Relationship between changes in quality of life and genitourinary toxicity grade after brachytherapy with I-125 alone for localised prostate cancer.

Background: The relationship between the grading of toxicities based on toxicity criteria and longitudinal changes in quality of life (QOL) scores after permanent prostate brachytherapy (PPB) for localized prostate cancer remains unclear. This study aimed to evaluate these relationships. Materials and methods: We assessed 107 patients treated with PPB using Iodine-125 alone from May 2007 to April 2010. Disease-specific QOL scores before PPB and at 1, 3, 6, 12, and 24 months after PPB were retrospectively evaluated with the Expanded Prostate Cancer Index Composite (EPIC), focusing on urinary domains. Toxicities were graded using the Radiation therapy oncology group and the European organization for research and treatment of cancer toxicity criteria. Results: The median follow-up duration was 116 (range 18-148) months. Thirty-four patients (31.8%) developed grade ≥ 2 acute genitourinary (GU) toxicities; six (5.6%) developed grade ≥ 2 late GU toxicities. The general urinary domain score dropped significantly at 1 month (77.1 ± 14.1) post-PPB compared to the baseline score (92.2 ± 8.2), and then gradually returned to the baseline level by 12 months (93.7 ± 8.3) post-PPB. Reductions in the general urinary domain scores, including its subscale scores at 1, 3, and 6-months post-PPB were significantly greater among patients with grade ≥ 2 GU toxicity than among those with grade 0-1 GU toxicity. Changes in urinary domain scores demonstrated a close relationship with acute GU toxicity grades after PPB. Conclusions: Longitudinal assessments of the EPIC QOL scores provided additional information regarding time-course changes in GU toxicities after PPB.

Risk of secondary malignancy after radiotherapy for breast cancer: long-term follow-up of Japanese patients with breast cancer.

PURPOSE: There have been very few reports of secondary malignancies after breast cancer treatment in Asia, particularly in Japan. This study aimed to evaluate the risk of secondary malignancies after radiotherapy (RT) in Japanese breast cancer patients. METHODS: This single-center retrospective study included patients who underwent RT between July 1961 and September 2006 for postoperative breast cancer. A total of 702 patients with a follow-up period of more than 5 years were analyzed. All malignancies observed at more than 5 years after the start of RT were defined as secondary malignancies. To calculate the relative risk (RR) of secondary malignancies, we applied data from the National Cancer Center in Japan. RESULTS: The median observation period was 9.7 (interquartile range 7.1-18.2) years. The cumulative person-years of observation were 6879.4. The RR of contralateral breast cancer increased by 1.85-fold (95% confidence interval [CI] 1.05-3.26) among patients compared with that among the general population; however, the difference was not significant (p = 0.053). The RR of secondary malignancies other than breast cancer increased by 2.71-fold (95% CI 1.99-3.70, p < 0.001) among the patients compared with the general population. Even when only malignancies detected more than 10 years after RT were defined as secondary malignancies, the RR of secondary malignancies other than breast cancer was 1.91 (95% CI 1.33-2.73, p < 0.001). CONCLUSION: The incidence of secondary malignancies after RT may be somewhat higher in Japanese patients with breast cancer than in the general population.

Metabolic characterization of aggressive breast cancer cells exhibiting invasive phenotype: impact of non-cytotoxic doses of 2-DG on diminishing invasiveness.

BACKGROUND: Metabolic reprogramming is being recognized as a fundamental hallmark of cancer, and efforts to identify drugs that can target cancer metabolism are underway. In this study, we used human breast cancer (BC) cell lines and established their invading phenotype (INV) collected from transwell inserts to compare metabolome differences and evaluate prognostic significance of the metabolome in aggressive BC invasiveness. METHODS: The invasiveness of seven human BC cell lines were compared using the transwell invasion assay. Among these, INV was collected from SUM149, which exhibited the highest invasiveness. Levels of metabolites in INV were compared with those of whole cultured SUM149 cells (WCC) using CE-TOFMS. The impact of glycolysis in INV was determined by glucose uptake assay using fluorescent derivative of glucose (2-NBDG), and significance of glycolysis, or tricarboxylic acid cycle (TCA) and electron transport chain (ETC) in the invasive process were further determined in aggressive BC cell lines, SUM149, MDA-MB-231, HCC1937, using invasion assays in the presence or absence of inhibitors of glycolysis, TCA cycle or ETC. RESULTS: SUM149 INV sub-population exhibited a persistent hyperinvasive phenotype. INV were hyper-glycolytic with increased glucose (2-NBDG) uptake; diminished glucose-6-phosphate (G6P) levels but elevated pyruvate and lactate, along with higher expression of phosphorylated-pyruvate dehydrogenase (pPDH) compared to WCC. Notably, inhibiting of glycolysis with lower doses of 2-DG (1 mM), non-cytotoxic to MDA-MB-231 and HCC1937, was effective in diminishing invasiveness of aggressive BC cell lines. In contrast, 3-Nitropropionic acid (3-NA), an inhibitor of succinate dehydrogenase, the enzyme that oxidizes succinate to fumarate in TCA cycle, and functions as complex II of ETC, had no significant effect on their invasiveness, although levels of TCA metabolites or detection of mitochondrial membrane potential with JC-1 staining, indicated that INV cells originally had functional TCA cycles and membrane potential. CONCLUSIONS: Hyper-glycolytic phenotype of invading cells caters to rapid energy production required for invasion while TCA cycle/ETC cater to cellular energy needs for sustenance in aggressive BC. Lower, non-cytotoxic doses of 2-DG can hamper invasion and can potentially be used as an adjuvant with other anti-cancer therapies without the usual side-effects associated with cytotoxic doses.

The 5-year outcomes of moderately hypofractionated radiotherapy (66 Gy in 22 fractions, 3 fractions per week) for localized prostate cancer: a retrospective study.

BACKGROUND: Hypofractionated radiotherapy using fewer and larger fractional doses may be more beneficial than conventional external-beam radiotherapy for localized prostate cancer. We evaluated the 5-year outcomes of moderately hypofractionated radiotherapy for localized prostate cancer. METHODS: We retrospectively evaluated 195 patients with localized prostate cancer (T1-3N0M0) who underwent intensity-modulated radiotherapy (IMRT) (66 Gy delivered in fractions of 3 Gy every other weekday) between May 2005 and December 2011. Patients received androgen deprivation therapy depending on the perceived intermediate or high risk of their disease. A prostate-specific antigen nadir +2.0 ng/ml indicated biochemical failure. We assessed toxicity using the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer (RTOG/EORTC) criteria, and patient-reported outcomes using the Expanded Prostate Cancer Index Composite (EPIC). RESULTS: The risk classifications (proportion) were low risk (13.8%), intermediate risk (35.9%), and high risk (50.3%). The median follow-up was 69 months. Thirteen (6.66%) patients experienced biochemical failure within a median of 40 months (interquartile range, 25-72 months). The 5-year overall survival rate and no biological evidence of disease rate were 97.7% and 92.4%, respectively. Based on the RTOG/EORTC criteria, no patient experienced acute or late toxicity of grade 3 or higher. The EPIC scores revealed significant differences in the average value of all domains (p < 0.01). At 1 month postradiotherapy completion, the general urinary and bowel domain scores had decreased, but these scores returned to baseline level by 3 months post radiotherapy. CONCLUSIONS: The moderately hypofractionated radiotherapy protocol yielded short-term satisfactory clinical outcomes with acceptable toxicity.

Intensity-modulated radiation therapy for small cell carcinoma of the prostate: A case report.

Small cell carcinomas (SCC) make up only 1% of malignancies of the prostate. Reports of several case series have described outcomes of surgery and chemotherapy for SCC of the prostate, but few reports address radiotherapy. We treated a case of SCC of the prostate with intensity-modulated radiation therapy (IMRT) consisting of 70 Gy administered in 35 fractions followed by hormonal therapy using only luteinizing hormone-releasing hormone (LH-RH) agonist. The tumor volume decreased remarkably by 4 months after IMRT. The rapid decrease in tumor size of this SCC of the prostate seemed to suggest a similar high radiosensitivity to that of SCC of the lung, but the tumor increased rapidly thereafter within the radiation fields, and pelvic lymph node metastases had developed by 24 months after IMRT. By 28 months after IMRT, multiple lung metastases developed, and the patient died of SCC of the prostate 31 months after initial diagnosis.

The prognostic value of rectal invasion for stage IVA uterine cervical cancer treated with radiation therapy.

BACKGROUND: The prognostic value of rectal invasion is still unclear in stage IVA cervical cancer. The objective of this study is to evaluate patient outcome and prognostic factors in stage IVA cervical cancer treated with radiation therapy. METHODS: A retrospective review of the medical records of patients treated with definitive photon radiation therapy for pathologically proven stage IVA cervical cancer between 1980 and 2010 was performed. Eligible patients for the present study were diagnosed with clinical stage IVA cervical cancer by cystoscopy or/and proctoscopy, and they received definitive radiation therapy consisting of a combination of external beam radiotherapy and high-dose-rate brachytherapy. All patients underwent CT scans of the abdomen and pelvis. RESULTS: Among the 67 stage IVA patients studied, 53 patients were stage IVA on the basis of bladder invasion, 7 according to rectal mucosal invasion, and 7 because of both bladder and rectal mucosal invasion. Median follow-up of all patients and surviving patients was 19 months (range, 2-235 months) and 114 months (range, 14-223 months), respectively. The 5-year local control (LC), disease-free survival (DFS), and overall survival (OS) rate were 55, 17, and 24%, respectively. Rectal invasion had significant impact on DFS, but bladder invasion had the opposite effect (p = 0.00006 and 0.005, respectively). There were significant differences of LC, DFS and OS rates between patients with and without rectal invasion (p = 0.006, 0.00006 and 0.05, respectively). CONCLUSIONS: Patients with stage IVA cervical cancer had poor prognosis, with 5-year survival of only 24%. Furthermore, in stage IVA, rectal invasion might be a worse prognostic factor than bladder invasion.

Carbon ion beam combined with cisplatin effectively disrupts triple negative breast cancer stem-like cells in vitro.

AIMS: Although a relatively small proportion of all breast cancer (BC), triple negative (TN) BC is responsible for a relatively large proportion of BC deaths because of its worse clinical outcome. To investigate whether a carbon ion beam alone or in combination with cisplatin (CDDP) has a beneficial effect compared to X-rays, we target triple negative (TN) breast cancer stem-like cells (CSCs). METHODS: Human breast CSCs sorted from MDA-MB-231 and MDA-MB-453 cells were treated with a carbon ion beam or X-ray irradiation alone or in combination with CDDP, and then colony, spheroid and tumor formation assays, RT-PCR Array analysis, and immunofluorescence γH2AX foci assay were performed. RESULTS: The colony, spheroid formation, and tumorigenicity assays confirmed that CD44+/CD24- and ESA+/CD24- cells have CSC properties in MDA-MB-231 and MDA-MB-453 cells, respectively. The proportion of CSCs was more enriched after CDDP combination with either X-ray or carbon ion beam, however carbon ion beam combined with CDDP significantly suppressed colony and spheroid formation and more significantly inhibited cell cycle progression (sub-G1 arrest) compared to X-ray combined with CDDP or carbon ion beam alone. RT-PCR Array analysis showed that carbon ion beam combined with CDDP significantly induced apoptosis-related Cytochrome c, almost completely eliminated expression of the CSC markers CD44 and ESA, and significantly inhibited angiogenesis, and metastasis-related HIF1α and CD26 compared to carbon ion beam alone, X-ray alone, or X-ray combined with CDDP. The immunofluorescence assay showed that not only the number but also the size of γH2AX foci in CSCs were larger 24 h after carbon ion beam combined with CDDP compared to those of X-ray alone and X-ray combined with CDDP. CONCLUSIONS: Carbon ion beam combined with CDDP has superior potential to kill TN breast CSCs with irreparable severe DNA damage and enhanced apoptosis.

Clinical outcomes of carbon ion radiotherapy for locally advanced adenocarcinoma of the uterine cervix in phase 1/2 clinical trial (protocol 9704).

BACKGROUND: This study sought to evaluate the toxicity and efficacy of carbon ion radiotherapy (C-ion RT) for locally advanced adenocarcinoma of the uterine cervix in a phase 1/2 clinical trial. METHODS: The treatment consisted of whole-pelvic irradiation of 36.0 gray equivalents (GyE) in 12 fractions and local boost with dose escalation from 26.4 to 38.4 GyE in 8 fractions. The dose escalation was performed with careful observation of acute normal tissue responses. Total dose to the cervical tumor was 62.4 to 74.4 GyE in 20 fractions. RESULTS: Between April 1998 and February 2010, 58 patients were treated with C-ion RT in this clinical trial. The number of patients with stage IIB, IIIB, and IVA disease were 20, 35, and 3, respectively. Median tumor size was 5.5 cm (range, 3.0-11.8 cm). Twenty-seven patients had pelvic lymph node metastases. The median follow-up period was 38 months. All patients completed the treatment schedule. Grade 2 or higher late toxicity was found in 8 patients: 5 with bladder and 2 with small intestine grade 2 toxicities, and 1 patient had grade 4 rectal complication, which was surgically salvaged. The 5-year local control rate, local control rate including salvage surgery, and overall survival rate in all cases were 54.5%, 68.2%, and 38.1%, respectively. CONCLUSIONS: Dose escalation of C-ion RT for adenocarcinoma of the uterine cervix was accomplished without severe toxicities except in 1 case. Although the number of patients in this study was small, the results support continued investigation and analysis to confirm therapeutic efficacy.

Dose-escalation study of carbon ion radiotherapy for locally advanced squamous cell carcinoma of the uterine cervix (9902).

OBJECTIVE: The authors performed phase I/II clinical trial to evaluate the toxicity and efficacy of carbon ion radiotherapy (C-ion RT) for locally advanced squamous cell carcinoma of the uterine cervix. METHODS: Between April 2000 and January 2006, 22 patients for Protocol 9902 were treated with C-ion RT. The number of patients with stage IIB, IIIB, and IVA diseases was 1, 18, and 3, respectively. All patients had bulky tumors measuring 4.0-12.0 cm (median 6.2 cm). The whole pelvic dose was fixed at 39.0 GyE for 13 fractions, and additional 15.0 GyE for 5 fractions was given to the gross tumor volume (GTV) and surrounding tissues. With regard to local boost, a dose-escalation study was planned for 2 fractions to GTV. Total dose to the cervical tumor was 64.0-72.0 GyE for 20 fractions. RESULTS: All patients completed the scheduled therapy and no patient developed Grade 2 or higher acute toxicity. There was no Grade 3 or higher late complications at each dose. The 5-year overall survival rate and local control rate were 50.0% and 68.2%, respectively. Seven out of the 16 patients who received 64.0-68.0 GyE developed local recurrences, but all patients who received 72.0 GyE maintained local control. CONCLUSIONS: There were no severe acute or late complications in this trial. C-ion RT has the potential to improve the treatment for locally advanced bulky cervical cancer by applying a total dose of 72.0 GyE, with the results lending incentive to further investigations to confirm the therapeutic efficacy.

[Problems after radiation therapy].

The rate of severe late adverse effects has decreased with the highly accurate administration of radiation therapy; however, the total number of patients who suffer from late effects has not decreased because of the increased total number of patients and better survival rates. Late adverse effects, occurring more than a few months after irradiation, include the extension and collapse of capillaries, thickening of the basement membrane, and scarring of tissue due to loss of peripheral vessels. The main causes of these late effects are the loss of stromal cells and vascular injury. This is in contrast to early reactions, which occur mainly due to the reorganization of slow-growing non-stem cell renewal systems such as the lung, kidney, heart, and central nervous system. In addition, the patient's quality of life is impaired if acute reactions such as mouth or skin dryness are not alleviated. Most adverse effects are radiation dose dependent, and the thresholds differ according to the radiosensitivity of each organ. These reactions occur with a latency period of a few months to more than 10 years. Understanding the clinical and pathological status, through discussion with radiation oncologists, is the essential first step. Some of the late effects have no effective treatment, but others can be treated by steroids or hyperbaric oxygen therapy. An appropriate decision is important.

Involved-field radiotherapy in older patients with superficial thoracic esophageal squamous cell carcinoma: long-term outcomes and recurrence patterns.

PURPOSE: An optimal radiotherapy field for superficial esophageal carcinoma is yet to be established. We evaluated the long-term outcomes and recurrence patterns of involved-field radiotherapy (IFRT) in older patients with superficial thoracic esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: Fifty-four patients (49 men and 5 women; mean age, 77 [range: 66-90] years) who underwent IFRT for superficial thoracic ESCC between January 2003 and January 2019 were retrospectively reviewed. Concurrent chemotherapy was administered at the discretion of the attending physician. The primary endpoint was overall survival. The secondary endpoints were progression-free survival and complete response rate. RESULTS: The tumors were localized in the upper, middle, and lower thoracic esophagus in 2, 40, and 12 patients, respectively. All patients underwent IFRT using anteroposterior and anterior-posterior oblique opposed beams (off-cord). The prescribed total doses were 50.4, 59.4-61.2, and 66-70 Gy for 6, 40, and 8 patients, respectively. Concurrent chemotherapy was administered to 33 patients. The median follow-up duration was 57 months. The median overall survival was 115 months. The 5-year overall and progression-free survival rates were 71.7% and 60.1%, respectively. Forty-nine patients had a complete response at one month after IFRT (complete response rate: 90.7%). Twenty patients had recurrence; there were 13 in-field and 7 out-of-field recurrence cases. The radiation-related adverse events were generally mild. Grade 3 late toxicity was observed in one patient. CONCLUSIONS: The efficacy of IFRT was suggested to be comparable to that of standard treatments. Therefore, IFRT can be a promising approach for treating superficial ESCC in older adults, especially those with severe comorbidities.

Changes in Intratumor Blood Flow After Carbon-Ion Radiation Therapy for Early-Stage Breast Cancer.

Purpose: This study aimed to quantify the changes in intratumoral blood flow after carbon-ion radiation therapy (CIRT) for early-stage breast cancer and analyze their clinical significance. Patients and Methods: We included 38 patients with early-stage breast cancer who underwent CIRT. Dynamic imaging was performed using a 3T superconducting magnetic resonance scanner to quantify the washin index (idx), which reflects contrast uptake, and washout idx, which reflects the rate of contrast washout from tumor tissue. The changes in the apparent diffusion coefficient, washin idx, and washout idx were examined before CIRT and at 1 and 3 months after treatment. Clinical factors and imaging features were examined using univariate and receiver operating characteristic curve analyses to identify factors predicting clinical complete response (cCR). Results: The median observation period after CIRT was 51 (range: 12-122) months. During the observation period, 31 of the 38 patients achieved cCR, and 22 achieved cCR within 12 months. Tumor size (P < .001), washin idx (P = .043), and washout idx (P < .001) decreased significantly 1-month after CIRT. In contrast, the apparent diffusion coefficient values (P < .001) increased significantly 1-month after CIRT. Univariate analysis suggested that the washin idx after 1 and 3 months of CIRT was associated with cCR by 12 months post-CIRT (P = .028 and .021, respectively). No other parameters were associated with cCR by 12 months post-CIRT. Furthermore, receiver operating characteristic curve analyses showed that the area under the curve values of washin idx after 1 and 3 months of CIRT was 0.78 (specificity 75%, sensitivity 80%) and 0.73 (specificity 75%, sensitivity 71%), respectively. Conclusion: Tumor changes can be quantified early after CIRT using contrast-enhanced magnetic resonance imaging in patients with breast cancer. Washin idx values 1 and 3 months after CIRT were associated with cCR within 12 months post-CIRT.

Predictors of Adverse Gastrointestinal Events After Stereotactic Body Radiation Therapy for Liver Tumors.

BACKGROUND/AIM: To identify predictors of adverse gastrointestinal (GI) events related to stereotactic body radiation therapy (SBRT) for liver tumors. PATIENTS AND METHODS: We retrospectively analyzed 56 patients who underwent SBRT for liver tumors at our institution between 2016 and 2021. The α/ß ratio of the GI tract (stomach, duodenum, and large intestine) was assumed to be 3 Gy in the Linear-Quadratic model (LQ model). The dose to the GI tract, that is, the biologically effective dose 3 (BED3) was converted to a 2 Gy equivalent dose (Gy2/3=2 Gy equivalent dose, α/ß=3). Using this 2 Gy equivalent dose, predictors of adverse GI events of Grade 2 or higher were investigated. RESULTS: The median observation period was 10 months (0-40 months) and median age was 77 years (range=29-93 years). Forty-three of the 56 patients had hepatocellular carcinoma and the other 13 had metastatic liver tumors. Tumors were irradiated with 30-54 Gy/5-18 fractions of planning target volume D95% prescription (80% isodose). Eight of the 56 patients had Grade 2 or higher adverse GI events. By univariate analysis, GI D1cc, Dmax, V20, V25, V30, and V35 were all significant predictors of Grade 2 or higher adverse GI events. Among these, gastrointestinal V35 was the most significant predictor of Grade 2 or higher adverse GI events. CONCLUSION: For SBRT of liver tumors, GI V35 was the best predictor of Grade 2 or higher adverse GI events.

A long-term survival case of bladder cancer with distant metastases: abscopal effect of brain metastases after stereotactic radiotherapy with immune checkpoint blockade therapy to lung metastases.

Brain metastases from bladder cancer are rare, with a poor prognosis. There is no standard treatment for bladder cancer with brain metastases; thus, palliative therapy is generally provided. We report a case of abscopal effect in a single brain metastasis from bladder cancer in a patient treated with focal stereotactic radiotherapy (total dose = 52 Gy, administered in eight fractions) with immune checkpoint blockade therapy for lung metastases, who achieved long-term disease-free survival (> 4 years). To our knowledge, although there have been some reports on abscopal effects in bladder cancer, there are no previous reports on patients with brain metastases. To date, the brain metastasis, which showed an "abscopal effect," continues to maintain complete regression.

Hyperbaric oxygen therapy for radiation cystitis in patients with prostate cancer: a long-term follow-up study.

OBJECTIVE: To assess the safety and efficacy of hyperbaric oxygen (HBO) for treating radiation cystitis a long-term follow-up study was done in patients with prostate cancer, the second most common malignancy in Japan. PATIENTS AND METHODS: A total of 38 patients at an age of 68 ± 8 years with radiation cystitis following irradiation of prostate cancer were treated with HBO at 2 absolute atmospheric pressures for 90 min daily. The average number of HBO treatment sessions in each patient was 62 ± 12. The follow-up period was 11.6 ± 3.7 years. We evaluated objective and subjective symptoms periodically with special reference to the initiation timing of HBO therapy. RESULTS: High efficacy ratios of objective and subjective findings were obtained at 2 and 4 (79-95%) years, respectively. After 7 years' follow-up, these ratios decreased slightly (72-83%) but still remained stable thereafter (75-88%) without any serious accident. Comparison of late morbidity scores before and 11.6 years after HBO therapy showed significant improvement (p < 0.0005). Twenty-eight patients (74%) obtained nonrecurrent outcome. They had received 18% lower (p < 0.001) radiation dosage than recurrent patients. The interval between the onset of hematuria and start of HBO treatment in nonrecurrent patients was 30% shorter (p < 0.001) than that of recurrent patients. CONCLUSIONS: We elucidated the long-term safety and beneficial effect of HBO therapy of radiation cystitis in patients with prostate cancer. Early application of HBO treatment after the onset of hematuria appears to produce favorable outcome.

Combining Carbon-Ion Irradiation and PARP Inhibitor, Olaparib Efficiently Kills BRCA1-Mutated Triple-Negative Breast Cancer Cells.

Background: Triple-negative breast cancer (TNBC) exhibits poor prognosis due to the lack of targets for hormonal or antibody-based therapies, thereby leading to limited success in the treatment of this cancer subtype. Poly (ADP-ribose) polymerase 1 (PARP1) is a critical factor for DNA repair, and using PARP inhibitor (PARPi) is one of the promising treatments for BRCA-mutated (BRCA mut) tumors where homologous recombination repair is impaired due to BRCA1 mutation. Carbon ion (C-ion) radiotherapy effectively induces DNA damages in cancer cells. Thus, the combination of C-ion radiation with PARPi would be an attractive treatment for BRCA mut TNBC, wherein DNA repair systems can be severely impaired on account of the BRCA mutation. Till date, the effectiveness of C-ion radiation with PARPi in BRCA mut TNBC cell killing remains unknown. Purpose: Triple-negative breast cancer cell lines carrying either wild type BRCA1, BRCA wt, (MDA-MB-231), or the BRCA1 mutation (HCC1937) were used, and the effectiveness of PARPi, olaparib, combined with C-ion beam or the conventional radiation, or X-ray, on TNBC cell killing were investigated. Methods: First, effective concentrations of olaparib for BRCA mut (HCC1937) cell killing were identified. Using these concentrations of olaparib, we then investigated their radio-sensitizing effects by examining the surviving fraction of MDA-MB-231 and HCC1937 upon X-ray or C-ion irradiation. In addition, the number of γH2AX (DSB marker) positive cells as well as their expression levels were determined by immunohistochemistry, and results were compared between X-ray irradiated or C-ion irradiated cells. Furthermore, PARP activities in these cells were also observed by performing immunohistochemistry staining for poly (ADP-ribose) polymer (marker for PARP activity), and their expression differences were determined. Results: Treatment of cells with 25 nM olaparib enhanced radio-sensitivity of X-ray irradiated HCC1937, whereas lower dose (5 nM) olaparib showed drastic effects on increasing radio-sensitivity of C-ion irradiated HCC1937. Similar effect was not observed in MDA-MB-231, not possessing the BRCA1 mutation. Results of immunohistochemistry showed that X-ray or C-ion irradiation induced similar number of γH2AX-positive HCC1937 cells, but these induction levels were higher in C-ion irradiated HCC1937 with increased PARP activity compared to that of X-ray irradiated HCC1937. Elevated induction of DSB in C-ion irradiated HCC937 may fully activate DSB repair pathways leading to downstream activation of PARP, subsequently enhancing the effectiveness of PARPi, olaparib, with lower doses of olaparib exerting noticeable effects in cell killing of C-ion irradiated HCC1937. Conclusions: From this study, we demonstrate that C-ion irradiation can exert significant DSB in BRCA mut TNBC, HCC1937, with high PARP activation. Thus, PARPi, olaparib, would be a promising candidate as a radio-sensitizer for BRCA mut TNBC treatment, especially for C-ion radiotherapy.

Secondary cancers after carbon-ion radiotherapy and photon beam radiotherapy for uterine cervical cancer: A comparative study.

BACKGROUND: There are limited studies on the risk of secondary cancers after carbon-ion radiotherapy (CIRT). We assessed the incidence of secondary cancers in patients treated with CIRT for cervical cancer. We also evaluated the incidence of secondary cancers in patients who received standard photon radiotherapy (RT) throughout the same period. METHODS: This retrospective study included patients with cervical cancer who underwent curative RT at our hospital. All cancers discovered for the first time after RT were classified as secondary cancers. To compare the risk of secondary cancers among cervical cancer survivors to the general population, standardized incidence ratios (SIRs) were calculated. RESULTS: The analysis included a total of 197 and 417 patients in the CIRT and photon RT groups, respectively. The total person-years during the observation period were 1052.4 in the CIRT group and 2481.5 in the photon RT group. The SIR for all secondary cancers was 1.1 (95% confidence interval [CI], 0.6-2.1) in the CIRT group and 1.4 (95% CI, 1.0-2.1) in the photon RT group. The 10-year cumulative incidence of all secondary cancers was 9.5% (95% CI, 4.0-21.5) in the CIRT group and 9.4% (95% CI, 6.2-14.1) in the photon RT group. The CIRT and photon RT groups were not significantly different in incidence (p = 0.268). CONCLUSIONS: The incidence of secondary cancers after CIRT for cervical cancer was similar to that after photon RT. Validation of our findings after long-term observation is warranted.

[Questionnaire Survey of Japanese Medical Physicists on Working Conditions in 2020].

The questionnaire survey was conducted in 2020 to investigate the working conditions of qualified medical physicists in Japan. We developed a web-based system for administering the questionnaire and surveyed 1,228 qualified medical physicists. The number of received responses was 405. We summarized the results of the survey by job category. The obtained results showed that most of the people working as certified medical physicists met the following conditions: (1) position of healthcare occupation, (2) direct supervisor is a medical doctor or a medical physicist, (3) licensed or passed an examination for a Class I Radiation Protection Supervisor, (4) without the license of professional radiotherapy technologist, (5) master's or doctor's degree, (6) being assigned to the section that is different from the radiological technologist section. The average annual salary was approximately 600,000 yen higher for those employed as medical physicists than for those employed as radiotherapy technologists. The percentage of work performed by a certified medical physicist in radiation therapy greatly varies depending on whether the physicist is dedicated to treatment planning and equipment quality control. Alternatively, the proportion of the true duties of medical physicists in charge of radiation therapy, as considered by qualified medical physicists in radiation therapy, was the same regardless of whether they were working full-time or not. The results of this survey updated the working status of certified medical physicists in Japan. We will continue to conduct the survey periodically and update the information to contribute to the improvement of the working conditions of medical physicists and policy recommendations.

Measurement of biological washout rates depending on tumor vascular status in15O in-beam rat-PET.

Objective.The biological washout of positron emitters should be modeled and corrected in order to achieve quantitative dose range verification in charged particle therapy based on positron emission tomography (PET). This biological washout effect is affected by physiological environmental conditions such as blood perfusion and metabolism, but the correlation to tumour pathology has not been studied yet.Approach.The aim of this study was to investigate the dependence of the biological washout rate on tumour vascular status in rat irradiation. Two types of tumour vascularity conditions, perfused and hypoxic, were modelled with nude rats. The rats were irradiated by a radioactive15O ion beam and time activity curves were acquired by dynamic in-beam PET measurement. Tumour tissue sections were obtained to observe the histology as well. The biological washout rate was derived using a single-compartment model with two decay components (medium decay,k2mand slow decay,k2s).Main results.Allk2mvalues in the vascular perfused tumour tissue were higher than the values of the normal tissue. Allk2mvalues in the hypoxic tumour tissue were much lower than the values of the vascular perfused tumour tissue and slightly lower than the values of the normal tissue.Significance.The dependency of the biological washout on the tumour vasculature conditions was experimentally shown.

Plastic scintillation dosimeter with a conical mirror for measuring 3D dose distribution.

PURPOSE: To test the measurement technique of the three-dimensional (3D) dose distribution measured image by capturing the scintillation light generated using a plastic scintillator and a scintillating screen. METHODS: Our imaging system constituted a column shaped plastic scintillator covered by a Gd2 O2 S:Tb scintillating screen, a conical mirror and a cooled CCD camera. The scintillator was irradiated with 6 MV photon beams. Meanwhile, the irradiated plan was prepared for the static field plans, two-field plan (2F plan) and the conformal arc plan (CA plan). The 2F plan contained 16 mm2 and 10 mm2 fields irradiated from gantry angles of 0° and 25°, respectively. The gantry was rotated counterclockwise from 45° to 315° for the CA plan. The field size was then obtained as 10 mm2 . A Monte Carlo simulation was performed in the experimental geometry to obtain the calculated 3D dose distribution as the reference data. Dose response was acquired by comparing between the reference and the measurement. The dose rate dependence was verified by irradiating the same MU value at different dose rates ranging from 100 to 600 MU/min. Deconvolution processing was applied to the measured images for the correction of light blurring. The measured 3D dose distribution was reconstructed from each measured image. Gamma analysis was performed to these 3D dose distributions. The gamma criteria were 3% for the dose difference, 2 mm for the distance-to-agreement and 10% for the threshold. RESULTS: Dose response for the scintillation light was linear. The variation in the light intensity for the dose rate ranging from 100 to 600 MU/min was less than 0.5%, while our system presents dose rate independence. For the 3D dose measurement, blurring of light through deconvolution processing worked well. The 3D gamma passing rate (3D GPR) for the 10 × 10 mm2 , 16 × 16 mm2 , and 20 × 20 mm2 fields were observed to be 99.3%, 98.8%, and 97.8%, respectively. Reproducibility of measurement was verified. The 3D GPR results for the 2F plan and the CA plan were 99.7% and 100%, respectively. CONCLUSIONS: We developed a plastic scintillation dosimeter and demonstrated that our system concept can act as a suitable technique for measuring the 3D dose distribution from the gamma results. In the future, we will attempt to measure the 4D dose distribution for clinical volumetric modulated arc radiation therapy (VMAT)-SBRTplans.