Comparing different boost concepts and beam configurations for proton therapy of pancreatic cancer.

Background and Purpose: Interfractional geometrical and anatomical variations impact the accuracy of proton therapy for pancreatic cancer. This study investigated field-in-field (FIF) and simultaneous integrated boost (SIB) concepts for scanned proton therapy treatment with different beam configurations. Materials and Methods: Robustly optimized treatment plans for fifteen patients were generated using FIF and SIB techniques with two, three, and four beams. The prescribed dose in 20 fractions was 60 Gy(RBE) for the internal gross tumor volume (IGTV) and 46 Gy(RBE) for the internal clinical target volume. Verification computed tomography (vCT) scans was performed on treatment days 1, 7, and 16. Initial treatment plans were recalculated on the rigidly registered vCTs. V100% and D95% for targets and D2cm3 for the stomach and duodenum were evaluated. Robustness evaluations (range uncertainty of 3.5 %) were performed to evaluate the stomach and duodenum dose-volume parameters. Results: For all techniques, IGTV V100% and D95% decreased significantly when recalculating the dose on vCTs (p < 0.001). The median IGTV V100% and D95% over all vCTs ranged from 74.2 % to 90.2 % and 58.8 Gy(RBE) to 59.4 Gy(RBE), respectively. The FIF with two and three beams, and SIB with two beams maintained the highest IGTV V100% and D95%. In robustness evaluations, the ΔD2cm3 of stomach was highest in two beams plans, while the ΔD2cm3 of duodenum was highest in four beams plans, for both concepts. Conclusion: Target coverage decreased when recalculating on CTs at different time for both concepts. The FIF with three beams maintained the highest IGTV coverage while sparing normal organs the most.

Simultaneous boost radiotherapy versus conventional dose radiotherapy for patients with newly diagnosed glioblastoma: a multi-institutional analysis.

We compared survival outcomes of high-dose concomitant boost radiotherapy (HDCBRT) and conventional dose radiotherapy (CRT) for newly diagnosed glioblastoma (GB). Patients treated with intensity-modulated radiation therapy for newly diagnosed GB were included. In HDCBRT, specific targets received 69, 60, and 51 Gy in 30 fractions, while 60 Gy in 30 fractions was administered with a standard radiotherapy method in CRT. Overall survival (OS) and progression-free survival (PFS) were compared using the Log-rank test, followed by multivariate Cox analysis. The inverse probability of treatment weighting (IPTW) method was also applied to each analysis. Among 102 eligible patients, 45 received HDCBRT and 57 received CRT. With a median follow-up of 16 months, the median survival times of OS and PFS were 21 and 9 months, respectively. No significant differences were observed in OS or PFS in the Kaplan-Meier analyses. In the multivariate analysis, HDCBRT correlated with improved OS (hazard ratio, 0.49; 95% confidence interval, 0.27-0.90; P = 0.021), and this result remained consistent after IPTW adjustments (P = 0.028). Conversely, dose suppression due to the proximity of normal tissues and IMRT field correlated with worse OS and PFS (P = 0.008 and 0.049, respectively). A prospective study with a stricter protocol is warranted to validate the efficacy of HDCBRT for GB.

Late genitourinary toxicity in salvage radiotherapy for prostate cancer after radical prostatectomy: impact of daily fraction doses.

OBJECTIVE: To evaluate the impact of daily fraction doses on late genitourinary (GU) toxicity after salvage radiotherapy (SRT) for prostate cancer. METHODS: This multi-institutional retrospective study included 212 patients who underwent SRT between 2008 and 2018. All patients received image-guided intensity-modulated SRT at a median dose of 67.2 Gy in 1.8-2.3 Gy/fraction. The cumulative rates of late grade ≥2 GU and gastrointestinal (GI) toxicities were compared using Gray test, stratified by the ≤2.0 Gy/fraction (n = 137) and ≥2.1 Gy/fraction groups (n = 75), followed by multivariate analyses. The total dose was represented as an equivalent dose in 2-Gy fractions (EQD2) with α/ß = 3 Gy. RESULTS: After a median follow-up of 63 months, the cumulative rates of 5-year late grade ≥2 GU and GI toxicities were 14% and 2.5%, respectively. The cumulative rates of 5-year late grade ≥2 GU toxicity in the ≥2.1 Gy/fraction and ≤2.0 Gy/fraction groups were 22% and 10%, respectively (P = .020). In the multivariate analysis, ≥2.1 Gy/fraction was still associated with an increased risk of late grade ≥2 GU toxicity (hazard ratio, 2.37; 95% confidence interval, 1.12-4.99; P = .023), while the total dose was not significant. CONCLUSION: The present results showed that ≥2.1 Gy/fraction resulted in a higher incidence of late grade ≥2 GU toxicity in SRT. ADVANCES IN KNOWLEDGE: The impact of fraction doses on late GU toxicity after SRT remains unknown. The results suggest that higher fraction doses may increase the risk of late GU toxicity in SRT.

Impact of radiation doses on clinical relapse of biochemically recurrent prostate cancer after prostatectomy.

The relationship between radiation doses and clinical relapse in patients receiving salvage radiotherapy (SRT) for biochemical recurrence (BCR) after radical prostatectomy (RP) remains unclear. We identified 292 eligible patients treated with SRT between 2005 and 2018 at 15 institutions. Clinical relapse-free survival (cRFS) between the ≥ 66 Gy (n = 226) and < 66 Gy groups (n = 66) were compared using the Log-rank test, followed by univariate and multivariate analyses and a subgroup analysis. After a median follow-up of 73 months, 6-year biochemical relapse-free survival, cRFS, cancer-specific survival, and overall survival rates were 58, 92, 98, and 94%, respectively. Six-year cRFS rates in the ≥ 66 Gy and < 66 Gy groups were 94 and 87%, respectively (p = 0.022). The multivariate analysis revealed that Gleason score ≥ 8, seminal vesicle involvement, PSA at BCR after RP ≥ 0.5 ng/ml, and a dose < 66 Gy correlated with clinical relapse (p = 0.015, 0.012, 0.024, and 0.0018, respectively). The subgroup analysis showed the consistent benefit of a dose ≥ 66 Gy in patients across most subgroups. Doses ≥ 66 Gy were found to significantly, albeit borderline, increase the risk of late grade ≥ 2 GU toxicity compared to doses < 66 Gy (14% vs. 3.2%, p = 0.055). This large multi-institutional retrospective study demonstrated that a higher SRT dose (≥ 66 Gy) resulted in superior cRFS.

[Case of Long-Term Response to Radiotherapy for Intramedullary Spinal Cord Metastasis from Ovarian Cancer after Surgery].

Intramedullary spinal cord metastasis(ISCM)often causes spinal cord neuropathy and should be treated as an oncologic emergency. However, it recurs in most cases after treatment, ISCM is a disease with a very unfavorable prognosis. Herein, we report a successfully treated case of ISCM with emergent and high-dose radiotherapy. A 53-year-old woman had difficulty walking without assistance 2 years after surgery for ovarian cancer. She received emergent radiotherapy at a total dose of 50 Gy in 25 fractions. Her neurological symptoms dramatically improved over 3 weeks after radiotherapy. ISCM has been controlled using the imaging tests at 5 years after radiotherapy. We believe that both emergent and high-dose radiotherapy were effective for ISCM.

Symptomatic radiation-induced rib fractures after stereotactic body radiotherapy for early-stage non-small cell lung cancer.

Background and purpose: The present study investigated the relationships between the risk of radiation-induced rib fractures (RIRF) and clinical and dosimetric factors in stereotactic body radiotherapy (SBRT) for early-stage non-small cell lung cancer (NSCLC). We also examined dosimetric parameters associated with symptomatic or asymptomatic RIRF and the dosimetric threshold for symptomatic RIRF. Materials and methods: We reviewed 244 cases of early-stage NSCLC treated with SBRT. Gray's test and the Fine-Gray model were performed to examine the relationships between clinical and dosimetric factors and grade ≥ 2 (i.e., symptomatic) RIRF. The effects of each dose parameter on grade ≥ 1 and ≥ 2 RIRF were assessed with the Fine-Gray model. The t-test was used to compare each dose parameter between the grade 1 and grade ≥ 2 groups. Optimal thresholds were tested using receiver operating characteristic (ROC) curves. Results: With a median follow-up period of 48 months, the 4-year cumulative incidence of grade ≥ 1 and grade ≥ 2 RIRF were 26.4 % and 8.0 %, respectively. Regarding clinical factors, only age was associated with the development of grade ≥ 2 RIRF (p = 0.024). Among dosimetric parameters, only V40Gy significantly differed between the grade 1 and grade ≥ 2 groups (p = 0.015). The ROC curve analysis of grade ≥ 2 RIRF showed that the optimal diagnostic thresholds for D3cc, D4cc, D5cc, and V40Gy were 45.86 Gy (area under the curve [AUC], 0.706), 39.02 Gy (AUC, 0.705), 41.62 Gy (AUC, 0.702), and 3.83 cc (AUC, 0.730), respectively. These results showed that V40Gy ≤ 3.83 cc was the best indicator of grade ≥ 2 RIRF. The 4-year incidence of grade ≥ 2 RIRF in the V40Gy ≤ 3.83 cc vs. > 3.83 cc groups was 1.8 % vs. 14.2 % (p = 0.001). Conclusion: The present results recommend V40Gy ≤ 3.83 cc as the threshold for grade ≥ 2 RIRF in SBRT.

Dosimetric and radiobiological analyses of a de-escalation strategy for elective nodal regions in human papillomavirus-associated oropharyngeal cancer.

Introduction: In this simulation study, we examined the effects of a de-escalation strategy with a reduced dose to subclinical nodal regions in patients with human papillomavirus (HPV)-associated oropharyngeal carcinoma (OPC). Methods: We created two patterns of intensity-modulated radiotherapy for 16 patients with HPV-associated OPC. In the standard and de-escalation plans, the initial field including elective nodal regions received 46 and 30 Gy, followed by 20 and 36 Gy to the cutdown field, respectively. Comparison metrics were set for each organ at risk (OAR). We compared these metric values and the probability of adverse effects based on the normal tissue complication probability (NTCP) model between the two plans. Results: Both plans generally met the dose constraints for the targets and all OAR. Among the comparison metrics, the mean doses to the brain, pharyngeal constrictor muscle, thyroid, and skin and the dose to a 1 % volume of the skin were higher in the standard plan than in the de-escalation plan (P = 0.031, 0.007, < 0.001, < 0.001, and 0.006, respectively). NTCP analyses revealed that the probability of adverse effects in the ipsilateral parotid gland and thyroid was higher in the standard plan than in the de-escalation plan (standard vs. de-escalation plans: ipsilateral parotid gland, 6.4 % vs. 5.0 %, P = 0.016; thyroid, 3.3 % vs. 0.5 %, P < 0.001). Conclusions: A de-escalation strategy with elective nodal regions is a promising treatment to prevent a decline in the quality of life in patients with HPV-associated OPC, particularly xerostomia, dysphagia, and hypothyroidism.

Clinical Outcomes of Radiation Therapy for Angiosarcoma of the Scalp and Face: A Multi-Institutional Observational Study.

Angiosarcoma of the scalp and face (ASF) is a rare, aggressive tumor often treated with multimodal therapy, including radiation therapy (RT). This study assessed RT outcomes for ASF and identified prognostic factors. Data from 68 non-metastatic ASF patients undergoing RT with or without other therapies were analyzed. Median radiation dose was 66 Gy in 33 fractions (interquartile range (IQR) 60-70 Gy in 28-35 fractions). Local control (LC), progression-free survival (PFS), and overall survival (OS) rates were calculated using Kaplan-Meier analysis. Multivariate analyses and adverse event evaluation were conducted. Median patient age was 75 years (IQR 71-80 years), with a median follow-up of 17 months (IQR 11-42 months). One-/three-year LC rates were 57/37%, PFS rates were 44/22%, and OS rates were 81/44%. Multivariate analyses showed that an equivalent dose in a 2 Gy fraction (EQD2) >66 Gy correlated with improved LC (HR 2.35, 95% CI 1.03-5.32, p = 0.041). Combining chemotherapy (HR 2.43, 95% CI 1.08-5.46, p = 0.032) or surgery (HR 2.41, 95% CI 1.03-5.59, p = 0.041) improved PFS. No factors influenced OS. Late grade 3+ toxicities occurred in 1%, with one patient developing a grade 4 skin ulcer. These findings suggest that EQD2 > 66 Gy and combining chemotherapy or surgery can enhance LC or PFS in ASF. Further prospective studies are needed to determine the optimal treatment strategy for this rare malignancy, particularly in elderly patients.

Clinical and dosimetric factors for symptomatic radiation pneumonitis after stereotactic body radiotherapy for early-stage non-small cell lung cancer.

Background and purpose: The present study attempted to identify risk factors for symptomatic radiation pneumonitis (RP) after stereotactic body radiotherapy (SBRT) in patients with early-stage non-small cell lung cancer (NSCLC). Materials and methods: We reviewed 244 patients with early-stage NSCLC treated with SBRT. The primary endpoint was the incidence of grade ≥2 RP. Gray's test was performed to examine the relationship between clinical risk factors and grade ≥2 RP, and the Fine-Gray model was used for a multivariate analysis. The effects of each dose parameter on grade ≥2 RP were evaluated with the Fine-Gray model and optimal thresholds were tested using receiver operating characteristic (ROC) curves. Results: With a median follow-up period of 48 months, the 4-year cumulative incidence of grade ≥2 RP was 15.3%. Gray's test revealed that tumor size, a central tumor, interstitial pneumonia, and the biologically effective dose correlated with RP. In the multivariate analysis, a central tumor and interstitial pneumonia remained significant factors (p < 0.001, p = 0.002). Among dose parameters, the total lung volume (%) receiving at least 8 Gy (V8), V10, V20, and the mean lung dose correlated with RP (p = 0.012, 0.011, 0.022, and 0.014, respectively). The results of the Fine-Gray model and ROC curve analyses showed that V10 >16.7% was the best indicator of symptomatic RP among dose parameters. Conclusion: The present results suggest that a central tumor and interstitial pneumonia are independent risk factors for symptomatic RP and lung V10 ≤16.7% is recommended as the threshold in SBRT.

Intensity-modulated radiation therapy with the central shielding technique for patients with uterine cervical cancer†.

We aimed to examine outcomes and toxicities of intensity-modulated radiation therapy (IMRT) with the central shielding (CS) technique for patients with uterine cervical cancer. This retrospective study included 54 patients with International Federation of Gynecology and Obstetrics IB-IVA cancer. Whole pelvic radiotherapy or extended-field radiotherapy were performed at the dose of 50.4 Gy in 28 fractions with helical tomotherapy (HT). Six patients had para-aortic lymph node metastases. The CS technique with HT was utilized after a total dose of 28.8-41.4 Gy to reduce doses to the rectum and bladder. The prescribed dose of intracavitary brachytherapy was mainly 18-24 Gy in three or four fractions at point A. Concurrent chemotherapy was used for 47 patients (87%). Median follow-up time was 56 months. Seventeen patients (31%) developed recurrence. The recurrence of the cervix was observed in two patients (4%). The 5-year rates of the locoregional control, progression-free survival (PFS) and overall survival were 79, 66 and 82%, respectively. Among several factors evaluated, histological type of adenocarcinoma was only a significantly worse prognostic factor for PFS by multivariate analysis (hazard ratio, 4.9 [95% confidence interval, 1.3-18], P = 0.018). Grade 2 or higher late toxicities were observed in nine patients (17%). Two patients (4%) each had grade 3 proctitis and grade 3 ileus, respectively. No grade 4 toxicity or treatment-related death was observed. The results suggest that IMRT with the CS technique allows a high local control without increasing the risk of complications for cervical cancer patients.

Non-Surgical Definitive Treatment for Operable Breast Cancer: Current Status and Future Prospects.

This article reviews the results of various non-surgical curative treatments for operable breast cancer. Radiotherapy is considered the most important among such treatments, but conventional radiotherapy alone and concurrent chemoradiotherapy do not achieve high cure rates. As a radiosensitization strategy, intratumoral injection of hydrogen peroxide before radiation has been investigated, and high local control rates (75-97%) were reported. The authors treated 45 patients with whole-breast radiotherapy, followed by stereotactic or intensity-modulated radiotherapy boost, with or without a radiosensitization strategy employing either hydrogen peroxide injection or hyperthermia plus oral tegafur-gimeracil-oteracil potassium. Stages were 0-I in 23 patients, II in 19, and III in 3. Clinical and cosmetic outcomes were good, with 5-year overall, progression-free, and local recurrence-free survival rates of 97, 86, and 88%, respectively. Trials of carbon ion radiotherapy are ongoing, with promising interim results. Radiofrequency ablation, focused ultrasound, and other image-guided ablation treatments yielded complete ablation rates of 20-100% (mostly ≥70%), but long-term cure rates remain unclear. In these treatments, combination with radiotherapy seems necessary to treat the extensive intraductal components. Non-surgical treatment of breast cancer is evolving steadily, with radiotherapy playing a major role. In the future, proton therapy with the ultra-high-dose-rate FLASH mode is expected to further improve outcomes.

Comparison of Recurrence Patterns between Adenocarcinoma and Squamous Cell Carcinoma after Stereotactic Body Radiotherapy for Early-Stage Lung Cancer.

We compared recurrence patterns between adenocarcinoma (ADC) and squamous cell carcinoma (SCC) after stereotactic body radiotherapy (SBRT) for early-stage lung cancer. Patients with ADC and SCC histology, who were treated with SBRT for clinical stage IA1-IIA lung cancer at our institution, were included in the analysis. The rates of disease-free survival (DFS), overall survival (OS), local recurrence (LR), lymph node metastasis (LNM), and distant metastasis (DM) were calculated using the Kaplan-Meier method or the cumulative incidence function. Among the 204 patients analyzed, 138 and 66 were in the ADC and SCC groups, respectively. The median follow-up period was 60 months. The five-year DFS and OS rates were 57% vs. 41% and 69% vs. 48% in the ADC and SCC groups, respectively (p = 0.015 and 0.019, respectively). In the multivariate analysis, the histological type was not associated with DFS or OS. Five-year LR, LNM, and DM rates were 10% vs. 24%, 12% vs. 20%, and 25% vs. 27% in the ADC and SCC groups, respectively (p = 0.0067, 0.074, and 0.67, respectively). The multivariate analysis identified the histological type of SCC as an independent factor for LR (hazard ratio, 2.41; 95% confidence interval, 1.21-4.77; p = 0.012). The present results suggest that the risk of LR after SBRT is higher for SCC than for ADC.

Acute genitourinary toxicity of pencil beam scanning proton therapy for localized prostate cancer: utility of the transition zone index and average urinary flow rate in predicting acute urinary retention.

BACKGROUND: The purpose of this study was to evaluate the incidence of acute genitourinary toxicities in patients undergoing pencil beam scanning proton therapy for prostate cancer and investigate predictive factors associated with acute urinary retention. METHODS: A total of 227 patients treated between 2018 and 2021 were divided into the normo-fractionated proton therapy group (n = 107) and the moderately hypo-fractionated proton therapy group (n = 120), with prescribed doses of 76-78 Gy relative biological effectiveness in 38-39 fractions and 60-63 Gy relative biological effectiveness in 20-21 fractions, respectively. Uroflowmetry parameters and the transition zone index were prospectively evaluated. RESULTS: Forty-five patients (42%) in the normo-fractionated proton therapy and 33 (28%) in the moderately hypo-fractionated proton therapy developed acute grade 2 genitourinary toxicities (P = 0.02). The most common acute genitourinary toxicity was acute urinary retention. Thirty-nine patients (36%) treated with normo-fractionated proton therapy and 27 (23%) treated with moderately hypo-fractionated proton therapy developed grade 2 acute urinary retention (P = 0.02). No patients developed grade ≥ 3 toxicity. Univariate analysis showed the transition zone index, prostate volume, international prostate symptom score, voided volume, maximum flow rate and average flow rate were associated with grade 2 acute urinary retention. Multivariate analysis in both groups revealed the transition zone index (P = 0.025 and 0.029) and average flow rate (P = 0.039 and 0.044) were predictors of grade 2 acute urinary retention. CONCLUSIONS: The incidence of acute genitourinary toxicities was lower in the moderately hypo-fractionated proton therapy compared with the normo-fractionated proton therapy. Lower pretreatment average flow rate and a higher transition zone index were useful predictors of grade 2 acute urinary retention.

Optimal timing of a γH2AX analysis to predict cellular lethal damage in cultured tumor cell lines after exposure to diagnostic and therapeutic radiation doses.

Phosphorylated H2AX (γH2AX) is a sensitive biomarker of DNA double-strand breaks (DSBs). To assess the adverse effects of low-dose radiation (<50 mGy), γH2AX levels have typically been measured in human lymphocytes within 30 min of computed tomography (CT) examinations. However, in the presence of DSB repair, it remains unclear whether γH2AX levels within 30 min of irradiation completely reflect biological effects. Therefore, we investigated the optimal timing of a γH2AX analysis to predict the cell-surviving fraction (SF). Three tumor cell lines were irradiated at different X-ray doses (10-4000 mGy), and the relationships between SF and relative γH2AX levels were investigated 15 min and 2, 6, 12 and 24 h after irradiation. Data were analyzed for high-dose (0-4000 mGy) and low-dose (0-500 mGy) ranges. Correlations were observed between SF and the relative number of γH2AX foci/nucleus at 12 h only (R2 = 0.68, P = 0.001 after high doses; R2 = 0.37, P = 0.016 after low doses). The relative intensity of γH2AX correlated with SF 15 min to 12 h after high doses and 2 to 12 h after low doses, with the maximum R2 values being observed 2 h after high doses (R2 = 0.89, P < 0.001) and 12 h after low doses (R2 = 0.65, P < 0.001). Collectively, cellular lethal damage in tumor cells was more accurately estimated with residual DSBs 12 h after low-dose (10-500 mGy) irradiation. These results may contribute to determination of the optimal timing of biodosimetric analyses using γH2AX in future studies.

Daily irradiation versus irradiation at two- to three-day intervals in stereotactic radiotherapy for patients with 1-5 brain metastases: study protocol for a multicenter open-label randomized phase II trial.

BACKGROUND: Radiobiological daily changes within tumors are considered to be quite different between stereotactic radiotherapy (SRT) (e.g., 50 Gy in 4 fractions) and conventional radiotherapy (e.g., 60 Gy in 30 fractions). We aim to assess the optimal interval of irradiation in SRT and compare outcomes of daily irradiation with irradiation at two- to three-day intervals in SRT for patients with one to five brain metastases (BM). METHODS: This study is conducted as a multicenter open-label randomized phase II trial. Patients aged 20 or older with one to five BM, less than 3.0 cm diameter, and Karnofsky Performance Status ≥70 are eligible. A total of 70 eligible patients will be enrolled. After stratifying by the number of BMs (1, 2 vs. 3-5) and diameter of the largest tumor (< 2 cm vs. ≥ 2 cm), we randomly assigned patients (1:1) to receive daily irradiation (Arm 1), or irradiation at two- to three-day intervals (Arm 2). Both arms are performed with total dose of 27-30 Gy in 3 fractions. The primary endpoint is an intracranial local control rate, defined as intracranial local control at initially treated sites. We use a randomized phase II screening design with a two-sided α of 0∙20. The phase II trial is positive with p < 0.20. All analyses are intention to treat. This study is registered with the UMIN-clinical trials registry, number UMIN000048728. DISCUSSION: This study will provide an assessment of the impact of SRT interval on local control, survival, and toxicity for patients with 1-5 BM. The trial is ongoing and is recruiting now. TRIAL REGISTRATION: UMIN000048728. Date of registration: August 23, 2022. https://center6.umin.ac.jp/cgi-bin/ctr/ctr_view_reg.cgi?recptno=R000055515 .

Definitive radiotherapy with stereotactic or IMRT boost with or without radiosensitization strategy for operable breast cancer patients who refuse surgery.

For breast cancer (BC) patients who refused surgery, we developed a definitive treatment employing modern sophisticated radiation techniques. Thirty-eight operable BC patients were treated by conventionally fractionated whole-breast (WB) radiotherapy in combination with stereotactic (for primary tumor) or intensity-modulated (for primary tumor with/without regional lymph nodes [LN]) radiotherapy (IMRT) boost. Standard doses were 50 Gy/25 fractions, 21 Gy/3 fractions and 20 Gy/8 fractions, respectively, for the three radiation modalities. Disease stages were 0 (ductal carcinoma in situ [DCIS]) in seven patients, I in 12, II in 16 and III in three. In 26 patients, intratumoral hydrogen peroxide injection or hyperthermia with oral tegafur-gimeracil-oteracil potassium (S-1) was also used to sensitize the tumors to radiation. Hormonal and standard systemic therapy were administered in 25 and 13 patients, respectively. Complete and partial responses were obtained in 19 patients each; in patients with partial response, no further regrowth of the residual mass was observed, except for two patients who developed local recurrence. During a follow-up of 8-160 months (median, 50 months for living patients), two, one and two patients developed local relapse, sub-clavicular node metastasis and distant metastasis, respectively. The 5-year rates for overall, progression-free and local relapse-free survival were 97.2, 90.9 and 93.4%, respectively. Fourteen patients developed Grade 3 radiation dermatitis but all recovered after treatment. In 47%, the affected breast became better-rounded, and the nipple of the irradiated breast became higher by ≥1 cm than the contralateral nipple. Our method might be a treatment option for operable BC patients.

Maternal and Fetal Pharmacokinetic Analysis of Cannabidiol during Pregnancy in Mice.

Cannabidiol (CBD), a major component of cannabis, has various effects, such as antiemetic and anxiolytic activities, and has recently been marketed as a supplement. The number of people using CBD during pregnancy is increasing, and there are concerns about its effects on the fetus. In addition, the scientific evidence supporting the fetal safety of CBD use during pregnancy is insufficient. To investigate CBD transfer from the mother to the fetus, a single intravenous dose of CBD was administered to pregnant mice in this study, and fetal pharmacokinetics (distribution and elimination) was analyzed. The transfer of CBD from the maternal blood to the fetus was rapid, and the compound accumulated in the fetal brain, liver, and gastrointestinal tract. Conversely, little CBD was transferred from the mother to the amniotic fluid. We analyzed the pharmacokinetics of CBD using a two-compartment model and found that the maternal and fetal half-lives of CBD were approximately 5 and 2 hours, respectively. Furthermore, we performed a moment analysis of the pharmacokinetics of CBD, observing a mean residence time of less than 2 hours in both the mother and fetus. These results suggest that once-daily CBD intake during pregnancy is unlikely to result in CBD accumulation in the mother or fetus. SIGNIFICANCE STATEMENT: CBD is currently marketed as a supplement, and despite its increasing use during pregnancy, little information concerning its fetal effects has been reported. In the present study, CBD was administered to pregnant mice, and the pharmacokinetics in the fetus was investigated using a two-compartment model and moment analysis. The results of these analyses provide important information for estimating the risk to the fetus if CBD is mistakenly consumed during pregnancy.

Anti-degranulating activity in rat basophil leukemia RBL-2H3 cells of flavanone glycosides and their aglycones in citrus fruits.

The anti-degranulating activity of flavonoids present in Citrus fruits was comprehensively evaluated. Among these, hesperetin and naringenin, respectively aglycones of hesperidin and narirutin, showed significant activity. The targets of hesperetin and naringenin were found: hesperetin inhibited phosphorylation of Syk and Akt, while naringenin suppressed the expression of Lyn and inhibited the phosphorylation of Akt. These results suggest that hesperetin and naringenin inhibit degranulation by suppression of pathway signals and reduce the symptoms of allergy by inhibiting phosphorylation of Akt, which leads to the suppression of cytokines. In addition, hesperetin showed inhibitory activity against the degranulation induced by calcium ionophores, indicating that hesperetin exerts its inhibitory activity by stabilizing the membrane structure.