Prognostic analysis of radiation-induced liver damage following carbon-ion radiotherapy for hepatocellular carcinoma.

BACKGROUND: Radiation-induced liver damage (RILD) occasionally occurs following carbon-ion radiotherapy (CIRT) for liver tumors, such as hepatocellular carcinoma (HCC), in patients with impaired liver function disease. However, the associated risk factors remain unknown. The present study aimed to determine the risk factors of RILD after CIRT. METHODS: We retrospectively analyzed 108 patients with HCC treated with CIRT at the Osaka Heavy Ion Therapy Center between December 2018 and December 2022. RILD was defined as a worsening of two or more points in the Child-Pugh score within 12 months following CIRT. The median age of the patients was 76 years (range 47-95 years), and the median tumor diameter was 41 mm (range 5-160 mm). Based on the pretreatment liver function, 98 and 10 patients were categorized as Child-Pugh class A and B, respectively. We analyzed patients who received a radiation dose of 60 Gy (relative biological effectiveness [RBE]) in four fractions. The median follow-up period was 9.7 months (range 2.3-41.1 months), and RILD was observed in 11 patients (10.1%). RESULTS: Multivariate analysis showed that pretreatment Child-Pugh score B (p = 0.003, hazard ratio [HR] = 6.90) and normal liver volume spared from < 30 Gy RBE (VS30 < 739 cm3) (p = 0.009, HR = 5.22) were significant risk factors for RILD. The one-year cumulative incidences of RILD stratified by Child-Pugh class A or B and VS30 < 739 cm3 or ≥ 739 cm3 were 10.3% or 51.8% and 39.6% or 9.2%, respectively. CONCLUSION: In conclusion, the pretreatment Child-Pugh score and VS30 of the liver are significant risk factors for RILD following CIRT for HCC.

Circulating Plasma Exosomal PD-L1 Predicts Prognosis of Head and Neck Squamous Cell Carcinoma After Radiation Therapy.

Purpose: Radiation therapy is widely used to treat head and neck squamous cell carcinoma (HNSCC). This study evaluated the association between circulating plasma programmed death-ligand 1 (PD-L1) and the outcomes of patients with HNSCC after radiation therapy. Methods and Materials: In this retrospective observational study, plasma samples of 76 patients with HNSCC who underwent radiation therapy from June 2019 to August 2021 were analyzed. These plasma samples were obtained before radiation therapy. The median follow-up was 32.5 months. Total and exosomal PD-L1 was measured by enzyme-linked immunosorbent assay and retrospectively analyzed for association with overall survival (OS), progression-free survival (PFS), and local control (LC). Prognostic factors among patients' characteristics and circulating PD-L1 in plasma were evaluated by univariate (log-rank test) and multivariate (Cox proportional hazards model) analyses. Results: The median concentration of total PD-L1 in plasma was 115.1 pg/mL (95% CI, 114.7-137.9 pg/mL), and the median concentration of exosomal PD-L1 was 2.8 pg/mL (95% CI, 6.0-13.0 pg/mL). Univariate and multivariate analyses showed exosomal PD-L1 as a prognostic factor for PFS and LC. Patients with high exosomal PD-L1 in plasma had poor PFS and LC compared with those with low exosomal PD-L1, indicating that 1-year PFS was 79.2% versus 33.3% (P < .001) and 1-year LC was 87.3% versus 50.0% (P < .001) in patients with high and low exosomal PD-L1, respectively. However, exosomal PD-L1 in plasma had no significant effect on OS. Total PD-L1 in plasma did not correlate with PFS, LC, and OS. Conclusions: The pretreatment circulating exosomal PD-L1 in plasma of patients with HNSCC was a prognostic factor after radiation therapy.

Real-World Results of Stereotactic Body Radiotherapy for 399 Medically Operable Patients with Stage I Histology-Proven Non-Small Cell Lung Cancer.

Surgery is the standard treatment for stage I non-small cell lung cancer (NSCLC); however, no clear randomized trial demonstrates its superiority to stereotactic body radiotherapy (SBRT) regarding survival. We aimed to retrospectively evaluate the treatment outcomes of SBRT in operable patients with stage I NSCLC using a large Japanese multi-institutional database to show real-world outcome. Exactly 399 patients (median age 75 years; 262 males and 137 females) with stage I (IA 292, IB 107) histologically proven NSCLC (adenocarcinoma 267, squamous cell carcinoma 96, others 36) treated at 20 institutions were reviewed. SBRT was prescribed at a total dose of 48-70 Gy in 4-10 fractions. The median follow-up period was 38 months. Local progression-free survival rates were 84.2% in all patients and 86.1% in the T1, 78.6% in T2, 89.2% in adenocarcinoma, and 70.5% in squamous cell subgroups. Overall 3-year survival rates were 77.0% in all patients: 90.7% in females, 69.6% in males, and 41.2% in patients with pulmonary interstitial changes. Fatal radiation pneumonitis was observed in two patients, all of whom had pulmonary interstitial changes. This real-world evidence will be useful in shared decision-making for optimal treatment, including SBRT for operable stage I NSCLC, particularly in older patients.

Evidence of increases of phytol and chlorophyllide by enzymatic dephytylation of chlorophylls in smoothie made from spinach leaves.

Phytol is a diterpene alcohol found abundantly in nature as the phytyl side chain of chlorophylls. Free form of phytol and its metabolites have been attracting attention because they have a potential to improve the lipid and glucose metabolism. On the other hand, phytol is unfavorable for those who suffering from Refsum's disease. However, there is little information on the phytol contents in leafy vegetables rich in chlorophylls. This study indicated that raw spinach leaves contain phytol of 0.4-1.5 mg/100 g fresh weight. Furthermore, crude enzyme extracted from the leaves showed the enzyme activities involved in dephytylation of chlorophyll derivatives and they were high at mild alkaline pH and around 45°C, and lowered at 55°C or above. Under the optimum pH and temperature for such enzymes determined in the model reaction using the crude enzyme, phytol content in the smoothie made from raw spinach leaves increased with an increase of chlorophyllide, another reaction product. Comparison between the increased amounts of phytol and chlorophyllide showed that the enzymatic dephytylation of chlorophylls was critically responsible for the increase of phytol in the smoothie. PRACTICAL APPLICATION: Phytol, which is released by the enzymes related to chlorophyll metabolism in plants, has been investigated because of its potential abilities to improve the lipid metabolism and blood glucose level. In contrast to such health benefits, they are known to be toxic for patients suffering from Refsum's disease. This research for the first time reports the phytol content in raw spinach leaves and that phytol can be increased in the smoothie made from spinach leaves by the action of endogenous enzymes on chlorophyll derivatives under a certain condition. These results help control phytol content in the smoothies.

Increased toxicities associated with dose escalation of stereotactic body radiation therapy in prostate cancer: results from a phase I/II study.

BACKGROUND: This dose-escalation study evaluated the toxicity and efficacy of different stereotactic body radiation therapy (SBRT) doses for selecting an optimal dose for prostatic adenocarcinoma (PCa). MATERIALS AND METHODS: This clinical trial was registered at UMIN (UMIN000014328). Patients with low- or intermediate-risk PCa were equally assigned to 3 SBRT dose levels: 35, 37.5, and 40 Gy per 5 fractions. The primary endpoint was the occurrence rate of late grade ≥2 genitourinary (GU) and gastrointestinal (GI) adverse events at 2 years, while the secondary endpoint was the 2-year biochemical relapse-free (bRF) rate. Adverse events were evaluated using the Common Terminology Criteria for Adverse Events version 4.0. RESULTS: Seventy-five patients (median age, 70 years) were enrolled from March 2014 to January 2018, of whom 10 (15%) and 65 (85%) had low- and intermediate-risk PCa, respectively. The median follow-up time was 48 months. Twelve (16%) patients received neoadjuvant androgen deprivation therapy. The 2-year occurrence rates of grade 2 late GU and GI toxicities were 34 and 7% in all cohorts, respectively (35 Gy: 21 and 4%; 37.5 Gy: 40 and 14%; 40 Gy: 42 and 5%). The occurrence risk of GU toxicities significantly increased with dose escalation (p = 0.0256). Grades 2 and 3 acute GU toxicities were observed in 19 (25%) and 1 (1%), respectively. Grade 2 acute GI toxicity was observed in 8 (11%) patients. No grade ≥3 GI or ≥4 GU acute toxicity or grade ≥3 late toxicity was observed. Clinical recurrence was detected in 2 patients. CONCLUSIONS: An SBRT dose of 35 Gy per 5 fractions is less likely to cause adverse events in patients with PCa than 375- and 40-Gy SBRT doses. Higher doses of SBRT should be applied with caution.

Stereotactic ablative body radiotherapy with a central high dose using CyberKnife for metastatic lung tumors.

BACKGROUND: The CyberKnife system features a robotically-positioned linear accelerator to deliver real-time image-guided stereotactic ablative body radiotherapy (SABR). It achieves steep dose gradients using irradiation from hundreds of different directions and increases the central dose of the gross tumor volume (GTV) without increasing the marginal dose to the planning target volume. We evaluated the effectiveness and safety of SABR with a central high dose using CyberKnife for metastatic lung tumors. METHODS: A total of 73 patients with 112 metastatic lung tumors treated with CyberKnife were retrospectively analyzed. Local control, progression-free survival, and overall survival were calculated using the Kaplan-Meier method. The median age was 69.2 years. The most common primary sites were the uterus (n = 34), colorectum (n = 24), head and neck (n = 17), and esophagus (n = 16). For peripheral lung tumors, the median radiation dose was 52 Gy in 4 fractions, whereas for centrally located lung tumors, it was 60 Gy in 8-10 fractions. The dose prescription was defined as 99% of the solid tumor components of the GTV. The median maximum dose within the GTV was 61.0 Gy. The GTV and planning target volume were enclosed conformally by the 80% and 70% isodose lines of the maximum dose, respectively. The median follow-up period was extended to 24.7 months; it was 33.0 months for survivors. RESULTS: The 2-year local control, progression-free survival, and overall survival rates were 89.1%, 37.1%, and 71.3%, respectively. Toxicities of grade ≥ 2 were noted as grade 2 and 3 radiation pneumonitis in one patient each. The two patients with grade 2 or higher radiation pneumonitis had both received simultaneous irradiation at two or three metastatic lung tumor sites. No toxicity of grade ≥ 2 was observed in patients with metastasis in one lung only. CONCLUSIONS: SABR with a central high dose using CyberKnife for metastatic lung tumors is effective with acceptable toxicity. TRIAL REGISTRATION: Number: 20557, Name: Stereotactic ablative radiotherapy using CyberKnife for metastatic lung tumor, URL: http://www.radonc.med.osaka-u.ac.jp/pdf/SBRT.pdf , Date of registration: April 1, 2021 (retrospectively registered), Date of enrollment: May 1, 2014.

Clearance Profile of Circulating Tumor Human Papillomavirus DNA During Radiotherapy Predicts Clinical Outcomes in Human Papillomavirus-Related Oropharyngeal Cancer.

PURPOSE: This study aimed to examine whether circulating tumor human papillomavirus type 16 (HPV16) DNA (ctHPV16DNA) can help identify patients with locally advanced HPV16-related oropharyngeal squamous cell carcinoma who may benefit from deintensified treatment. MATERIALS AND METHODS: We serially collected blood samples before, during, and after treatment from 22 patients who received 70 Gy radiotherapy alone and longitudinally quantified ctHPV16DNA using droplet digital polymerase chain reaction. We correlated the clearance profile of ctHPV16DNA with clinical outcomes. RESULTS: The percentage of patients with detectable ctHPV16DNA decreased after every 10 Gy of radiotherapy. By contrast, the percentage of patients who later developed treatment failure among patients with detectable ctHPV16DNA gradually increased as radiotherapy proceeded, reaching 100% after 60 Gy of radiotherapy. We defined patients with and without detectable ctHPV16DNA after receiving 40 Gy as having slow and rapid clearance profiles, respectively. All 12 patients with a rapid clearance profile remained disease-free after radiotherapy. Of the 10 patients with a slow clearance profile, three had persistent or progressive disease at response evaluation after radiotherapy and one developed distant metastasis during follow-up (ie, four patients experienced treatment failure). The median follow-up for surviving patients was 38.6 months, and the 3-year failure-free survival rates of patients with rapid and slow clearance profiles were 100% and 58%, respectively (P = .02). Neither baseline ctHPV16DNA levels nor metabolic tumor volume was an independent predictor of the pattern of the clearance profile. CONCLUSION: In patients with HPV16-related oropharyngeal squamous cell carcinoma receiving radiotherapy, a slow ctHPV16DNA clearance profile could prelude unfavorable outcomes. Monitoring ctHPV16DNA is essential for determining the clearance profile, which might help optimize treatment intensity individually.

Evaluation of Lung and Liver Tumor Dose Coverage Treated With the CyberKnife Synchrony System With Consideration of Measured Tracking Errors.

BACKGROUND/AIM: Lung and liver tumor dose coverage was evaluated for the CyberKnife synchrony respiratory tracking system (SRTS) with consideration of the motion tracking accuracy measured for motion patterns of individual patients. PATIENTS AND METHODS: Seven treatment plans of six cases treated with the SRTS were evaluated. The motion phantom was moved with the motion data derived from the treatment log files. A laser emitted from the linac head to the moving phantom block was recorded with a webcam, and the tracking accuracy was evaluated. The dose volume histogram (DVH) of planning target volume (PTV) and gross tumor volume (GTV) were calculated by a pencil beam algorithm with shifting the beams with Gaussian random numbers mimicking the measured tracking errors. RESULTS: The tracking errors measured with the motion phantom in the lateral direction were within ±2 mm for 90% of beam-on time. The tracking errors in the longitudinal direction were within ±3.0 mm and ±1.1 mm for 90% and 50% of beam-on time, respectively. Although one case showed a decrease in the dose covering 95% of PTV (D95%) by 1.8%, the change in the dose covering 99% of GTV (D99%) was within 1%. CONCLUSION: This study evaluated the motion tracking errors of the SRTS by a motion phantom moved with the patients' respiration signal, and the impact of the tracking errors on the target coverage was calculated. Even for respiratory patterns with large maximum tracking errors, sufficient GTV coverage is achievable if the beam is accurately delivered for high percentage of beam-on time.

COVID-19 vaccine-induced Recurrence of the Radiation Recall Phenomenon in the Laryngeal Mucosa Due to a VEGF Inhibitor.

Purpose: The radiation recall phenomenon (RRP) is a rare and unexpected late complication of radiation therapy (RT). Although predominantly in the skin, RRP of the upper respiratory tract has also been reported. In general, RRP is caused by anticancer agents, and the COVID-19 vaccine has also been reported to cause RRP in recent years. Methods and Materials: A 50-year-old woman who had received RT around the larynx 3 years prior and was receiving a docetaxel + ramucirumab (RAM) regimen experienced recurrent sore throat. The administration of RAM was discontinued after a gastroscopic examination revealed mucosal bleeding from around the larynx, which was thought to be RRP caused by RAM, a vascular endothelial growth factor inhibitor. Results: After the remission of the RRP, the patient received a COVID-19 vaccine (Pfizer-BioNTech). Five days later, the appearance of cough and recurrence of sore throat worsened with time, and marked stridor was observed. The patient was admitted, and steroid pulse therapy was administered for 3 days starting on day 18 after vaccination. On day 50 after vaccination, edema of the vocal cords improved. Conclusions: When administering COVID-19 vaccines, considering that these vaccines may cause RRP is important, because RRP can be fatal in patients with a history of RT in the laryngeal region and treated with vascular endothelial growth factor inhibitors.

Long-term Outcomes of Radiation Therapy for Prostate Cancer in Elderly Patients Aged ≥75 Years.

BACKGROUND/AIM: This study aimed to evaluate the treatment outcomes of radiation therapy (RT) for localized prostate cancer in elderly patients aged ≥75 years. PATIENTS AND METHODS: We retrospectively investigated data of patients aged ≥75 years with prostate cancer who underwent intensity-modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) with doses of 70-78 Gy in 35-39 fractions between September 2008 and June 2016. Overall survival (OS), recurrence-free (RF) rates, and occurrence rates of toxicities were calculated. RESULTS: Eighty-eight patients were enrolled in the study. Nineteen patients died, and nine patients reported PSA failure within the follow-up period. The median follow-up time was 83.5 months. The median age was 77 years. In the cohort, 6 were low-risk, 36 were intermediaterisk, and 46 were high-risk patients. The 5-/7-year OS and RF rates were 87.9%/80.2% and 93.5%/89.1%, respectively. By risk, the 5-/7-year RF rates were 100%/80% in the low-, 100%/100% in the intermediate-, and 87.6%/82.7% in the high-risk groups, respectively. The cumulative incidence rates of Grade ≥3 genitourinary and gastrointestinal toxicities were 1.3% and 3.5% at 5 years and 3.3% and 3.5% at 7 years, respectively. CONCLUSION: IMRT and VMAT are effective treatment options for elderly patients with prostate cancer and in a good general condition.

Radiation therapy enhances systemic antitumor efficacy in PD-L1 therapy regardless of sequence of radiation in murine osteosarcoma.

Recent studies demonstrate that immune checkpoint blockade (ICB) increases the chances of the abscopal effect, an anti-tumor effect outside the radiation field in radiation therapy. However, the optimal sequence between radiation and ICB remains unclear. To investigate the impact of sequence of radiation in anti-PD-L1 antibody (P1) therapy on immune microenvironments and antitumor efficacies in local and abscopal tumors, metastatic LM8 osteosarcoma cells were inoculated into both legs of C3H mice. For irradiation, only one side leg was irradiated at 10 Gy. Then mice were divided into four groups: administrated anti-PD-L1 antibody three times (P1 monotherapy), receiving radiation 3 days prior to P1 therapy (P1+pre-Rad), and receiving concurrent radiation with P1 therapy (P1+conc-Rad). Thereafter, tumor immune microenvironment and tumor volume changes were analyzed in irradiated and unirradiated tumors. The P1+pre-Rad regimen increased the proportion of CD8+ programmed cell death 1 (PD-1)+ granzyme B (GzmB)+ reinvigorated T cells and decreased the proportion of CD8+ PD-1+ GzmB- exhausted T cells than P1+conc-Rad regimen in unirradiated tumors. Combination regimens suppressed tumor growth in irradiated tumors compared with that in P1 monotherapy. In both irradiated and unirradiated tumors, significant tumor growth suppression and prolonged overall survival were observed under both combination treatment regimens compared with P1 monotherapy. However, no distinct differences in unirradiated tumor volume and survival were observed between P1+pre-Rad and P1+conc-Rad groups. These results suggest that local irradiation is necessary to improve systemic treatment efficacy in P1 therapy regardless of sequence of local irradiation.

High Dose Local Photon Irradiation Is Crucial in Anti-CTLA-4 Antibody Therapy to Enhance the Abscopal Response in a Murine Pancreatic Carcinoma Model.

Pancreatic cancer is an extremely treatment-resistant neoplasm to chemotherapy and immunotherapy. The combination of photon beam irradiation and anti-CTLA-4 antibody (C4) for the anti-tumor effect enhancement at local and distant tumors (abscopal tumors) was investigated using the pancreatic ductal adenocarcinoma (PDAC) mouse model. Pan02 cells were bilaterally inoculated to both legs of C57BL/6 mice. High dose photon beams in a hypofractionation or a single fraction were delivered to the tumors on one leg. Monotherapy with C4 via i.p. was not effective for PDAC. The high dose irradiation to the local tumors produced significant shrinkage of irradiated tumors but did not induce the abscopal responses. In contrast, the combination therapy of high dose photon beam irradiation in both hypofractionation and a single fraction with C4 enhanced the anti-tumor effect for abscopal tumors with significantly prolonged overall survival. The flow cytometric analysis revealed that the combination therapy dramatically decreased the regulatory T cell (Treg) proportion while increasing the cytotoxic T lymphocytes in both local and abscopal tumors. These results suggest that high dose photon beam irradiation plays an important role in C4 therapy to enhance the abscopal response with immune microenvironment changes in PDAC, regardless of the fractionation in radiation therapy.

Stereotactic Ablative Radiotherapy Using CyberKnife for Stage I Non-small-cell Lung Cancer: A Retrospective Analysis.

BACKGROUND/AIM: We evaluated the effectiveness and safety of stereotactic ablative radiotherapy (SABR) delivered using Cyberknife in patients with stage I non-small-cell lung cancer. PATIENTS AND METHODS: The clinical results of 153 patients with 161 lung cancers treated with CyberKnife between May 2014 and August 2020 at the Osaka University Hospital were retrospectively analyzed. The median age was 80 years (range=48-99 years). Nine patients (5.6%) had interstitial pneumonia. The median radiation dose was 52 Gy (range=40-70 Gy) in 4-10 fractions, and the median follow-up extended to 21.4 months (range=0-68.9 months). RESULTS: The 2-year local control, progression-free, and overall survival rates were 91.9%, 61.7%, and 84.8%, respectively. Toxicities of grade ≥3 were observed in 13 (8.1%) patients; one patient with interstitial pneumonia developed grade 5 radiation pneumonitis and one patient developed grade 5 bronchopulmonary hemorrhage. CONCLUSION: In patients with stage I non-small-cell lung cancer, SABR using Cyberknife was effective with acceptable toxicity.

Poly (ADP-ribose) polymerase inhibitors sensitize cancer cells to hypofractionated radiotherapy through altered selection of DNA double-strand break repair pathways.

PURPOSE: Poly (ADP-ribose) polymerase inhibitors (PARPi) are known to induce radiosensitization. However, the exact mechanisms of radiosensitization remain unclear. We previously reported that PARPi may have a unique radiosensitizing effect to enhance ß-components of the linear-quadratic model. The aim of this study was to evaluate PARPi in combination with high-dose-per-fraction radiotherapy and to elucidate the underlying mechanisms of its radiosensitization. MATERIALS AND METHODS: Radiosensitizing effects of PARPi PJ34, olaparib, and veliparib were measured using a colony-forming assay in the human cancer cell lines, HCT116, NCI-H460, and HT29. Six different radiation dose fractionation schedules were examined by tumor regrowth assay using three-dimensional multicellular spheroids of HCT116, NCI-H460, SW620, and HCT15. The mechanisms of radiosensitization were analyzed by measuring DNA double-strand breaks (DSB), DNA damage responses, chromosomal translocations, cellular senescence, and cell cycle analysis. RESULTS: Olaparib and PJ34 were found to show radiosensitization preferentially at higher radiation doses per fraction. Similar results were obtained using a mouse model bearing human tumor xenografts. A kinetic analysis of DNA damage responses and repairs showed that olaparib and PJ34 reduced the homologous recombination activity. However, a neutral comet assay showed that PJ34 treatment did not affect the physical rejoining of DNA-DSBs induced by ionizing radiation. Cell cycle analysis revealed that olaparib and PJ34 strikingly increased G1 tetraploid cells following irradiation, leading to premature senescence. The C-banding analysis of metaphase spreads showed that olaparib and PJ34 significantly increased ionizing radiation-induced dicentric chromosomes. The data suggests that PARPi olaparib and PJ34 altered the choice of DNA-DSB repair pathways rather than reducing the total amount of DNA-DSB repair, which resulted in increased repair errors. Increased quadratic misrepair was one of the mechanisms of PARP-mediated radiosensitization, preferentially at the higher dose range compared to the lower dose range. CONCLUSION: PARPi may be a promising candidate to combine with stereotactic hypofractionated radiotherapy, aiming at high-dose region-directed radiosensitization.

Characteristics of microSilicon diode detector for electron beam dosimetry.

A microSilicon™ (PTW type 60023), a new unshielded diode detector succeeding Diode E (model 60017, PTW), was characterized for electron beam dosimetry and compared with other detectors. Electron beams generated from a TrueBeam linear accelerator were measured using the microSilicon, Diode E, and microDiamond synthetic single-crystal diamond detector. Positional accuracy of microSilicon was measured by data collected in air and water. The percent depth dose (PDD), off-center ratio (OCR), dose-response linearity, dose rate dependence, and cone factors were evaluated. The PDDs were compared with data measured using a PPC40 plane-parallel ionization chamber. The maximum variations of depth of 50% and 90% of the maximum dose, and practical depth among all detectors and energies were 0.9 mm. The maximum variations of the bremsstrahlung dose among all detectors and energies were within 0.3%. OCR showed good agreement within 1% for the flat and tail regions. The microSilicon detector showed a penumbra width similar to microDiamond, whereas Diode E showed the steepest penumbra shape. All detectors showed good dose-response linearity and stability against the dose rate; only Diode E demonstrated logarithmic dose rate dependency. The cone factor measured with microSilicon was within ±1% for all energies and cone sizes. We demonstrated that the characteristics of microSilicon is suitable for electron beam dosimetry. The microSilicon detector can be a good alternative for electron beam dosimetry in terms of providing an appropriate PDD curve without corrections, high spatial resolution for OCR measurements and cone factors.

Chk1 suppression leads to a reduction in the enhanced radiation-induced invasive capability on breast cancer cells.

Radiation therapy is generally effective for treating breast cancers. However, approximately 30% of patients with breast cancer experience occasional post-treatment local and distant metastasis. Low-dose (0.5 Gy) irradiation is a risk factor that promotes the invasiveness of breast cancers. Although an inhibitor of checkpoint kinase 1 (Chk1) suppresses the growth and motility of breast cancer cell lines, no study has investigated the effects of the combined use of a Chk1 inhibitor and radiation on cancer metastasis. Here, we addressed this question by treating the human breast cancer cell line MDA-MB-231 (in vitro) and mouse mammary tumor cell line 4 T1 (in vitro and in vivo) with γ-irradiation and the Chk1 inhibitor PD407824. Low-dose γ-irradiation promoted invasiveness, which was suppressed by PD407824. Comprehensive gene expression analysis revealed that low-dose γ-irradiation upregulated the mRNA and protein levels of S100A4, the both of which were downregulated by PD407824. We conclude that PD407824 suppresses the expression of S100A4. As the result, γ-irradiation-induced cell invasiveness were inhibited.

Dose rate in the highest irradiation area of the rectum correlates with late rectal complications in patients treated with high-dose-rate computed tomography-based image-guided brachytherapy for cervical cancer.

The purpose of this study was to evaluate the effect of dose rate to the rectum on late rectal complications in patients treated with computed tomography (CT)-based image-guided brachytherapy (IGBT) for cervical cancer. The subjects were 142 patients with cervical cancer who underwent Ir-192 high-dose-rate (HDR)-IGBT between March 2012 and January 2018. The dose rate to the rectum was calculated using in-house software. The minimum, mean and maximum effective dose rate (EDR) was calculated for voxels of the rectal volume covered by cumulative doses >D0.1cc, >D2cc, and > D5cc. The average EDR of three to four brachytherapy sessions was calculated (EDR for patients; EDRp). The total dose of the rectum was calculated as the biologically equivalent dose in 2-Gy fractions (EQD2). The associations between EDRp for D0.1cc, D2cc, and D5cc and the respective rectal EQD2 values with late rectal complications were then analyzed. The median follow-up period was 40 months. Patients with rectal complications of ≥Grade 1 received a significantly higher mean EDRp for D0.1cc-5cc and had a greater EQD2 for D0.1cc-5cc. Multivariate analysis was performed using the mean EDRp for D2cc, EQD2 for D2cc, heavy smoking and BMI. Of these four variables, mean EDRp for D2cc (HR = 3.38, p = 0.004) and EQD2 for D2cc (HR = 2.59, p = 0.045) emerged as independent predictors for late rectal complications. In conclusion, mean EDRp and EQD2 were associated with late rectal complications in patients treated with HDR CT-based IGBT for cervical cancer.

Local hyperthermia combined with CTLA-4 blockade induces both local and abscopal effects in a murine breast cancer model.

PURPOSE: To evaluate the antitumor efficacy in local and distant tumors induced by local hyperthermia with CTLA-4 blockade. METHODS: A mouse breast cancer cell line was inoculated into both sides of the legs of mice. The mice were treated with three administrations of CTLA-4 blockade, a single application of local hyperthermia (42.5 °C for 20 min) to the tumor on one side of the leg, or the combination of the two. Tumor growth in locally heated tumors (HT tumors) and unheated distant tumors (UnHT tumors) and overall survival were evaluated. RESULTS: In the combination group, tumor volume significantly decreased for both HT and UnHT tumors compared with the tumors in the untreated and local hyperthermia monotherapy groups. Remarkable efficacy was only observed in the combination therapy group, in which 7 of 18 mice responded to HT and UnHT tumors, with significant prolonged overall survival. CONCLUSIONS: Combination therapy enhanced the antitumor response not only in HT tumors but also in UnHT tumors and prolonged overall survival.

Correction of lateral response artifacts from flatbed scanners for dual-channel radiochromic film dosimetry.

In this study, we evaluated the inter-unit variability of the lateral response artifact for multiple flatbed scanners, focusing on the dual-channel method, and investigated the correction method of the lateral non-uniformity. Four scanners with A3+ paper-size and five scanners with A4 paper-size were evaluated. To generate the dose-response curves, small pieces of the Gafchromic EBT3 and EBT-XD films were irradiated, and five of the pieces were repeatedly scanned by moving them on the scanner to evaluate the lateral non-uniformity. To calculate the dose distribution accounting for the lateral non-uniformity, linear functions of the correction factor, representing the difference between the pixel values at offset position and the scanner midline, were calculated for red and blue color channels at each lateral position. Large variations of the lateral non-uniformity among the scanners were observed, even for the same model of scanner. For high dose, red color showed pixel value profiles similar to symmetric curves, whereas the profiles for low dose were asymmetric. The peak positions changed with dose. With correction of the lateral non-uniformity, the dose profiles of the pyramidal dose distribution measured at various scanner positions and that calculated with a treatment planning system showed almost identical profile shapes at all high-, middle- and low-dose levels. The dual-channel method used in this study showed almost identical dose profiles measured with all A3+ and A4 paper-size scanners at any positions when the corrections were applied for each color channel.