significant. CONCLUSION: In our planning approach for prostate IMRT, a decrease in MLC width from 10 to 5 mm contributed to further rectal dose reduction, which was the most important predictor of late rectal toxicity.

Long-term outcomes of intensity-modulated radiation therapy combined with neoadjuvant androgen deprivation therapy under an early salvage policy for patients with T3-T4N0M0 prostate cancer.

BACKGROUND: Long-term outcomes of dose-escalated intensity-modulated radiation therapy (IMRT) combined with neoadjuvant (NA) androgen deprivation therapy (ADT) under an early salvage policy in patients with locally advanced prostate cancer (LAPC) were evaluated. METHODS: Data from 120 patients with T3-T4N0M0 adenocarcinoma of the prostate treated with IMRT were analyzed. NA-ADT with a median duration of 6 months was provided in all cases. Seventy-eight Gy, at 2 Gy per fraction, was delivered to the prostate and seminal vesicles. Adjuvant ADT (A-ADT) was not provided for any patient following the completion of IMRT. Salvage ADT (S-ADT) commenced when PSA values >4 ng/ml. RESULTS: The median follow-up period was 97 months. S-ADT was initiated in 39 patients. The median PSA value at the initiation of S-ADT was 5.7 ng/ml. The 8-year biochemical relapse-free survival, prostate cancer-specific survival, overall survival and S-ADT-free rates were 53.2 % [95 % confidence interval (CI) 43.4, 62.1], 96.6 % (95 % CI 91.2, 98.7), 89.1 % (95 % CI 81.5, 93.7) and 66.6 % (95 % CI 60, 74.6), respectively. The estimated 8-year cumulative incidence rates of grade 2-3 late gastrointestinal, and grade 2-3 genitourinary toxicity were 7.6 and 10.7 %, respectively. No grade 4 toxicity was observed. CONCLUSIONS: High-dose IMRT, combined with NA-ADT for LAPC, was associated with favorable long-term disease-specific and overall survival outcomes, despite non-provision of A-ADT under the early S-ADT provision policy. This approach may represent a viable alternative to uniform provision of long-term A-ADT, because two-thirds of the patients maintained ADT-free status over an 8-year period after IMRT. Prospective trials will be required.

Ten-year outcomes of intensity-modulated radiation therapy combined with neoadjuvant hormonal therapy for intermediate- and high-risk patients with T1c-T2N0M0 prostate cancer.

BACKGROUND: We aimed to analyze the 10-year outcomes of intensity-modulated radiation therapy (IMRT) combined with neoadjuvant hormonal therapy (HT) for patients with intermediate- and high-risk T1c-T2N0M0 prostate cancer. METHODS: Fifty patients with T1c-T2N0M0 prostate cancer, who were treated with high-dose IMRT combined with neoadjuvant HT, were evaluated. Of these patients, 19 and 31 were classified into the intermediate- and high-risk groups, respectively. Neoadjuvant HT was administered over a median duration of 6 months; 74 and 78 Gy in 2 Gy per fraction were essentially delivered to the intermediate- and high-risk cases, respectively. Adjuvant HT was not administered to any of the patients after the completion of IMRT. RESULTS: Over a median follow-up period of 118 months, the 10-year prostate-specific antigen failure-free survival, prostate-specific antigen failure-free, salvage hormonal therapy-free, prostate cancer-specific survival, and overall survival rates were 70.2 %, 78.7 %, 89.2 %, 100 %, and 88.8 %, respectively. No grade 3 or higher acute or late toxicities were observed. The 10-year likelihoods of developing grade 2 late urinary and rectal toxicities were 13.7 % and 4.2 %, respectively. Compared with the outcomes of a cohort of historical controls who were locally irradiated with 70 Gy by three-dimensional conformal radiotherapy, the prostate-specific antigen failure-free rate was significantly better in the IMRT groups (78.7 % vs. 53.4 % at 10 years; p = 0.027). CONCLUSIONS: High-dose IMRT combined with neoadjuvant HT achieved not only high prostate-specific antigen control, but also excellent survival outcomes with acceptable morbidities, for a Japanese cohort of intermediate- and high-risk T1c-T2N0M0 prostate cancer patients, and these results warrant further investigation.

CLINICAL OUTCOMES OF EXTERNAL-BEAM RADIOTHERAPY COMBINED WITH NEOADJUVANT ANDROGEN DEPRIVATION THERAPY FOR HIGH-RISK PROSTATE CANCER.

(Purpose) We investigated the outcome of external-beam radiotherapy (EBRT) with neoadjuvant androgen deprivation therapy (NeoADT) for high-risk prostate cancer defined by National Comprehensive Cancer Network (NCCN) guideline. (Patients and method) From 2002 to 2013, 70 patients with high-risk prostate cancer (PSA ≥20 ng/ml or clinical T stage ≥T3a, Gleason score ≥8) were treated with NeoADT and EBRT. EBRT consisted of three-dimensional conformal or intensity modulated radiotherapy with or without whole-pelvic radiation. Biochemical failure was defined according to the Phoenix definition. Biochemical progression-free survival (bPFS) and overall survival (OS) were calculated by Kaplan-Meier method, and prognostic factors for bPFS were analyzed by using the Cox proportional hazard model. (Result) The median age and initial prostate-specific antigen (PSA) level were 72 years old and 25.2 ng/ml, respectively. 43 patients had PSA level ≥20 ng/ml, 51 patients had clinical stage ≥T3a, 27 patients had Gleason score ≥8. The number of risk factors patients possessed was 1 (RiskN-1) in 31 patients, 2 (RiskN-2) in 27 patients and 3 (RiskN-3) in 12 patients. Median EBRT dose and duration of Neo ADT were 74 Gy and13.0 months, respectively. Whole-pelvic radiation was administered in 7 patients. After median follow-up of 4.8 years, biochemical and clinical failure occurred in 23 and 2 patients, respectively. No patients died of cancer. Five-year/8-year bPFS and OS were 63%/54% and 100%/91%, respectively. In multivariate analysis, three high-risk factor of NCCN guideline (PSA, clinical stage, Gleason score) did not predict outcome after EBRT independently, but RiskN (-1 vs -2, 3, HR 35.35, 95%CI 2.51-498.05, p<0.01) and pre-EBRT PSA (continuous, hazard ratio 1.31, 95%CI 1.01-1.71, p<0.05) were the significant predictors of bPFS. Five-year/8-year bPFS in RiskN-1 group and RiskN-2 or -3 group were 89%/79% and 47%/39%, respectively. Grade 3/4 adverse events (CTCAE ver4.0-JCOG) occurred in 2 patients. (Conclusion) Median dose of 74 Gy EBRT with intermediate-term NeoADT was safe and beneficial for high-risk prostate cancer. The number of risk factors and pre-EBRT PSA level were the independent prognostic factors for biochemical progression-free survival.

Long-term outcomes of dynamic conformal arc irradiation combined with neoadjuvant hormonal therapy in Japanese patients with T1c-T2N0M0 prostate cancer: case series study.

OBJECTIVE: There are few reports of the outcomes of external beam radiotherapy in Asian males with localized prostate cancer. The aim of this study is to evaluate the long-term outcomes of external beam irradiation using three-dimensional two-dynamic conformal arc therapy, combined with neoadjuvant hormonal therapy, in patients with T1c-T2N0M0 prostate cancer. METHODS: Between March 2003 and August 2007, 150 Japanese patients with T1c-T2N0M0 prostate cancer were definitively treated with three-dimensional two-dynamic conformal arc therapy. The median age, pretreatment prostate-specific antigen values and neoadjuvant hormonal therapy period were 73 years, 9.4 ng/ml and 6 months, respectively. In principle, 74 Gy was delivered to the planning target volume, although the total dose was reduced to 70 Gy in patients with unfavorable risk factors, such as severe diabetes mellitus or anticoagulant therapy. No adjuvant hormonal therapy was given to any patient. Salvage hormonal therapy was started when the prostate-specific antigen value exceeded 4 ng/ml in a monotonically increasing manner. RESULTS: The median follow-up period was 79 months. Salvage hormonal therapy was initiated in 10 patients and the median prostate-specific antigen value at the initiation was 4.7 ng/ml. The 5-year Kaplan-Meier estimates of the biochemical relapse-free survival rate, the salvage hormonal therapy -free rate and the overall survival rate were 83.3% (95% confidence interval = 77.1-89.6%), 94.3% (95% confidence interval = 90.4-98.1%) and 96.3% (95% confidence interval = 93.1-99.5%), respectively. The 5-year cumulative incidence rates of developing more than Grade 2 late rectal and urinary toxicities were 5.5 and 2.9%, respectively. CONCLUSIONS: Three-dimensional two-dynamic conformal arc therapy, with up to 74 Gy, in patients with T1c-T2N0M0 prostate cancer with neoadjuvant hormonal therapy was well tolerated and achieved good biochemical control and survival outcomes.

Efficacy and safety of the pterional keyhole approach for the treatment of anterior circulation aneurysms.

Keyhole surgery is partly replacing the standard pterional approach in patients undergoing surgery to treat aneurysms of the anterior circulation. We describe the pterional keyhole approach for the clipping of anterior circulation aneurysms and discuss the efficacy and safety of our keyhole craniotomy procedure. We treated 103 patients with 111 intracranial aneurysms by surgical clipping via the pterional keyhole approach and retrospectively compared the characteristics and clinical outcomes of the keyhole procedure and the standard pterional approach. We also compared the surgical results of the keyhole approach when the operator was an experienced neurosurgeon or a less experienced neurosurgeon guided by an experienced colleague. All keyhole operations were carried out successfully without enlargement of the craniotomy or a change to a different approach. The outcomes of the keyhole and the standard pterional approach in patients with subarachnoid hemorrhage were not significantly different. Favorable outcomes were obtained in patients with unruptured aneurysms treated by either experienced or less experienced surgeons. The pterional keyhole approach offers the same surgical possibilities as conventional pterional approaches for the treatment of anterior circulation aneurysms. It is safe and simple and yields favorable outcomes even if the operators are less experienced neurosurgeons. Careful patient selection and sufficient opening of the sylvian fissure are the key points for good outcomes and the prevention of intraoperative complications.

Development of a dose verification system for Vero4DRT using Monte Carlo method.

Vero4DRT is an innovative image-guided radiotherapy system employing a C-band X-ray head with gimbal mechanics. The purposes of this study were to propose specific MC models of the linac head and multileaf collimator (MLC) for the Vero4DRT and to verify their accuracy. For a 6 MV photon beam delivered by the Vero4DRT, a simulation code was implemented using EGSnrc. The linac head model and the MLC model were simulated based on its specification. Next, the percent depth dose (PDD) and beam profiles at depths of 15, 100, and 200 mm were simulated under source-to-surface distance of 900 and 1000 mm. Field size was set to 150 × 150 mm2 at a depth of 100 mm. Each of the simulated dosimetric metrics was then compared with the corresponding measurements by a 0.125 cc ionization chamber. After that, intra- and interleaf leakage, tongue-and-groove, and rounded-leaf profiles were simulated for the static MLC model. Meanwhile, film measurements were performed using EDR2 films under similar conditions to simulation. The measurement for the rounded-leaf profile was performed using the water phantom and the ionization chamber. The leaf physical density and abutting leaf gap were adjusted to obtain good agreement between the simulated intra- and interleaf leakage profiles and measurements. For the MLC model in step-and-shoot cases, a pyramid and a prostate IMRT field were simulated, while film measurements were performed using EDR2. For the linac head, exclusive of MLC, the difference in PDD was < 1.0% after the buildup region. The simulated beam profiles agreed to within 1.3% at each depth. The MLC model has been shown to reproduce dose measurements within 2.5% for static tests. The MLC is made of tungsten alloy with a purity of 95%. The leaf gap of 0.015 cm and the MLC physical density of 18.0 g/ cm3, which provided the best agreement between the simulated and measured leaf leakage, were assigned to our MC model. As a result, the simulated step-and-shoot IMRT dose distributions agreed with the film measurements to within 3.3%, with exception of the penumbra region. We have developed specific MC models of the linac head and the MLC in the Vero4DRT system. The results have demonstrated that our MC models have high accuracy. 

Molecular epidemiology of canine GM1 gangliosidosis in the Shiba Inu breed in Japan: relationship between regional prevalence and carrier frequency.

BACKGROUND: Canine GM1 gangliosidosis is a fatal disease in the Shiba Inu breed, which is one of the most popular traditional breeds in Japan and is maintained as a standard breed in many countries. Therefore, it is important to control and reduce the prevalence of GM1 gangliosidosis for maintaining the quality of this breed and to ensure supply of healthy dogs to prospective breeders and owners. This molecular epidemiological survey was performed to formulate an effective strategy for the control and prevention of this disease. RESULTS: The survey was carried out among 590 clinically unaffected Shiba Inu dogs from the 8 districts of Japan, and a genotyping test was used to determine nation-wide and regional carrier frequencies. The number and native district of affected dogs identified in 16 years from 1997 to June 2013 were also surveyed retrospectively. Of the 590 dogs examined, 6 dogs (1.02%, 6/590) were carriers: 3 dogs (2.27%, 3/132) from the Kinki district and the other 3 dogs from the Hokkaido, Kanto, and Shikoku districts. The retrospective survey revealed 23 affected dogs, among which, 19 dogs (82.6%) were born within the last 7 years. Of the 23 affected dogs, 12 dogs (52.2%) were from the Kinki district. Pedigree analysis demonstrated that all the affected dogs and carriers with the pedigree information have a close blood relationship. CONCLUSIONS: Our results showed that the current carrier frequency for GM1 gangliosidosis is on the average 1.02% in Japan and rather high in the Kinki district, which may be related to the high prevalence observed over the past 16 years in this region. This observation suggests that carrier dogs are distributed all over Japan; however, kennels in the Kinki district may face an increased risk of GM1 gangliosidosis. Therefore, for effective control and prevention of this disease, it is necessary to examine as many breeding dogs as possible from all regions of Japan, especially from kennels located in areas with high prevalence and carrier frequency.

Risk factors predicting the outcome of salvage radiotherapy in patients with biochemical recurrence after radical prostatectomy.

OBJECTIVES: Salvage radiotherapy is the only curative treatment for patients with prostate cancer showing biochemical progression after radical prostatectomy. In this study, we evaluated the clinicopathological parameters that influence the outcome of salvage radiotherapy. METHODS: Medical records of 49 patients who underwent salvage radiotherapy after radical prostatectomy from 1997 to 2008 at the Graduate School of Medicine, Kyoto University, were retrospectively reviewed. Radiotherapy was carried out with 66 Gy on the prostatic bed. RESULTS: Biochemical progression-free survival after salvage radiotherapy at 2, 5 and 7 years was 51.0%, 42.2% and 42.2%, respectively. Significant parameters predicting biochemical progression after salvage radiotherapy by Cox regression analysis were prostatectomy Gleason score sum ≥ 8 (hazard ratio 0.08; 95% confidence interval 0.03-0.22; P=0.001), prostate-specific antigen nadir after radical prostatectomy ≥ 0.04 ng/mL (hazard ratio 0.30; 95% confidence interval 0.13-0.69; P=0.005) and negative surgical margin (hazard ratio 0.28; 95% confidence interval 0.12-0.70; P=0.006). When the patients were subgrouped by these risk factors, the 5-year progression-free survival rates after salvage radiotherapy were 77.8%, 50.0% and 6.7% in patients with 0, 1 and ≥ 2 predictors, respectively. CONCLUSION: In order to discriminate favorable candidates for salvage radiotherapy, Gleason score of prostatectomy, prostate-specific antigen nadir after prostatectomy and positive surgical margin represent independent predictors. Thus, progression-free survival might be more precisely predicted according to the presence/absence of these risk factors. The significance of this risk classification should be confirmed by large prospective studies.

Positional accuracy of novel x-ray-image-based dynamic tumor-tracking irradiation using a gimbaled MV x-ray head of a Vero4DRT (MHI-TM2000).

PURPOSE: To verify the positional accuracy of a novel x-ray-image-based dynamic tumor-tracking (DTT) irradiation technique using the gimbaled MV x-ray head of a Vero4DRT (MHI-TM2000). METHODS: Verification of the x-ray-image-based DTT was performed using three components: a three-dimensional moving phantom with a steel ball target, a laser displacement gauge, and an orthogonal kV x-ray imaging subsystem with a gimbaled MV x-ray head and the system controller of the Vero4DRT. The moving phantom was driven based on seven periodic patterns [peak-to-peak amplitude (A): 20-40 mm, breathing period (T): 2-5 s] and 15 patients' aperiodic respiratory patterns (A: 6.5-22.9 mm, T: 1.9-5.8 s). The target position was detected in real time with the orthogonal kV x-ray imaging subsystem using the stereo vision technique. Subsequently, the Vero4DRT predicted the next position of the target, and then the gimbaled MV x-ray head tracked the corresponding orientation of the target. The displacements of the target were measured synchronously using the laser displacement gauge. The difference between the target positions predicted by the Vero4DRT and those measured by the laser displacement gauge was computed as the prediction error (E(P)), and the difference between the target positions tracked by the gimbaled MV x-ray head and predicted target positions was computed as the mechanical error (E(M)). Total tracking system error (E(T)) was defined as the difference between the tracked and measured target positions. RESULTS: The root mean squares (RMSs) of E(P), E(M), and E(T) were up to 0.8, 0.3, and 0.7 mm, respectively, for the periodic patterns. Regarding the aperiodic patterns, the median RMSs of E(P), E(M), and E(T) were 1.2 (range, 0.9-1.8) mm, 0.1 (range, 0.1-0.5) mm, and 1.2 (range, 0.9-1.8) mm, respectively. From the results of principal component analysis, tracking efficiency, defined as the ratio of twice the RMS of E(T) to A, was improved for patients with high respiratory function (R = 0.91; p < 0.01). CONCLUSIONS: The present study demonstrated that the Vero4DRT is capable of high-accuracy x-ray-image-based DTT. E(T) was caused primarily by E(P), and E(M) was negligible. Furthermore, principal component analysis showed that tracking efficiency could be improved with this system, especially for patients with high respiratory function.

Detailed dosimetric evaluation of intensity-modulated radiation therapy plans created for stage C prostate cancer based on a planning protocol.

BACKGROUND: Intensity-modulated radiation therapy (IMRT) has been employed as a precision radiation therapy with higher conformity to the target. Although clinical outcomes have been reported for many investigations, detailed treatment planning results have not been mentioned to date. The aim of this study was to evaluate the dose specifications of our IMRT treatment plans for locally advanced prostate cancer. METHODS: Seventy-seven clinically applied IMRT plans treated between September 2003 and December 2005, in which patients were irradiated with 78 Gy in the prone position, were retrospectively analyzed. Dosimetric data output from dose volume histograms were evaluated in detail. RESULTS: The mean dose ± standard deviation, homogeneity index, and conformity index to the planning target volume (PTV) were 78.3 ± 0.7 Gy (100.4 ± 0.9%), 13.7 ± 3.0, and 0.83 ± 0.04, respectively. For the clinical target volume, the mean dose was 80.3 ± 0.7 Gy (102.9 ± 0.9%).The V40, V60, and V70 Gy of the rectal wall were 58.3 ± 2.8, 29.6 ± 2.7, and 15.2 ± 3.0%, respectively. Planning difficulties were encountered in patients whose bowels were displaced downward, as constraints imposed by the bowel position altered the dose index of the PTV. In many cases, additional bowel optimization parameters were required to satisfy constraints for organs at risk. However, major deviation could be avoided by inverse planning with computer optimization. CONCLUSION: IMRT allowed the creation of acceptable and practical treatment plans for locally advanced prostate cancer. Reports regarding detailed dosimetric evaluations are mandatory for interpreting clinical outcomes in the future.

Long-term outcomes of three-dimensional conformal radiation therapy combined with neoadjuvant hormonal therapy for Japanese patients with T1c-T2N0M0 prostate cancer.

BACKGROUND: The outcomes of three-dimensional conformal radiation therapy (3D-CRT) combined with neoadjuvant hormonal therapy (NAHT) in Japanese patients with T1c-T2N0M0 prostate cancer, with initiation of salvage hormonal therapy (SHT) at a relatively early phase, were analyzed. METHODS: Fifty-nine Japanese patients with T1c-T2N0M0 prostate cancer who received radical 3D-CRT between January 1999 and January 2003 were evaluated. The median age, initial prostate-specific antigen (PSA) level, and duration of NAHT were: 72 years, 9.4 ng/ml, and 6 months, respectively. Seventy Gy was given in 35 fractions confined to the prostate ± seminal vesicles. AHT was not administered after 3D-CRT in any patients. RESULTS: The median follow-up period was 89 months. The median PSA value at the time of initiation of SHT was 4.7 ng/ml (range 0.1-21.6 ng/ml). The overall, disease-specific, PSA failure-free (based on the Phoenix definition), and SHT-free survival rates at 8 years were 82.8% (95% confidence interval [CI] 72.4-93.2), 100%, 62.4% (47.1-77.8), and 82.6% (71.3-94.0), respectively. Only one patient developed grade 3 late toxicity. CONCLUSIONS: The PSA control rates in our series of Japanese patients with stage T1c-T2N0M0 prostate cancer treated with the standard dose of 3D-CRT combined with NAHT seemed at least comparable to those reported from Western countries; as well, the patients had excellent outcomes. The present outcomes can be used as basic data for evaluating the impact of dose escalation with intensity-modulated radiation therapy for Japanese patients with prostate cancer in the future.

Highly hypofractionated intensity-modulated radiation therapy for nonmetastatic prostate cancer with a simultaneous integrated boost to intraprostatic lesions: a planning study.

PURPOSE: The purpose of this planning study was to develop an acceptable technique for highly hypofractionated intensity-modulated radiation therapy using simultaneous integrated boost technique (SIB-hHF-RT) for nonmetastatic National Comprehensive Cancer Network high-risk prostate cancer. MATERIALS AND METHODS: We created SIB-hHF-RT plans for 14 nonmetastatic prostate cancer patients with MRI-detectable intraprostatic lesions (IPLs) and without intestines locating close to the seminal vesicle and prostate. We prescribed 57 Gy for IPLs and 54 Gy for the remainder of planning target volume (PTV) in 15 fractions. The IPLs were contoured based on magnetic resonance imaging, and PTV was generated by adding 6-8-mm margins to the clinical target volume. For the dose-volume constraints of organs at risk (OARs), the same constraints as 54 Gy plans were used so as not to increase the toxicity. RESULTS: All created plans fulfilled the dose-volume constraints of all targets and OARs. The median estimated beam-on time was 108.5 s. For patient-specific quality assurance, the global gamma passing rates (3%/2 mm) with 10% dose threshold criteria were greater than 93% in all cases and greater than 95% in 11 cases. CONCLUSION: SIB-hHF-RT plans were developed that fulfill the acceptable dose-volume constraints and pass patient-specific quality assurance. We believe these plans can be applied to selected patients with nonmetastatic prostate cancer.