Comparison of sexual function after robot-assisted radical prostatectomy and carbon-ion radiotherapy for Japanese prostate cancer patients using propensity score matching.

BACKGROUND: The quality of life of patients is an important consideration when selecting treatments for localized prostate cancer (PCa). We retrospectively compared sexual function after robot-assisted radical prostatectomy (RARP) and carbon-ion radiotherapy (CIRT) using propensity score matching. METHODS: In total, 127 Japanese PCa patients treated with RARP and 190 treated with CIRT monotherapy were evaluated. We evaluated the Expanded Prostate Cancer Index Composite (EPIC) score before treatment and 12 and 24 months after treatment. After propensity score matching, data from 101 patients from each group were analyzed. The study protocol was approved by the Institutional Review Board of Gunma University Hospital (no. IRB2020-050, 1839). RESULTS: After propensity score matching, the mean EPIC sexual function summary scores in the RARP and CIRT groups were 46.4 and 48.2, respectively. At 12 and 24 months after treatment, these scores were 27.9 (39.9% decrease) and 28.2 (39.2% decrease) in the RARP group and 41.4 (14.1% decrease) and 41.6 (13.7% decrease) in the CIRT group, respectively. Both groups demonstrated significantly decreased scores after 12 and 24 months of treatment compared to before treatment (all p < 0.05). At 12 and 24 months, the sexual function summary score was significantly higher in the CIRT group than in the RARP group (p < 0.001). CONCLUSIONS: There was a smaller decrease in the EPIC sexual function score in the CIRT group than in the RARP group. These results provide useful information for treatment decision-making of Japanese PCa patients.

Radiotherapy for ductal carcinoma of the prostate: an analysis based on the Japanese radiation oncology study group survey.

BACKGROUND: The clinical characteristics of prostate ductal carcinoma is still unclear, and treatment strategy has not yet been established due to its rarity. Therefore, we conducted a multicenter survey of radiation therapy for prostate ductal carcinoma in Japan. METHOD: Data of patients with ductal carcinoma of the prostate treated with radiation therapy between 1996 and 2018 were extracted from the database of each facility. RESULTS: Fifty-two treatment records of 41 patients were collected from nine institutions. The treatment purpose and situations were varied curative intent to palliation. Twenty-eight patients received curative treatments. The median follow-up period of these patients was 68 months. Androgen deprivation therapy was combined with radiation therapy in 26 cases (93%). X-ray and particle irradiation was used. Radiation dose range was 63-78 Gy; 5-year overall survival, progression-free survival and biochemical relapse-free survival were 87.0, 79.3 and 79.3%, respectively. One patient experienced Grade 3 radiation proctitis and one experienced Grade 3 radiation cystitis. There were no Grade 4 or worse adverse events. CONCLUSION: Most patient received similar treatment with adenocarcinoma of prostate, and the clinical results were compatible. For more reliable evidence, further studies are required.

Survey of malignant pleural mesothelioma treatment in Japan: Patterns of practice and clinical outcomes in tomotherapy facilities.

We conducted a nationwide survey of tomotherapy for malignant pleural mesothelioma (MPM) in Japan. Fifty-six facilities were surveyed and data on 31 patients treated curatively between 2008 and 2017 were collected from 14 facilities. Twenty patients received hemithorax irradiation after extrapleural pneumonectomy (EPP) (first group). Five patients received irradiation without EPP (second group), while six received salvage radiotherapy for local recurrence (salvage group). Among the seven patients not undergoing EPP, five (four in the second group and one in the salvage group) were treated with lung sparing pleural irradiation (LSPI) and two with irradiation to visible tumors. Two-year overall survival (OS) rates in the first and second groups were 33% and 60%, respectively (median, 13 vs 30 months, P = 0.82). In the first and second groups, 2-year local control (LC) rates were 53 and 67%, respectively (P = 0.54) and 2-year progression-free survival (PFS) rates were 16% and 60%, respectively (P = 0.07). Distant metastases occurred in 15 patients in the first group and three in the second group. In the salvage group, the median OS was 18 months. Recurrence was observed in the irradiated volume in four patients. The contralateral lung dose was higher in LSPI than in hemithorax irradiation plans (mean, 11.0 ± 2.2 vs 6.1 ± 3.1 Gy, P = 0.002). Grade 3 or 5 lung toxicity was observed in two patients receiving EPP and hemithorax irradiation, but not in those undergoing LSPI. In conclusion, outcomes of EPP and hemithorax irradiation were not satisfactory, whereas LSPI appeared promising and encouraging.

Radiotherapy Patterns of Care for Locally-advanced Non-small Cell Lung Cancer in the Pre- and Post-durvalumab Era: A Region-wide Survey in a Japanese Prefecture.

The promising results of the PACIFIC study led to the approval of consolidation durvalumab for coverage by the National Health Insurance (NHI) in 2018 for patients with locally-advanced unresectable non-small cell lung carcinoma (NSCLC) treated with definitive concurrent chemoradiotherapy (CCRT). However, the effect of NHI coverage on the patterns of care for this population remains unclear. Here, we conducted a questionnaire-based survey to determine the patterns of care for patients with stage II-III NSCLC treated with definitive radiotherapy in 2017 (pre-durvalumab era) or in 2019 (post-durvalumab era). Data were obtained from 11 radiotherapy facilities in Gunma prefecture, which has a population of 1.94 million. We identified 80 and 83 patients with stage II-III NSCLC who received definitive radiotherapy in Gunma in 2017 and 2019, respectively. At a given facility, CCRT was the treatment of choice in a significantly greater proportion of patients in 2019 than in 2017 (66% ± 20% vs 51% ± 29%, P = 0.041). Intensity-modulated radiotherapy (IMRT) was more frequent in 2019 than in 2017 (24% vs 1.2%). Carboplatin plus paclitaxel was used for CCRT at higher rate in 2019 than in 2017 (73% vs 44%). Consolidation durvalumab was performed in 73% (40/55) of CCRT-treated patients in 2019, and the treatment was performed for the planned 12 months in 45% (18/40) of patients. These data indicate that NHI coverage of durvalumab might be a possible reason for choosing CCRT in patients with stage II-III NSCLC in the real-world setting.

Intensity-Modulated Radiation Therapy with Simultaneous Integrated Boost for Clinically Node-Positive Prostate Cancer: A Single-Institutional Retrospective Study.

This study aimed to evaluate clinical outcomes and the toxicity of intensity-modulated radiation therapy with simultaneous integrated boost (SIB-IMRT) combined with androgen-deprivation therapy for clinically node-positive (cN1) prostate cancer. We retrospectively analyzed 97 patients with cN1 prostate cancer who received SIB-IMRT between June 2008 and October 2017 at our hospital. The prescribed dosages delivered to the prostate and seminal vesicle, elective node area, and residual lymph nodes were 69, 54, and 60 Gy in 30 fractions, respectively. Kaplan-Meier analysis was used to determine 5-year biochemical relapse-free survival (bRFS), relapse-free survival (RFS), overall survival (OS), and prostate cancer-specific survival (PCSS). Toxicity was evaluated using the Common Terminology Criteria for Adverse Events ver. 4.0. Over a median follow-up duration of 60 months, the 5-year bRFS, RFS, OS, and PCSS were 85.1%, 88.1%, 92.7% and 95.0%, respectively. Acute Grade 2 genito-urinary (GU) and gastro-intestinal (GI) toxicities were observed in 10.2% and 2.1%, respectively, with no grade ≥3 toxicities being detected. The cumulative incidence rates of 5-year Grade ≥2 late GU and GI toxicities were 4.7% and 7.4%, respectively, with no Grade 4 toxicities being detected. SIB-IMRT for cN1 prostate cancer demonstrated favorable 5-year outcomes with low incidences of toxicity.

Long-term outcome of hypofractionated intensity-modulated radiotherapy using TomoTherapy for localized prostate cancer: A retrospective study.

BACKGROUND: Recently, the clinical outcome of prostate cancer treated by hypofractionated radiation therapy has been reported. However, there are few reports from Japan. In Hidaka Hospital, hypofractionated intensity-modulated radiotherapy (HIMRT) for prostate cancer was initiated in 2007. The purpose of this study is to analyze the long-term outcome. METHODS: Ninety-two patients with localized prostate cancer treated with HIMRT at Hidaka Hospital between 2007 and 2009 were retrospectively analyzed. HIMRT was delivered using TomoTherapy. The prescription dose was 66 Gy at 95% of the PTV in 22 fractions performed 3 days a week over 7 weeks in all patients. The overall survival rate, biochemical relapse-free rate, and acute and late toxicities were evaluated. RESULTS: The median follow-up duration was 78 (range 14-100) months. The median age at the start of the HIMRT was 72 (range 46-84) years. The disease characteristics were as follows: stage T1c, 45; T2a, 20; T2b, 5; T2c, 1; T3a, 13; T3b, 6; T4, 2; Gleason score 6, 13; 7, 44; 8, 20; 9, 15; 10, 0; pretreatment PSA ≤10 ng/mL, 42; 10 to ≤20, 27; and >20, 23. According to the D'Amico classification system, 10, 37, and 45 patients were classified as low-risk, intermediate-risk, and high-risk. The overall survival rate, the cause-specific survival rate, and the biochemical relapse-free rate at 5 years was 94.7%, 100% and 98.9%, respectively. Severe acute toxicity (grade 3 or more) was not observed. The late urinary toxicity was 52.2% in grade 0, 28.3% in grade 1, 19.6% in grade 2, and 2.2% in grade 3. The late rectal toxicity was 78.3% in grade 0, 7.6% in grade 1, 9.8% in grade 2, and 4.3% in grade 3. CONCLUSIONS: The present study demonstrated that HIMRT using TomoTherapy for prostate cancer has a favorable outcome with tolerable toxicity.

SUVmax-based Parameters of FDG-PET/CT Reliably Predict Pathologic Complete Response After Preoperative Hyperthermo-chemoradiotherapy in Rectal Cancer.

BACKGROUND/AIM: To determine the most reliable predictor for pathologic complete response (pCR) in patients who underwent preoperative chemoradiotherapy and regional hyperthermia (HCRT) for rectal cancer. PATIENTS AND METHODS: Thirty-six patients were enrolled. The local control status of the patients was assessed using 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT), magnetic resonance imaging (MRI), and colonoscopy before and after HCRT. The relationships between various parameters of these clinical examinations and pCR were analyzed. RESULTS: Ten (28%) patients achieved pCR. The accuracies of predicting pCR using FDG-PET/CT, MRI, and colonoscopy were 78%, 61%, and 75%, respectively. FDG-PET/CT was the only independent predictive modality for pCR (p=0.021). The maximum standardized uptake value (SUVmax) and SUVmax normalized to liver uptake (SLR) after HCRT showed the highest sensitivity (90%) and the decreasing rate of SUVmax and SLR demonstrated the highest specificity (89%) for pCR. CONCLUSION: SUVmax-based parameters of FDG-PET/CT after HCRT were the most reliable predictors for pCR.

High linear energy transfer carbon-ion irradiation increases the release of the immune mediator high mobility group box 1 from human cancer cells.

Anti-tumor immunity modulates the local effects of radiation therapy. High mobility group box 1 (HMGB1) plays a pivotal role in activating antigen-specific T-cell responses. Here, we examined the relationship between linear energy transfer (LET) and HMGB1 release. We assessed the proportions of KYSE-70, HeLa and SiHa cells surviving after carbon-ion (C-ion) beam irradiation with different LET values, using a clonogenic assay. The D10, the dose at which 10% of cells survived, was calculated using a linear-quadratic model. HMGB1 levels in the culture supernatants of C-ion beam-irradiated tumor cells were assessed by enzyme-linked immunosorbent assay. The D10 doses for 13 keV/µm of C-ion irradiation in KYSE-70, HeLa and SiHa cells were 2.8, 3.9 and 4.1 Gy, respectively, whereas those for 70 keV/µm C-ion irradiation were 1.4, 1.9 and 2.3 Gy, respectively. We found that 70 keV/µm of C-ion irradiation significantly increased HMGB1 levels in the culture supernatants of all cell lines 72 h after irradiation compared with non-irradiated controls. Furthermore, 70 keV/µm of C-ion irradiation significantly increased HMGB1 levels in the culture supernatants of all cell lines 72 h after irradiation compared with 13 keV/µm. The results suggest that HMGB1 release from several cancer cell lines increases with increased LET.

Mice overexpressing latent matrix metalloproteinase-2 develop lung emphysema after short-term exposure to cigarette smoke extract.

Chronic obstructive pulmonary disease is the major growing cause of mortality and morbidity worldwide, and it is going to become the third most common cause of death by 2020. Chronic obstructive pulmonary disease is pathologically characterized by lung emphysema and small airway inflammation. Animal models are very important to get insights into the disease pathogenesis but current models of chronic obstructive pulmonary disease take a long time to develop. The need of a new model is compelling. In the present study we focus on the role of matrix metalloproteinases in the pathogenesis of chronic obstructive pulmonary disease and hypothesized that lung overexpression of latent matrix metalloproteinases-2 would allow the development of emphysema after short-term exposure to cigarette smoke extract inhalation. Human latent matrix metalloproteinases-2 transgenic mouse expressing high level of the protein in the lungs and wild type mouse were exposed to aerosolized cigarette smoke extract for two weeks. Transgenic mice showed significant lung emphysematous changes, increased infiltration of inflammatory cells and enhanced lung concentrations of inflammatory cytokines in the lungs compared to their wild type counterparts after inhalation of cigarette smoke extract. This novel mouse model will be a very useful tool for evaluating the mechanistic pathways and for development of novel therapies in cigarette smoke-associated lung emphysema.

The Impact of the Grid Size on TomoTherapy for Prostate Cancer.

Discretization errors due to the digitization of computed tomography images and the calculation grid are a significant issue in radiation therapy. Such errors have been quantitatively reported for a fixed multifield intensity-modulated radiation therapy using traditional linear accelerators. The aim of this study is to quantify the influence of the calculation grid size on the dose distribution in TomoTherapy. This study used ten treatment plans for prostate cancer. The final dose calculation was performed with "fine" (2.73 mm) and "normal" (5.46 mm) grid sizes. The dose distributions were compared from different points of view: the dose-volume histogram (DVH) parameters for planning target volume (PTV) and organ at risk (OAR), the various indices, and dose differences. The DVH parameters were used Dmax, D2%, D2cc, Dmean, D95%, D98%, and Dmin for PTV and Dmax, D2%, and D2cc for OARs. The various indices used were homogeneity index and equivalent uniform dose for plan evaluation. Almost all of DVH parameters for the "fine" calculations tended to be higher than those for the "normal" calculations. The largest difference of DVH parameters for PTV was Dmax and that for OARs was rectal D2cc. The mean difference of Dmax was 3.5%, and the rectal D2cc was increased up to 6% at the maximum and 2.9% on average. The mean difference of D95% for PTV was the smallest among the differences of the other DVH parameters. For each index, whether there was a significant difference between the two grid sizes was determined through a paired t-test. There were significant differences for most of the indices. The dose difference between the "fine" and "normal" calculations was evaluated. Some points around high-dose regions had differences exceeding 5% of the prescription dose. The influence of the calculation grid size in TomoTherapy is smaller than traditional linear accelerators. However, there was a significant difference. We recommend calculating the final dose using the "fine" grid size.

Radiotherapy for localized gastric mucosa-associated lymphoid tissue lymphoma: long-term outcomes over 10 years.

This study aimed to assess the long-term outcomes of radiotherapy in patients with localized gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Twenty-seven patients with Stage I gastric MALT lymphoma were treated with radiotherapy from 1999 to 2010. The median age was 65 years (range: 31-84). Fifteen patients were Helicobacter pylori-negative. Thirteen patients were treated with definitive radiotherapy alone. The other 14 patients who had refractory or residual disease following a prior treatment received salvage radiotherapy. The median dose of the radiotherapy was 30 Gy in 20 fractions (range: 30-39.5 Gy). The median follow-up period was 121 months (range: 8-176 months). The 5- and 10-year overall survival rates for all patients were 92% and 87%, respectively. No patients died from MALT lymphoma. Three patients died of other diseases at 8, 33 and 74 months after radiotherapy (myocardial infarction, pneumonia and hepatocellular carcinoma, respectively). No cases of local recurrence were observed during the follow-up period. There were no serious late gastric, liver or kidney complications during a median follow-up period of over 10 years. Two patients remain alive with distant metastases: a lung metastasis and an abdominal lymph node metastasis at 104 months and 21 months after radiotherapy, respectively. Excellent long-term local control was observed in patients with localized gastric MALT lymphoma after radiotherapy. However, lifelong follow-up should be conducted to detect cases of late recurrence, especially distant metastases.

Clinical outcomes of helical tomotherapy for super-elderly patients with localized and locally advanced prostate cancer: comparison with patients under 80 years of age.

We investigated the clinical outcomes of helical tomotherapy in 23 patients aged ≥80 years with localized and locally advanced prostate cancer and compared the results with data from 171 patients under 80 years. All patients received helical tomotherapy in our hospital between September 2009 and October 2012. The median follow-up periods were 35 months in the aged group and 34 months in the younger group. The median prescribed dose in helical tomotherapy was 78 Gy in 39 fractions (range, 72-78 Gy). The 3-year overall survival and biochemical relapse-free rates were 92% and 96% in the aged group and 99.4% and 97.3% in the younger group, respectively. There was no significant difference between the two groups in the biochemical relapse-free rates. The 3-year cumulative incidences of late Grade 2 or higher rectal toxicity and urinary toxicity were 13% and 4.8% in the aged group and 7.0% and 1.2% in the younger group, respectively. There was no significant difference between the aged group and the younger group in the cumulative incidence rates of rectal toxicity or urinary toxicity. No patients exhibited Grade 4 or higher toxicity, and all patients improved with conservative therapy. Helical tomotherapy in super-elderly patients with localized and locally advanced prostate cancer had good biochemical control rates without severe late toxicity. Definitive helical tomotherapy may be the treatment of choice for patients with localized and locally advanced prostate cancer, even in those older than 80 years of age.

Thrombomodulin inhibits the activation of eosinophils and mast cells.

Eosinophils and mast cells play critical roles in the pathogenesis of bronchial asthma. Activation of both cells leads to the release of pro-inflammatory mediators in the airway of asthmatic patients. Recently, we have shown that inhaled thrombomodulin inhibits allergic bronchial asthma in a mouse model. In the present study, we hypothesize that thrombomodulin can inhibit the activation of eosinophils and mast cells. The effect of thrombomodulin on the activation and release of inflammatory mediators from eosinophils and mast cells was evaluated. Thrombomodulin inhibited the eotaxin-induced chemotaxis, upregulation of CD11b and degranulation of eosinophils. Treatment with thrombomodulin also significantly suppressed the degranulation and synthesis of inflammatory cytokines and chemokines in eosinophils and mast cells. Mice treated with a low-dose of inhaled thrombomodulin have decreased number of eosinophils and activated mast cells and Th2 cytokines in the lungs compared to untreated mice. The results of this study suggest that thrombomodulin may modulate allergic responses by inhibiting the activation of both eosinophils and mast cells.

Solitary pulmonary nodule of benign metastasizing leiomyoma associated with primary lung cancer: a case report.

INTRODUCTION: Benign metastasizing leiomyoma in the lung is a very rare disease characterized by the growth of uterine leiomyoma tissue. In most cases there is a previous history of hysterectomy for uterine leiomyoma. CASE PRESENTATION: A 50-year-old Asian woman underwent a total abdominal hysterectomy for uterine leiomyoma at the age of 37 years old. She was referred to our hospital because of sudden anterior chest pain. A chest computed tomography scan revealed a ground-glass opacity in her left S10 lung segment and a solitary small nodule in her left bronchial segment, S4. We performed a left lower lobectomy and an upper lung partial resection in order to make a definitive diagnosis and to enable us to determine a further therapeutic strategy. The ground-glass opacity in her left S10 was a primary lung adenocarcinoma, while the small nodule in her left S4 was diagnosed as a benign metastasizing leiomyoma. No additional therapy was done and our patient was followed up with chest computed tomography. Up to date, repetitive evaluation by chest computed tomography has shown no sign of benign metastasizing leiomyoma or lung cancer recurrence. CONCLUSION: This is a very rare case of benign metastasizing leiomyoma of the lung associated with primary lung cancer. This comorbid association should be considered in the differential diagnosis when a solitary lung nodule is detected in a patient with a history of uterine leiomyoma.