Gy Total Dose Research Articles

Quercetin 3-O rutinoside prevents gastrointestinal injury through regulation of apoptosis in 7.5 Gy total body irradiated mice

BackgroundDespite the heightened threat to unforeseen nuclear/radiological exposures worldwide, no countermeasures are currently approved to prevent gastrointestinal (GI) toxicity induced by radiation in humans. PurposeIn this study, we aim to establish the gastroprotective role of flavonoid, Quercetin-3-O-rutinoside (Q-3-R) against 7.5 Gy total body gamma radiation dose that contributes to the hematopoietic syndrome. MethodsQ-3-R (10 mg/kg body weight) was administered intramuscularly to C57BL/6 male mice before exposure to 7.5 Gy and monitored for morbidity and mortality. The GI protection against radiation was ascertained by histopathological and xylose absorption studies. Intestinal apoptosis, crypt proliferation and apoptotic signaling were also investigated in different treatment groups. ResultsWe found that Q-3-R prevented the radiation-induced loss of mitochondrial membrane potential, maintained ATP levels, regulated the apoptotic pathway, and activated crypt cell proliferation in the intestine. Radiation-induced villi and crypt damage as well as mal-absorption were significantly minimized in the Q-3-R treated group. We observed 100% survival post Q-3-R administration against 33.3% lethality in 7.5 Gy (LD33.3/30) exposed C57BL/6 mice. The Q-3-R pre-treated mice that survived the 7.5 Gy dose revealed no pathological changes related to the development of fibrosis in the intestine and thickened mucosal wall till 4 months post irradiation. Complete hematopoietic recovery was observed in these surviving mice when compared to age matched control. ConclusionThe findings revealed that Q-3-R regulated the apoptotic process to achieve GI protection against LD33.3/30 dose (7.5 Gy) that primarily caused death due to hematopoietic failure. The recovery observed in mice survivors suggested that this molecule may also have the potential to minimize side effects on normal tissues during radiotherapy.

DNA Methylation Alterations in Fractionally Irradiated Rats and Breast Cancer Patients Receiving Radiotherapy.

Radiation-Induced CardioVascular Disease (RICVD) is an important concern in thoracic radiotherapy with complex underlying pathophysiology. Recently, we proposed DNA methylation as a possible mechanism contributing to RICVD. The current study investigates DNA methylation in heart-irradiated rats and radiotherapy-treated breast cancer (BC) patients. Rats received fractionated whole heart X-irradiation (0, 0.92, 6.9 and 27.6 Gy total doses) and blood was collected after 1.5, 3, 7 and 12 months. Global and gene-specific methylation of the samples were evaluated; and gene expression of selected differentially methylated regions (DMRs) was validated in rat and BC patient blood. In rats receiving an absorbed dose of 27.6 Gy, DNA methylation alterations were detected up to 7 months with differential expression of cardiac-relevant DMRs. Of those, SLMAP showed increased expression at 1.5 months, which correlated with hypomethylation. Furthermore, E2F6 inversely correlated with a decreased global longitudinal strain. In BC patients, E2F6 and SLMAP exhibited differential expression directly and 6 months after radiotherapy, respectively. This study describes a systemic radiation fingerprint at the DNA methylation level, elucidating a possible association of DNA methylation to RICVD pathophysiology, to be validated in future mechanistic studies.

Clinical benefits of oral capecitabine over intravenous 5-fluorouracyl regimen in case of neoadjuvant chemoradiotherapy followed by surgery for locally advanced rectal cancer.

Background: During the last decade, one of the most important treatment options for locally advanced, potencially resectable rectal tumours was neoadjuvant chemoradiotherapy (CRT) followed by surgery. Methods: Effects of the neoadjuvant treatment on surgical outcomes were retrospectively analysed in 185 patients with stage T2-T4 and N0-2, resectable rectal tumour among two patient groups defined by radiosensitizer agents. Group 1 (n = 94) involved radiotherapy (RT) with 50.4Gy total dose (25 × 1.8 Gy + 3 × 1.8Gy tumour bed boost), and intravenous 5-fluorouracil (5-FU) (350mg/m2) with leucovorin (20mg/m2) on the 1-5 and 21-25days, while Group 2 (n = 91) RT and orally administrated capecitabine (daily 2 × 825mg/m2) on RT days. Surgery was carried out after 8-10weeks. Side effects, perioperative complications, type of surgery, number of removed regional lymph nodes, resection margins and tumour regression grade (TRG) were analysed. Results: More favourable side effects were observed in Group 2. Despite the same rate of diarrhoea (Group 1 vs. Group 2: 54.3% vs. 56.0%), Grade 2-3 diarrhoea ratio was lower (p = 0.0352) after capecitabine (Group 2). Weight loss occurred in 17.0% and 2.2% (p = 0.00067), while nausea and vomiting was described in 38.3% and 15.4% (p = 0.00045) with 5-FU treatment and capecitabine respectively. Anaemia was observed in 33.0% and 22.0% (p = 0.0941). Complete tumour regression occurred in 25.3% after oral- and 13.8% after intravenous treatment (p = 0.049). Ratio of sphincter preservation was higher with laparoscopy than open surgery (72.3% vs. 39.7%) (p = 0.00001). Conclusion: The study confirms advantages of neoadjuvant chemoradiotherapy with oral capecitabine for rectal tumours, such as more favourable side effect profile and overall clinical outcome, with increased rate of complete tumour regression.

Predictors of Response to Salvage High-Dose plus Low-Dose Radiation in Checkpoint-Inhibitor Resistant Patients

<h3>Purpose/Objective(s)</h3> Patients (pts) with immune checkpoint inhibitor (ICI)-resistant advanced cancer have poor outcomes and limited alternative treatment options. High-dose radiation therapy (HD-RT) can augment local and systemic ICI effects and lead to tumor regression outside of the treatment field (abscopal effect). Low-dose RT (LD-RT) to secondary sites may further enhance responses by modulating the stroma and facilitating immune cell infiltration. Prior studies suggest that high BED regimens may better stimulate antitumor immune responses than lower BED regimens. We explored BED and baseline pt factors as predictors of response to salvage HD-RT plus LD-RT in a <i>post hoc</i> analysis of an ongoing phase II trial. <h3>Materials/Methods</h3> We included 56 (of 60) enrolled pts with follow up imaging in our analysis. All had metastatic solid tumors that progressed on ICI. Study treatment consisted of HD-RT to 1-2 sites plus LD-RT to 1+ additional sites. HD-RT regimens included conventional RT, comprised of 20-60 Gy in 4-5 fractions (fx), or stereotactic body RT (SBRT), comprised of 27-36 Gy in 3 fx, 50 Gy in 4 fx, or 60-70 Gy in 10 fx. LD-RT consisted of 1-10 Gy total doses given in 0.5-2 Gy fxs, with 7 Gy/5 fx being the most frequent. We evaluated relationships between pt responses (disease control at 4mo post-RT, DC; overall objective response, OR; time-to-progression, TTP) and patient- and treatment-related factors with logistic and Cox proportional hazard models. PFS and response outcomes were then assessed after stratifying by HD-RT BED₁₀ (BED>100 vs BED<100). <h3>Results</h3> Of 56 pts, 20 received HD-RT with BED >100 (range 106-119) and 36 with BED <100 (range 28-96). DC (SD or PR/CR per immune related response criteria, irRC) was achieved in 28/54 pts (52%; 2 pts not evaluable for response). OR (PR/CR) occurred in 15/54 pts (28%). On UVA, HD-RT BED₁₀ was predictive of both DC (OR 1.02, P = 0.03) and OR (OR 1.03, P = 0.008). Other factors, including age, gender, histology, fx count, baseline absolute lymphocyte count (bALC), and metastatic burden (MB) did not affect DC or OR. Stratifying by BED₁₀, median PFS was greater for the BED >100 cohort than BED <100 cohort (6.5mo vs 2.5mo, HR 0.43, P = 0.009), as were DCR (78% vs 39%, OR 5.5, P = 0.01) and ORR (OR 61% vs 11%, OR 12.6, P < 0.001). Cox multivariable analysis indicated that BED >100 (HR 0.27, P < 0.001), MB (HR 1.22, P = 0.001) and bALC (HR 0.43, P < 0.001) were independent predictors of TTP. However, when stratified by IO-class (PD1/PDL1 vs CTLA-4/combo) and histology (NSCLC vs other), only BED remained consistently significant. <h3>Conclusion</h3> Salvage HD-RT plus LD-RT is a unique therapeutic approach that can re-induce disease control after ICI progression. HD-RT regimens with a higher BED₁₀ – optimally >100 – will likely provide the greatest chance of treatment success with this strategy. Larger randomized trials are needed to further explore the role of salvage RT in ICI resistance.

Temporal Profiles of Symptom Scores after Palliative Radiotherapy for Bleeding Gastric Cancer with the Adjustment for the Palliative Prognostic Index: An Exploratory Analysis of a Multicenter Prospective Observational Study (JROSG 17-3)

<h3>Purpose/Objective(s)</h3> Although palliative radiotherapy for gastric cancer may improve some symptoms, it may also have negative impact due to its toxicity. We investigated whether symptoms improved after radiotherapy with adjustment for the Palliative Prognostic Index (PPI) considering that patients with limited survival tend to experience deterioration of symptoms. <h3>Materials/Methods</h3> This study was an exploratory analysis of a multicenter prospective observational trial (Japanese Radiation Oncology Study Group [JROSG] 17-3). We assessed six symptom scores (nausea, lack of appetite, fatigue, shortness of breath, pain at the irradiated area, and distress) based on the M. D. Anderson Symptom Inventory at registration and 2, 4, and 8 weeks thereafter. PPI prediction model contains five independent indicators: palliative performance scale, intake, edema, dyspnea at rest, and delirium. A higher PPI score means worse survival. We tested whether symptoms linearly improved after adjusting for the baseline PPI. Shared parameter models were used to account for potential bias in missing data. <h3>Results</h3> The present study analyzed all 55 patients enrolled in JROSG 17-3. The median age was 73 years (range, 50–93 years). The average PPI was 2.9 (95% confidence interval: 2.2–3.6). The median 20 Gy (range, 8–45 Gy) total radiation dose was delivered in a median of 5 fractions. At registration, 27 (49%), 36 (65%), 44 (80%), 38 (69%), 29 (53%) and 44 patients (80%) had nausea, lack of appetite, fatigue, shortness of breath, pain, and distress, respectively. All six symptoms were evaluable for 48 (87%), 36 (65%), and 28 (51%) patients at 2, 4, and 8 weeks, respectively. With time from registration as the only explanatory variable in the model, a significant linear decrease was observed in shortness of breath, pain, and distress (slopes, −0.26, −0.22, and −0.19, respectively). Given that the interaction terms (i.e., PPI × time) were not significantly associated with symptom scores in any of the six symptoms, only PPI was included as the main effect in the final multivariable models. After adjusting for the PPI, shortness of breath, pain, and distress significantly improved (slope, −0.25, −0.19, and −0.17; p < 0.001, 0.002, and 0.047, respectively). Higher PPI scores were associated with higher symptom scores in all six symptoms. <h3>Conclusion</h3> Shortness of breath, pain, and distress significantly improved after radiotherapy. Moreover, a higher PPI was significantly associated with higher symptom scores at all time points, including baseline. In contrast, PPI did not seem to influence the improvement of these symptoms. Regardless of the expected survival, patients receiving radiotherapy for gastric cancer can expect improvement in shortness of breath, pain, and distress over 8 weeks.

Adjuvant radiation therapy improves survival in stage IIIA (N2) non-small cell lung cancer with persistent N2 disease after neoadjuvant chemotherapy

ObjectivesRole of adjuvant radiation therapy in stage III (N2) non-small cell lung cancer has been controversial over the decades. Recent large, randomized trials have demonstrated that adjuvant radiation did not improve overall survival or disease-free survival; however, the trials either excluded or enrolled very few cases that have undergone neoadjuvant chemotherapy. Role of adjuvant radiation after neoadjuvant chemotherapy remains unclear. Whether the use of adjuvant radiation is associated with improved overall survival in those who have received neoadjuvant chemotherapy, especially in a subgroup of patients with persistent N2, is unknown. Materials and methodsPatients with clinical stage III (N2) non-small cell lung cancer diagnosed from 2004 through 2017 were queried to National Cancer Database. Eligibility criteria included completely resected (R0), pathological diagnosis, neoadjuvant multi-agent chemotherapy, information regarding post-surgical N2 status (persistent versus downstaged to pN0-1), adjuvant radiation (45 Gy+ versus none), and American Joint Commission on Cancer staging version (6th versus 7th). Those who have received neoadjuvant radiation with any dose or adjuvant radiation with less than 45 Gy total dose were excluded. Kaplan-Meier and log-rank tests were used for survival analyses. Propensity-score matching analysis was used for validation. All statistical analyses were two-sided, and p < 0.05 was required for statistical significance. ResultsA total of 1,855 patients met the eligibility criteria for analysis. In the overall cohort, there was a significant difference in overall survival between persistent N2 (Cohort P: N = 854, median survival 50.7 months) and downstaged N (Cohort D: N = 1,001, median survival 82.7 months). The use of adjuvant radiation showed a non-significant detrimental effect in overall survival in the overall and Cohort D (univariate p-values 0.27 and 0.077, respectively); however, both univariate and multivariate analyses demonstrated a significant improvement in overall survival in Cohort P (p = 0.004 and 0.028, respectively). These findings are also verified by propensity-score matching analysis (p = 0.0347). ConclusionsThis large-scale retrospective analysis suggests that adjuvant radiation may still have a role in persistent N2 disease after neoadjuvant chemotherapy. Further investigations are warranted.

388. PREOPERATIVE TREATMENT AND THORACOSCOPIC ESOPHAGECTOMY FOR BORDERLINE RESECTABLE ESOPHAGEAL CANCER

Abstract Preoperative DCF therapy is recommended for cStage II/III esophageal cancer based on the results of JCOG1109. However, there is no established treatment strategy for Borderline Resectable (BR) esophageal cancer that is suspected of invading vital organs. And the pros and cons of thoracoscopic surgery have not been clarified. We have been performing preoperative chemoradiotherapy (NACRT) followed by thoracoscopic subtotal esophagectomy for BR esophageal cancer. Details and short-term results are presented. After 2 courses of FP therapy and 40 Gy total dose (2 Gy x 20 times) of fractionated conventional irradiation, patients underwent thoracoscopic subtotal esophagectomy with D2 dissection if T4 factor was considered to have been removed by CT evaluation. From April 2017 to present, NACRT was performed in 25 BR esophageal cancer patients. Two of them were unresectable, and thoracoscopic subtotal esophagectomy was performed in 23 cases. All patients had squamous cell carcinoma. 4 patients had complications of Clavien-Dindo Grade III or higher. The median postoperative hospital stay was 23 days. Of the 23 cases that were resectable, R0 resection could be performed in 21 cases (91.3%). The pathological response of the primary tumor was Grade3 in 11 patients (47.8%), Grade2 in 5 (21.7%), and Grade1 in 7 (30.4%). Pathological-CR including regional lymph nodes was 7 cases (30.4%). NACRT is effective for BR esophageal cancer, and thoracoscopic subtotal esophagectomy can be performed safely. We would like to continue to study the long-term results of NACRT with more cases in the future.

CAN RADIOTHERAPY CAUSE DENTAL PULP NECROSIS? A SYSTEMATIC REVIEW AND META-ANALYSIS

Objectives To address whether radiotherapy could induce pulp necrosis in patients with head and neck cancer. Study Design A search was constructed according to patient, intervention, comparision, outcome and studies (PICOS) in the MEDLINE/PubMed, Cochrane Library, EMBASE, Web of Science, Scopus, and Open Grey databases. Clinical studies with pulp status assessment in patients with head and neck cancer subjected to radiotherapy were eligible. Risk of bias was evaluated using risk of bias in non-randomized studies- of interventions (ROBINS-I). RevMan software was used for meta-analysis. Results Out of the 171 potentially relevant records, 5 were included. Pulp status was assessed through cold thermal pulp sensitivity (CTPS), pulse oximetry, and electrical tests. Treatments were mostly radiotherapy alone, with intensity-modulated radiation therapy (IMRT) as the radiation modality (60-70 Gy total dose). All studies reported a significant reduction of CTPS responses in postradiotherapy periods (n = 4, I2 = 0%, P < .00001; n = 3, I2 = 0%, P < .00001). Electrical tests also revealed significant alterations postradiotherapy (n = 2, I2 = 68%, P < .00001). Pulp oxygenation presented no significant differences, yet meta-analysis was not feasible. Overall, 3 studies presented serious risk of bias and 2 presented moderate risk of bias. Conclusions CTPS and electrical tests revealed significant altered response postradiotherapy. However, cautious interpretation is required because they are not absolutely reliable tests, in addition to the quality of evidence presented. To address whether radiotherapy could induce pulp necrosis in patients with head and neck cancer. A search was constructed according to patient, intervention, comparision, outcome and studies (PICOS) in the MEDLINE/PubMed, Cochrane Library, EMBASE, Web of Science, Scopus, and Open Grey databases. Clinical studies with pulp status assessment in patients with head and neck cancer subjected to radiotherapy were eligible. Risk of bias was evaluated using risk of bias in non-randomized studies- of interventions (ROBINS-I). RevMan software was used for meta-analysis. Out of the 171 potentially relevant records, 5 were included. Pulp status was assessed through cold thermal pulp sensitivity (CTPS), pulse oximetry, and electrical tests. Treatments were mostly radiotherapy alone, with intensity-modulated radiation therapy (IMRT) as the radiation modality (60-70 Gy total dose). All studies reported a significant reduction of CTPS responses in postradiotherapy periods (n = 4, I2 = 0%, P < .00001; n = 3, I2 = 0%, P < .00001). Electrical tests also revealed significant alterations postradiotherapy (n = 2, I2 = 68%, P < .00001). Pulp oxygenation presented no significant differences, yet meta-analysis was not feasible. Overall, 3 studies presented serious risk of bias and 2 presented moderate risk of bias. CTPS and electrical tests revealed significant altered response postradiotherapy. However, cautious interpretation is required because they are not absolutely reliable tests, in addition to the quality of evidence presented.

Proton Sound Detector for beam range/dose measurement in FLASH hadron therapy

Proton Sound Detectors (ProSDs) sense (at low latency, <1 ms) the thermoacoustic signal generated by the fast energy deposition at the Bragg peak of a proton beam penetrating an energy absorber. ProSDs are especially promising for experimental monitoring of high pulse rate (FLASH) hadron therapy treatments working in-sync with the beam. This paper presents a mixed signal detector, capable of sensing and processing high rate (1k beam shots/sec) ionacoustic signals with low latency (<1 ms). The system was validated by measuring the dose deposition of a 20 MeV proton beam in water, achieving 3.43% precision (±2.75 GyRMS) after 50 ms acquisition (77.56 Gy total dose deposition).

Coincidence of Undifferentiated Pleomorphic Sarcoma and Epithelioid Leiomyosarcoma in a Patient; A Case Report

Introduction: Soft tissue sarcoma (STS) is a rare tumor with mesodermal origin. There are more than 100 different types of histology in sarcoma, which present different clinical behaviors. Liposarcoma, leiomyosarcoma, and undifferentiated pleomorphic sarcoma are among the most common pathologies Case Presentation: The patient was a 46-year-old man with 2 masses. The pathology of chest-wall mass (250 × 187 mm) was compatible with undifferentiated pleomorphic sarcoma (UPS). Arm mass (42 × 29 mm) pathology was suggestive of low-grade epithelioid leiomyosarcoma with smooth muscle differentiation. He received two cycles of mesna and doxorubicin and ifosfamide (MAI) regimen chemotherapy due to large and multiple masses, but the tumor size did not change. After consultation with an orthopedic oncosurgeon, wide masses resection was done. Adjuvant chemotherapy with an MAI regimen was continued for a total of 6 courses and radiation with a 60 Gy total dose to the posterior aspect of the chest wall. No recurrence or complications was observed after 4 months of follow-up. Conclusions: Multiple STS is rare; nevertheless, its probability, either synchronous or metachronous, should be considered during patient examine and follow-up. In the case of a secondary lesion, different histology is probable, and the patient should be biopsied and imaged.

The Protective Effects and Mechanism of Doxepin on Radiation-Induced Lung Injury in Rats.

Radiation-induced lung injuries (RILI) is one of the serious complications of radiotherapy posed by the damage of alveolar cells and inflammation over-reaction. We aimed to investigate the potential protective effects of doxepin on RILI (20 Gy total dose at 3 Gy/min of X-ray irradiation), as well as its underlying mechanism. For animal experiments, such parameters as Immunohistochemistry and hematoxylin and eosin (H&E) staining, WBC (white blood cell), CRP (C-reactive protein), Western blot, and q-PCR were detected. The results indicated that both survival status and weight increase of irradiated rats treated by doxepin (3 mg/kg/day, rat) were higher than those of treated with irradiation alone (Dosing started the day before irradiation). Further, histological examinations showed doxepin could tenuate the radiation injury, as indicated as alveolar inflammatory exudation and there was only mild interstitial inflammation infiltration. Western blotting and q-PCR showed that expression of NF-κβ in X group were higher than that in XMD group. For the first time, we reported doxepin functioned as a radioprotectant candidate, which provide a promising application of doxepin for protecting radiotherapy injuries.

Radiotherapy for vertebral hemangioma: the single-center experience of 80patients.

This study aimed to evaluate the therapeutic effect of radiotherapy and to determine possible prognostic factors in patients with painful vertebral hemangioma. In the last two decades, 80patients with vertebral hemangioma who received radiotherapy in our institute were evaluated in terms of pain response, treatment-related side effects, and prognostic factors. All patients were questioned 3months after radiotherapy for the evaluation of pain response and were divided into threegroups (complete response, partial response, and no change). Moreover, the visual analog scale (VAS) was used for pain response assessment in 46patients. Pain status was assessed to detect recurrence at each clinical examination during the follow-up period. Possible prognostic factors such as gender, size of the hemangioma, location, multilevel involvement and additional musculoskeletal disease on pain response were analyzed. In this study, 45individuals had lesions in the lumbar spine, 28in the thoracic, and 7in the cervical region. Furthermore, 51patients had additional musculoskeletal conditions such as disc herniation, degenerative diseases, spondylolisthesis, and compression fracture. Radiotherapy was performed with amedian daily dose of 2 Gy and amedian total dose of 40 Gy. Complete pain response occurred in 58.8% of patients, 26.2% of patients had partial pain response, and 15% of patients had no pain response. The overall response rate was 85%, and 7patients showed recurrent pain symptoms in the overall response group at routine follow-up. Additional musculoskeletal disorders were found to be the only prognostic factor associated with pain response. The median follow-up time was 60months. Secondary malignancy was not found in any of the patients in this short follow-up time. No acute or late radiation-associated side effects greater than gradeII were observed. To our best knowledge, this study is one of the largest single-institution radiotherapy series on vertebral hemangiomas reported to date. The obtained data support the efficacy and safety of radiotherapy in the treatment of painful vertebral hemangioma. Our study showed that additional musculoskeletal disease plays an important role in pain response. Other prognostic factors and treatment of vertebral hemangioma with stereotactic radiosurgery should be investigated in future studies.

Abstract DEB2-2: Con - One Week of Whole Breast RT is the New Standard of Care

Abstract The dual role of breast irradiation post lumpectomy for conservative treatment is to yield local cancer control comparable to that achieved with mastectomy while maintaining a sensate and cosmetically acceptable breast. Through application of a linear quadratic equation that characterizes the radiobiological relationship of total dose and dose per fraction to predict efficacy as well as tissue specific toxicity, breast radiation that is equally effective can be delivered with fewer treatments. This has allowed standard post lumpectomy breast radiation to be reduced to 15 -16 treatments from 25-28 with similar efficacy and toxicity confirmed in multiple clinical trials. The recent Fast Forward trial (Lancet 2020; 395: 1613-26) has now further advanced the application of this radiobiological model evaluating breast irradiation delivered in 5 treatments. This resulted in non-inferior recurrence events compared to 15-treatment breast irradiation. When using fewer treatments of larger radiation dose, small changes can result in significant toxicity effects. For example, with 1 Gy difference between 26 Gy and 27 Gy total dose treatment arms on the Fast Forward trial, significantly higher rates of breast adverse outcomes were seen. Additional experience with the 5-fraction breast irradiation is needed prior to its replacing the current 15-16 treatment standard. Citation Format: J White. Con - One Week of Whole Breast RT is the New Standard of Care [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr DEB2-2.

Hippocampal Dosimetry and Mnemonic Function Changes After Stereotactic Irradiation of Cavernous Sinus Meningiomas.

Introduction: It is believed that hippocampal exposure plays a major role in the development of memory disorders after cranial irradiation. This effect is evident in whole-brain irradiation and is less certain in local irradiation of intracranial targets. The present study aims to clarify the dosimetric features and dynamics of memory functions after local irradiation of the hippocampus when treating cavernous sinus meningiomas.Methods: The study included 28 patients (24 females and 4 males) with cavernous sinus meningiomas diagnosed according to typical clinical and radiological findings. The mean age was 52 years (30-65 years). Stereotactic radiotherapy in standard fractionation regimen (54 Gy total dose) was the primary treatment in all patients. Patients underwent memory testing (ability to reproduce and recognize) using a previously developed and validated methodology at standard time points: before the start of radiotherapy, at the end of the course, and 6 and 12 months after treatment. Hippocampal dose, dynamics of memory function, and their possible relationship were evaluated.Results: In total, 28 cavernous sinus meningiomas (15 left-sided and 13 right-sided) were treated. The mean target volume was 24.0 ccm (8.2 ccm to 53.8 ccm). Twelve months after radiotherapy, there was an increase in the median total number of recognition errors from 6.5 [4;11] to 9.5 [5;12], p=0.025, the median number of "old-similar" errors from 2 [1;3.25] to 3 [1.75;5], p=0.021, and the median number of "similar-old" errors from 3 [1;5] to 5.5 [3;7], p<0.001. The number of reproduction errors did not increase. A moderate correlation (p = 0.03, correlation coefficient = 0.41) was found between the dose to 10% of the ipsilateral hippocampus and the total number of reproduction errors at the end of the course. No other significant correlations were found at the end of radiotherapy and six and 12 months after it.Conclusion: Thus, even partial lateralized exposure of the hippocampus during irradiation of the cavernous sinus meningiomas affects its function in the form of specific pattern separation type disturbances, which are detected as early as 12 months after the impact. The hippocampus in this treatment should be considered as a critical structure whose sensitivity to irradiation requires additional assessment.

Adaptive radiation therapy strategies in the treatment of prostate cancer patients using hypofractionated VMAT.

PurposeTo perform a comprehensive evaluation of eight adaptive radiation therapy strategies in the treatment of prostate cancer patients who underwent hypofractionated volumetric modulated arc therapy (VMAT) treatment.Material and methodsThe retrospective study included 20 prostate cancer patients treated with 40 Gy total dose over five fractions (8 Gy/fraction) using VMAT. Daily cone beam computed tomography images were acquired before the delivery of every fraction and then, with the application of deformable image registration used for the estimation of daily dose, contouring and plan re‐optimization. Dosimetric benefits of the various ART strategies were quantified by the comparison of dose and dose‐volume metrics derived from treatment planning objectives for original treatment plan and adapted plans with the consideration of target volumes (PTV and CTV) as well as critical structures (bladder, rectum, left, and right femoral heads).ResultsPercentage difference (ΔD) between planning objectives and delivered dose in the D99% > 4000cGy (CTV) metric was −3.9% for the non‐ART plan and 2.1% to 4.1% for ART plans. For D99% > 3800cGy and Dmax < 4280cGy (PTV), ΔD was −11.2% and −6.5% for the non‐ART plan as well as −3.9% to −1.6% and −0.2% to 1.8% for ART plans, respectively. For D15% < 3200 cGy and D20% < 2800 cGy (bladder), ΔD was −62.4% and −68.8% for the non‐ART plan as well as −60.0% to −57.4% and −67.0% to −64.0% for ART plans. For D15% < 3200 cGy and D20% < 2800 cGy (rectum), ΔD was −11.4% and −8.15% for non‐ART plan as well as −14.9% to −9.0% and −11.8% to −5.1% for ART plans.ConclusionsDaily on‐line adaptation approaches were the most advantageous, although strategies adapting every other fraction were also impactful while reducing relative workload as well. Offline treatment adaptations were shown to be less beneficial due to increased dose delivered to bladder and rectum compared toother ART strategies.

Total Neoadjuvant Therapy for Locally Advanced Gastric Cancer: An Interim Study of Phase Ⅱ Clinical Trial

<h3>Purpose/Objective(s)</h3> To observe the safety and preliminary efficacy of the total neoadjuvant therapy (TNT) model of "neoadjuvant chemoradiotherapy plus consolidation neoadjuvant chemotherapy followed by radical surgery" for locally advanced gastric cancer (Clinical Trial registration number:NCT04062058). <h3>Materials/Methods</h3> Patients aged 18-75 years with a KPS status score ≥70 and clinical diagnosed as locally advanced gastric adenocarcinoma (GC) or Siewert Ⅱ/Ⅲ adenocarcinoma gastroesophageal junction cancer (GEJC) was prospectively enrolled. The neoadjuvant chemoradiotherapy (NCRT) was delivered with a total dose of 45Gy,1.8Gy/time firstly. Concurrent chemotherapy was S-1 at a dose of 40-60mg twice daily. Then, patients received four to six cycles consolidation neoadjuvant chemotherapy (CNCT) of oxaliplatin and S-1(SOX regimen) three weeks after neoadjuvant chemoradiotherapy; R0 resection with D2 lymphadenectomy was performed 4-6 weeks after the end of neoadjuvant therapy. <h3>Results</h3> A total of 28 patients who finished the whole therapy were enrolled from March 2018 to December 2020, of which, 78.6% were diagnosed as cT4, 85.7% were cN positive and 85.7% were stage Ⅲ in total clinical stage. Grade 3 or higher adverse reactions occurred in 3 cases (10.7%) during CRT, including thrombocytopenia, leukopenia and anorexia; 2 cases (7.4%) of leukopenia and 3 cases (11.1%) of thrombocytopenia occurred during CNCT. Twenty patients (71.4%) completed surgery among 28 patients and all of them completed R0 resection. The incidence of severe pathological reactions (Mandard score = 1-2) was 95.0% and 50.0% reached pCR. Three patients occurred surgery complications, including anastomotic leak, anastomotic stenosis and intra-abdominal sepsis. They all improved after symptomatic treatment. <h3>Conclusion</h3> Total neoadjuvant therapy for locally advanced GC and GEJC can reach a remarkable down-staging. It can be safely delivered and will not improve the surgery complications significantly.

Estimation of Dose-Response Correlations Regarding Significant Blood Count Drops After Radiotherapy for Prostate Cancer

It is accepted that radiation therapy can have some effect on hemoglobin/hematocrit, but it is not very well documented. The purpose of this study is to explore the effect of radiation monotherapy on hematocrit levels.Given that intensity modulated radiation therapy treats a large volume of normal tissue, we were concerned about the unrecognized effects of pelvic radiation therapy on blood counts. We prospectively obtained complete blood counts (CBCs) pretreatment, the end of treatment and 3 months post-RT from 2014-2016. With IRB approval we conducted a retrospective analysis of 221 patients treated with pelvic radiation for prostate adenocarcinoma. Given that the lifespan of RBCs is 120 days, we used the 3-month counts (approximately 130 days after 20 Gy is delivered). Dose volume histograms (DVHs) corresponding to 8 different contoured structures in the pelvis that were deemed significant in order to look for a correlation between pelvic structures and values of the CBC. These patients received either primary prostate radiation to 78 Gy total dose, or post-prostatectomy radiation for recurrence to 70 Gy total dose. Additionally, most of these patients had pelvic lymphatic irradiation (common iliac, external iliac, and internal iliac) to 54 Gy. Some patients received concomitant androgen ablation.Upon analysis, affected values were the RBC count, hemoglobin, and hematocrit. Hematocrit demonstrated the strongest correlation. Overall, the mean hematocrit dropped from 42.01% to 38.41% (8.57% decrease). Irradiated pelvic structures that correlated with significant decreases in hematocrit were the following: the bone volume of os coxae bilaterally superior to the acetabulum (OCUB), the entire os coxae bilaterally (OCTB), and the whole pelvis (BVWP). The OCUB showed the highest correlation, with a maximum AUC of 0.74 at V20 Gy with a volume threshold of 30%; odds ratio (OR) 9.8; confidence interval (CI) 2.9-32.9. Dose to the OCUB, showed an AUC of 0.73 with a dose of 23 Gy (OR 2.7, CI 1.3-5.6). For OCTB, maximum AUC of 0.69 was observed at V20 Gy where the volume threshold was 50%, (OR 9.3, CI 2.7-31.8). Mean dose analysis showed an AUC of 0.69 where the dose threshold was 28 Gy, odds ratio was 1.4 and CI 0.5-3.9 (not statistically significant). For BVWP a maximum AUC of 0.71 was seen at V20 Gy where the volume threshold was 40%, (OR 7.5, CI 2.2-25.4). Mean dose analysis showed an AUC of 0.72 where the dose threshold was 24 Gy, odds ratio was 2.6 and CI 1.1-6.1.These findings confirm the most radiosensitive sites of bone marrow in the pelvis. The doses to OCUB, OCTB and BVWP were found to correlate with a significant drop of hematocrit. A threshold of V20 Gy < 30% or mean dose < 23 Gy to OCUB may reduce almost ten-fold the risk for this endpoint.

Intracranial chordoma: radiosurgery, hypofractionated stereotactic radiotherapy and treatment outcomes.

The aim of the study was to assess the results of stereotactic radiosurgery and hypofractionated stereotactic radiotherapy (SRS/SRT) for skull base chordomas. Twenty-three patients aged 12-75 were treated with SRS/SRT due to skull base chordoma. In 19 patients SRS/SRT was a part of the primary therapy, while in 4, a part of the treatment of recurrence. In 4 patients SRS/SRT was used as a boost after conventional radiotherapy and in 19 cases it was the only irradiation method applied. Patients were irradiated to total dose of 6-35 Gy and median total equivalent dose of 52 Gy. During median follow-up of 39 months, 4 patients died. One-, two- and five-year OS was 95%, 89% and 69%, respectively. In nine patients, progression of the disease was diagnosed during study period. One-, two- and five-year progression free survival (PFS) from the end of radiotherapy was 81%, 59% and 43%, respectively. Radiotherapy was well tolerated and only two patients in our group experienced moderate treatment-related toxicity. SRS/SRT alone or in combination with surgery is a safe and effective method of irradiation of patients with skull base chordomas. High EQD2 is necessary to achieve satisfactory treatment results.

Prostatic basal cell carcinoma treated by chemoradiation with weekly cisplatine: case report and literature review

BackgroundBasal cell carcinoma of the prostate is a relatively rare entity. Their evolution is characterized by the frequency of local and/or distant relapses. Due to their rarity, the treatment is not consensual in the literature. We report here a case of Basal cell carcinoma of the prostate in a 40-year-old patient.Case presentationOur patient initially presented an obstructive lower urinary tract symptoms with a normal initial level of prostate specific antigen (PSA) test (3.5 ng/m). The transurethral resection of the prostate (TURP) was in favor of a prostatic basal cell carcinoma with its specific anatomopathological and immunohistochemical characteristics. The prostatic MRI and thoraco-abdominal CT realized after the TURP revealed a tumoral lesion of the prostatic peripheral zone with extra-capsular extension combined with right seminal vesicle invasion and a suggestion of posterior bladder wall adherence. No evidence of visceral or nodal metastases at this point. Considering the tumor being locally advanced, a concurrent chemoradiotherapy with intensity modulated technique was indicated after a multidisciplinary meeting with a 70 Gy total target dose delivered in 35 fractions and weekly Cisplatin. A year and a half after, he developed a cerebellous metastases revealed by intracranial hypertension with no other visceral lesion and complete local remission with the disappearance of the lower urinary tract symptoms and the pain and the appearance of a prostatic atrophy. The PSA level was still on the upper limit of normal. He underwent metastasectomy, and the anatomopathological study was in favor of a cerebellous metastasis of the known BCC. The patient presented postoperatively paraparesis of lower limbs with balance problems for which he was placed in palliative care with indication of postoperative radiation therapy in case of improvement of his general condition. He did not recover and deceased three months later.ConclusionsThe prostatic basal cell carcinoma is a rare aggressive entity often non-evoked at the clinical or radiological stages because of its unspecific appearance. The diagnostic of these tumors is based on histological examination and a large immunohistochemistry panel. Given its scarity, very few data is available for locally advanced non-metastatic stages treated by radiation therapy. We assess here a good local response with concurrent chemoradiation therapy.

Prognostic value of methylation status of MGMT gene promoter in patients with glioblastoma after combination treatment.

e14025 Background: The effectiveness of radiation therapy in the classical and stereotactic treatment regimens of the primary glioblastoma multiforme was analyzed and compared. Methods: 87 patients with primary glioblastoma multiforme were hospitalized during the study period. 17 patients of them were in the treatment group (stereotactic radiotherapy, dose per fraction 2 Gy, 60 Gy total dose, CTV 2.0 cm, PTV 0.1 cm - group 1), and 70 patients were in the control group (conventionally fractionated radiotherapy, dose per fraction 2 Gy, 60 Gy total dose, CTV 2.0 cm, PTV 0.5 cm - group 2). Patients of both groups were treated with alkylating agents as the third stage of complex treatment. MGMT methylation was evaluated by pyrosequencing. Results: The use of stereotactic radiation therapy allowed to conduct a full course of treatment without interruption, whereas in the second group, due to the development of adverse reactions, the course was interrupted for 7 patients (10%). The advantage of stereotactic radiation therapy was a less pronounced increase and rapid regression of neurological deficits during treatment, manifested by better local control for 6 months. Hypermethylation of MGMT was detected in 39% of glioblastoma cases and was not detected in non-tumor tissue. The presence of promoter methylation disrupts DNA repair and is associated with longer survival in glioblastoma patients receiving alkylating agents. Note that the median survival of patients with MGMT hypermethylation in the group 1 was 285 days (IQR = 323.75), and in the group without hypermethylation was significantly more than 338.5 days (IQR = 476) (p = 0.045). A similar trend was observed in the second group: in patients with hypermethylated MGMT, the median survival was 271 days (IQR = 337), the result is different from patients without hypermethylated MGMT – 342 days (IQR = 493) (p = 0.039). Conclusions: As a result, the application of the stereotactic approach of radiation therapy in the complex treatment of patients with glioblastoma and their classification by the MGMT methylation status with a cut-off point of 10% has the basis for improving the effectiveness and tolerability of radiation therapy and contributes to the overall survival of patients.