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Purpose Tumor mutational burden (TMB) is a surrogate biomarker of neo-antigens and high TMB status is associated with favorable response to immune-checkpoint inhibitors (ICIs). This study aimed to elucidate the association between TMB and the outcome of definitive radiotherapy in patients with cervical cancer. Materials and methods TMB and treatment outcome were retrospectively analyzed in patients with newly diagnosed cervical cancer treated with definitive radiotherapy available with somatic mutation data of pre-treatment tumors obtained using a commercially available gene panel. Results The study enrolled 98 patients (median follow-up period, 61 months). The median TMB was 9.5 mutations per megabase (range, 3.0–35.5 mutations per megabase). After dichotomization based on this median value, the 5-year overall survival (OS) for TMB-high patients was significantly worse than that of TMB-low patients (61.1% vs. 82.2%). Multivariate analysis identified high TMB status as a significant prognostic factor for worse OS, along with advanced stage, para-aortic lymph node involvement, and absence of concurrent chemotherapy. Conclusion These data indicate that TMB is a potential prognostic factor for worse survival in patients with cervical cancer treated with definitive radiotherapy, thereby providing a rationale for treatment of TMB-high cervical cancers with a combination of ICIs plus radiotherapy. Secondary abstract This retrospective study of 98 patients demonstrates for the first time that tumor mutational burden (TMB) is an independent prognostic factor for worse overall survival of patients treated with definitive radiotherapy, providing a rationale for treatment of TMB-high cervical cancers with a combination of immune-checkpoint inhibitors plus radiotherapy.

Background: Nasopharyngeal cancer is commonly associated with Epstein–Barr virus (EBV) infection, especially undifferentiated non-keratinized histology. EBV DNA quantification through nasopharyngeal brushing was previously reported to be not related to disease stage. This study aimed to reinvestigate the relationship of EBV viral load in tumor tissue with tumor extensiveness by more accurate EBV DNA quantification through microscopically confirmed tumor cells from nasopharyngeal biopsy. Method: The specimens for EBV DNA quantification were derived from histopathology slides which were pre-treated following the QIAsymphony® SP protocol for tissue DNA extraction. Then, the extracted DNA underwent real-time polymerase chain reaction (RT-PCR) using the artus® EBV RG PCR Kit for EBV DNA quantification. The tumor volume was determined by delineating the gross tumor based on 3D imaging of the patient’s nasopharynx. Result: Twenty-four subjects were included in this study. All subjects were stage III and above, with more males (75%) than females. EBV viral load in tumor cells was found to have no correlation to tumor volume both in local and nodal regions. The median local tumor volume was 81.3 cm3 ± 80 cm3. The median EBV viral load in tumor cells was 95,644.8 ± 224,758.4 copies/100 ng of DNA. The median nodal or regional tumor volume was 35.7 ± 73.63 cm3. Conclusion: EBV viral load from tumor cells from nasopharyngeal biopsy has no relationship with tumor extensiveness in nasopharyngeal cancer. The presence and amount of EBV in tumor cells did not translate into larger or smaller tumors. The EBV viral proteins and RNAs were perhaps more likely to confer some prognostic information due to the fact that those molecules were related to carcinogenesis.

Bevacizumab is a monoclonal antibody against vascular endothelial growth factor that exerts antitumor effect by preventing tumor angiogenesis. Gastrointestinal fistula is a common side effect of bevacizumab in combination with radiotherapy. This case of rectovaginal fistula indicates that the side effect may be unpredictable by the conventional dose‐volume parameters for the rectum.

Granulocyte‐colony stimulating factor‐producing uterine cervical cancer is a rare aggressive disease, which may be genetically distinct from other uterine cervical cancers.

Objective To elucidate tumor mutation profiles associated with outcomes of uterine cervical cancer (UCC) patients treated with definitive radiotherapy. Methods Ninety-eight patients with newly diagnosed and pathologically confirmed UCC (82 squamous cell carcinomas, 12 adenocarcinomas, and four adenosquamous carcinomas) who were treated with definitive radiotherapy were analyzed. DNA was extracted from pre-treatment tumor biopsy specimens. The exons of 409 cancer-related genes were sequenced using a next-generation sequencer. Genetic mutations were identified and analyzed for correlations with clinical outcome. Results Recurrent mutations were observed in PIK3CA (35.7%), ARID1A (25.5%), NOTCH1 (19.4%), FGFR3 (16.3%), FBXW7 (19.4%), TP53 (13.3%), EP300 (12.2%), and FGFR4 (10.2%). The prevalence of mutations in FGFR family genes (i.e., FGFR1–4) was almost as high (24.5%) as that in PIK3CA and ARID1A, both of which are well-studied drivers of UCC. Fifty-five percent (21 of 38) of the identified FGFR mutations were located in the FGFR protein tyrosine kinase domain. Five-year progression-free survival (PFS) rates for FGFR mutation-positive patients (n = 24) were significantly worse than those for FGFR mutation-negative patients (n = 74) (43.9% vs. 68.5%, respectively; P = 0.010). Multivariate analysis identified FGFR mutations as significant predictors of worse 5 year PFS (P = 0.005), independent of clinicopathological variables. Conclusions FGFR mutations are associated with worse PFS in UCC patients treated with definitive radiotherapy. These results warrant further validation in prospective studies.

Radiotherapy treatment strategies should be personalized based on the radiosensitivity of individual tumors. Clonogenic assays are the gold standard method for in vitro assessment of radiosensitivity. Reproducibility is the critical factor for scientific rigor; however, this is reduced by insufficient reporting of methodologies. In reality, the reporting standards of methodologies pertaining to clonogenic assays remain unclear. To address this, we performed a literature search and qualitative analysis of the reporting of methodologies pertaining to clonogenic assays. A comprehensive literature review identified 1672 papers that report the radiosensitivity of human cancer cells based on clonogenic assays. From the identified papers, important experimental parameters (i.e. number of biological replicates, technical replicates, radiation source and dose rate) were recorded and analyzed. We found that, among the studies, (i) 30.5% did not report biological or technical replicates; (ii) 47.0% did not use biological or technical replicates; (iii) 3.8% did not report the radiation source; and (iv) 32.3% did not report the dose rate. These data suggest that reporting of methodologies pertaining to clonogenic assays in a considerable number of previously published studies is insufficient, thereby threatening reproducibility. This highlights the need to raise awareness of standardization of the methodologies used to conduct clonogenic assays.

Background Nasopharyngeal cancer is endemic to Southeast Asia. However, there is limited clinical evidence of nasopharyngeal cancer in Indonesia, which has the largest population in Southeast Asia. Methods Patterns of care and treatment outcomes in 428 patients with newly-diagnosed and pathologically-confirmed nasopharyngeal cancer were retrospectively analyzed. Results Concurrent chemo-radiotherapy (CCRT) was the first-line treatment for stages I-IVB diseases. The 2-year overall survival (OS) of all patients were 100.0%, 100.0%, 93.8%, 86.2%, 82.9%, and 62.4% for stages I, II, III, IVA, IVB, and IVC, respectively. The 2-year OS of CCRT-treated patients were 100.0%, 100.0%, 92.6%, 82.4%, and 78.3% for stages I, II, III, IVA, and IVB, respectively. Conclusion The patterns of care and treatment outcomes were potentially consistent with world standards, needing future validation. This is the largest study of newly diagnosed nasopharyngeal cancer in Indonesia, a huge disease burden, providing an important basis for the clinical management of this disease.

Little information is available on the risk factors for nasolacrimal duct obstruction after radiotherapy for head and neck tumors. We investigated the incidence and predictive dosimetric parameters for nasolacrimal duct obstruction following carbon-ion radiotherapy for head and neck tumors.Twenty-eight patients with head and neck non-squamous cell carcinoma were analyzed in this single-institution prospective study. More than half of the tumors were located in the nasal cavity and maxillary sinus. Carbon-ion radiotherapy consisting of 57.6 or 64.0 Gy(relative biological effectiveness; RBE) in 16 fractions was administered. Nasolacrimal duct obstruction was recorded according to Common Terminology Criteria for Adverse Events version 4.0. Cutoff values were determined using receiver operating characteristic (ROC) curve analysis. VX indicates the volume irradiated with X Gy(RBE).The median follow-up period was 60.3 months. Incidences of Grade 1 and 2 nasolacrimal duct obstructions were 46% (13/28) and 7% (2/28), respectively; no Grade 3 or greater toxicities were recorded. Throughout the dose range, the volumes of the irradiated nasolacrimal ducts were significantly higher in the obstruction-positive patients than in the obstruction-negative patients (p 0.001 for V10, V20, V30, V40, V50, and V60). Cutoff values determined by the ROC curve analysis classified the obstruction-positive patients with an accuracy of96% over the entire range of V10-V60.The incidence and predictive dosimetric parameters for nasolacrimal duct obstruction after carbon-ion radiotherapy were demonstrated in a prospective cohort. These data should help optimize carbon-ion radiotherapy treatments for patients with head and neck tumors.

A hydrogen peroxide (H2O2)-soaked gauze has been used in combination with radiotherapy in anticipation of sensitizing tumors exposed to the skin surface. Although used empirically in the clinic, the method is rarely reported in the literature, making its efficacy and tolerability unclear. Here, we report a case of primary metastatic breast cancer whose primary tumor was treated with palliative radiotherapy using an H2O2-soaked gauze. The primary tumor in the right breast regrew after treatment with palbociclib plus letrozole followed by fulvestrant and denosumab. The tumor was exposed to the skin surface, causing exudation, bleeding, pain, and difficulty in raising the right upper limb. Radiotherapy (51 Gy in 17 fractions) using the H2O2-soaked gauze resolved the patient's symptoms and the tumor showed macroscopic complete remission at three months post-treatment. This case indicates that radiotherapy with an H2O2-soaked gauze is an effective and tolerable palliative treatment for superficially exposed tumors. This non-invasive and inexpensive method of radiosensitization warrants validation and optimization in a prospective setting.

Simple Summary Colorectal cancer (CRC) screening is effective for cancer detection in average-risk adults. For prostate cancer (PCa) patients considered for carbon ion radiotherapy (CIRT), pre-treatment CRC screening is performed empirically to avoid post-treatment colonoscopic manipulation. However, the outcomes of screening remain unclear. To address this, we analyzed the outcomes of 2412 PCa patients at average risk for CRC who underwent routine pre-CIRT CRC screening and found that the estimated CRC prevalence was greater than that reported by 17 previous large-scale screening studies analyzing average-risk adults. These data indicate the possibility that the prevalence of CRC in PCa patients is greater than that in general average-risk adults, warranting further research. Abstract Colorectal cancer (CRC) screening is effective for detecting cancer in average-risk adults. For prostate cancer (PCa) patients considered for carbon ion radiotherapy (CIRT), pre-treatment CRC screening is performed empirically to avoid post-treatment colonoscopic manipulation. However, the outcomes of screening this population remain unclear. Here, we compared the outcomes of routine pre-CIRT CRC screening of 2412 PCa patients at average risk for CRC with data from two published datasets: the Japan National Cancer Registry (JNCR) and a series of 17 large-scale screening studies analyzing average-risk adults. The estimated prevalence rate was calculated using the pooled sensitivity elucidated by a previous meta-analysis. Consequently, 28 patients (1.16%) were diagnosed with CRC. CRC morbidity was significantly associated with high pre-treatment levels of prostate-specific antigen (p = 0.023). The screening positivity rate in this study cohort exceeded the annual incidence reported in the JNCR for most age brackets. Furthermore, the estimated prevalence rate in this study cohort (1.46%) exceeded that reported in all 17 large-scale studies, making the result an outlier (p = 0.005). These data indicate the possibility that the prevalence of CRC in PCa patients is greater than that in general average-risk adults, warranting further research in a prospective setting.

The elevation of the serum squamous cell carcinoma (SCC) antigen unrelated to disease progression occurs during the follow-up of patients with cervical cancer treated with radiotherapy. Although known empirically, the incidence and characteristics of this non-cancer specific elevation in SCC remain unclear. Here, we examined the post-treatment kinetics of SCC in 143 consecutive patients with squamous cell carcinoma of the cervix treated with definitive radiotherapy, in all patients, progression-free disease status was confirmed by periodic monitoring for at least 36 months (median, 61 months). We found that the 5-year cumulative incidence of post-treatment SCC elevation was unexpectedly high at 37.3% (59/143 patients), and that 59.3% (35/59) of event-positive patients experienced multiple events. The median peak SCC level for a given event was 2.0 ng/mL (interquartile range, 1.7–2.9 ng/mL). The multivariate analysis showed that renal dysfunction was associated significantly with a greater incidence of SCC elevation (p = 0.046). In addition, the 5-year cumulative incidence of SCC elevation was significantly greater in patients with renal dysfunction than in those without (54.8% vs. 32.9%, respectively, hazard ratio, 2.1 [95% confidence interval, 1.1–4.2], p = 0.028). These data will be useful for monitoring cervical cancer patients treated with radiotherapy.

Radiotherapy induces an immune response in the cancer microenvironment that may influence clinical outcome. The present study aimed to analyse the alteration of CD8(+) T-cell infiltration and programmed death-ligand 1 (PD-L1) expression following radiotherapy in clinical samples from patients with uterine cervical squamous cell carcinoma. Additionally, the current study sought to analyse the association between these immune responses and clinical outcomes. A total of 75 patients who received either definitive chemoradiotherapy or radiotherapy were retrospectively analyzed. CD8(+) T-cell infiltration and PD-L1 expression were determined by immunohistochemistry using biopsy specimens before radiotherapy (pre-RT) and after 10 Gy radiotherapy (post-10 Gy). The PD-L1(+) rate was significantly increased from 5% (4/75) pre-RT to 52% (39/75) post-10 Gy (P

Background Adenoid cystic carcinoma (ACC) is a rare malignant tumor involving mostly the head and neck region, and frequently the salivary glands. The development of lung metastasis after treatment of the primary tumor is a common occurrence in ACC. Although lung metastases show a slow rate of growth, approximately 10% of patients die from distant metastases. The radioresistance of ACC limits the efficacy of conventional radiotherapy for lung metastases, and the optimal dose remains to be determined. Stereotactic body radiotherapy (SBRT) using CyberKnife can deliver a high dose to the lung tumor, while sparing the surrounding normal lung tissues, leading to favorable local control in non-squamous cell lung cancer and metastatic lung tumors. We report a case of lung metastases from ACC treated successfully with SBRT using CyberKnife. Case presentation A 76-year-old Japanese man with ACC who was treated with carbon ion radiotherapy for a primary oropharynx tumor presented with three metastatic lesions in the lung. The tumor masses were located in the right upper, right lower, and left lower lobes of the lungs. Surgical resection was not indicated because of the presence of multiple tumors. The patient underwent SBRT at 60 Gy in 10 sequential fractions for each tumor. The biologically effective dose based on an alpha/beta ratio of 2 Gy was 240 Gy per tumor. The percentage of the total lung volume irradiated with >20 Gy was 4.9%, 3.2%, and 2.6% for each tumor. The patient developed acute radiation pneumonitis during the initial therapy, which resolved at 6 months after the CyberKnife treatment. At 21 months after the first CyberKnife treatment, three tumors showed no signs of recurrence. No late toxicity was observed. Conclusions SBRT using CyberKnife is an effective and feasible approach to the management of multiple lung metastases of ACC.

Cervical stump cancer, which arises in the remaining uterine cervix of a woman with a history of supravaginal hysterectomy, accounts for 1.6-4.4% of all cervical cancers. The close proximity of the rectosigmoid colon to the primary tumor, which is due to the absence of the uterine corpus, should be considered carefully in the treatment planning of brachytherapy. Although three-dimensional image-guided brachytherapy (3D-IGBT) is used widely to treat cervical cancer in those with an intact uterine corpus, the safety and efficacy of 3D-IGBT for cervical stump cancer remains unclear. Here, we report a case of cervical stump cancer (T3bN1M0) treated successfully with definitive radiotherapy, which combined external beam radiotherapy and computed tomography (CT)-based IGBT. By applying the dose prescription concept used for definitive brachytherapy of cervical cancer with an intact uterine corpus, IGBT achieved satisfactory dose conformity to the tumor while sparing the adjacent rectosigmoid colon. This led to local tumor control for three years and eight months, with no late adverse effects. This case suggests that radiotherapy using CT-based IGBT is a safe and effective treatment for cervical stump cancer.

Introduction Three-dimensional image-guided brachytherapy (3D-IGBT) has become widespread, improving the outcomes of cervical cancers dramatically. In 2018, the International Federation of Gynecology and Obstetrics (FIGO) staging system for cervical cancer was revised. However, the influence of the revisions on the stage distribution and outcomes of cervical cancers treated with 3D-IGBT remains unclear. To address this issue, we assembled a study cohort that comprised solely of cases treated with definitive radiotherapy using 3D-IGBT and compared the stage distribution and outcomes between the FIGO 2009 and FIGO 2018 staging systems. Methods Patients with cervical squamous cell carcinoma treated with definitive radiotherapy using 3D-IGBT from 2009 through 2017 were retrospectively collected. The patients were stratified using the FIGO 2009 or 2018 criteria, and survival was analyzed by Kaplan-Meier methods. Results In 221 patients (median follow-up, 60 months), stage migration occurred in 52.9% of the patients. Patients classified with the 2018 criteria as stage IIICr had the highest proportion (43.8%) of migration, and were mainly from the 2009 stages IIB and IIIB. The 2009 and 2018 schemas showed comparable performance at stratifying 5-year overall survival (OS) and 5-year progression-free survival (PFS) for patients in stages IB–IVA. The 2018 criteria effectively stratified 5-year OS and PFS in the stage III substages. The 5-year OS and PFS for stage IIIC1r patients varied according to tumor T stage. Conclusion These results provide evidence for the utility of the revised 2018 FIGO staging system in the clinical management of cervical cancers in the 3D-IGBT era.

Micronuclei (MN) trigger antitumor immune responses via the cyclic GMP-AMP synthase-signaling effector stimulator of interferon genes (cGAS-STING) pathway. Radiotherapy induces MN in peripheral blood lymphocytes. However, data for solid tumors are lacking. Here, we analyzed MN post-radiotherapy in solid tumor samples. Tumor biopsy specimens were obtained from seven prospectively recruited patients with cervical cancer, before treatment and after receiving radiotherapy at a dose of 10 Gy (in five fractions). The samples were stained with 4′,6-diamidino-2-phenylindole dihydrochloride, and 200 nuclei per sample were randomly identified and assessed for the presence of MN or apoptosis, based on nuclear morphology. The median number of MN-harboring nuclei was significantly greater in samples from patients treated with radiotherapy than in pre-treatment samples (151 (range, 16–327) versus 28 (range, 0–61); p = 0.015). No significant differences in the number of apoptotic nuclei were observed between pre-treatment and 10 Gy samples (5 (range, 0–30) versus 12 (range, 2–30); p = 0.30). This is the first report to demonstrate MN induction by radiotherapy in solid tumors. The results provide clinical evidence of the activation of antitumor immune responses by radiotherapy.

The rate and characteristics of prostate-specific antigen (PSA) bounce post-radiotherapy remain unclear. To address this issue, we performed a meta-analysis. Reports of PSA bounce post-radiotherapy with a cutoff of 0.2 ng/mL were searched by using Medline and Web of Science. The primary endpoint was the occurrence rate, and the secondary endpoints were bounce characteristics such as amplitude, time to occurrence, nadir value, and time to nadir. Radiotherapy modality, age, risk classification, androgen deprivation therapy, and the follow-up period were extracted as clinical variables. Meta-analysis and univariate meta-regression were performed with random-effect modeling. Among 290 search-positive studies, 50 reports including 26,258 patients were identified. The rate of bounce was 31%, amplitude was 1.3 ng/mL, time to occurrence was 18 months, nadir value was 0.5 ng/mL, time to nadir was 33 months. Univariate meta-regression analysis showed that radiotherapy modality (29.7%), age (20.2%), and risk classification (12.2%) were the major causes of heterogeneity in the rate of bounce. This is the first meta-analysis of PSA bounce post-radiotherapy. The results are useful for post-radiotherapy surveillance of prostate cancer patients.

Recent widespread use of three-dimensional image-guided brachytherapy (3D-IGBT) has improved radiotherapy outcomes of cervical cancer dramatically. In 2018, the International Federation of Gynecology and Obstetrics (FIGO) staging system for cervical cancer was revised. However, the influence of the revisions on the stage distribution and outcomes of cervical cancers treated with 3D-IGBT remains unclear. Here, we retrospectively analyzed 221 patients with cervical squamous cell carcinoma treated with definitive radiotherapy using 3D-IGBT (median follow-up, 60 months). The stage distribution and outcomes were compared between the 2009 and 2018 schemas. Stage migration occurred in 52.9% of the patients. Patients classified with the 2018 criteria as stage IIICr had the highest proportion (43.8%) of migration, and were mainly from the 2009 stages IIB and IIIB. The 2009 and 2018 schemas showed comparable performance at stratifying 5-year overall survival (OS) and 5-year progression-free survival (PFS) for patients in stages IB&ndash, IVA. The 2018 criteria effectively stratified 5-year OS and PFS in the stage III substages. The 5-year OS and PFS for stage IIIC1r patients varied according to tumor T stage. These data provide evidence for the utility of the revised 2018 FIGO staging system in the clinical management of cervical cancers in the 3D-IGBT era.

Three-dimensional image-guided brachytherapy (3D-IGBT) using computed tomography (CT) is an essential component of definitive radiation therapy for uterine cervical cancer (UCC). Treatment planning for CT-based 3D-IGBT requires delineating the high-risk clinical target volume (CTVHR) and the organs at risk (OARs), which is difficult when the small intestine is adjacent to those delineation targets. Uncertainty in target delineation threatens the validity of 3D-IGBT treatment plans. To address this issue, we introduce the use of diatrizoate meglumine and diatrizoate sodium (gastrografin), an orally administrable iodine-based radiopaque contrast agent. We present two cases of UCC treated with CT-based 3D-IGBT and describe how intraluminal enhancement of the small intestine by oral gastrografin pretreatment facilitated discrimination between the small intestine and the adjacent CTVHR (case no.1) or the rectosigmoid colon (case no. 2). Oral gastrografin pretreatment is a simple and cost-effective method that allows distinguishing the small intestine from the adjacent delineation target (i.e., CTVHR and the OARs) in CT-based 3D-IGBT for UCC.

Cutaneous metastasis of solid malignancies can cause severe disfigurement, which reduces quality of life (QOL). This case indicates potential utility of photon radiotherapy for this disease, leading to recovery of QOL.

This study aimed to first elucidate prostate-specific antigen (PSA) kinetics in prostate cancer patients treated with carbon ion radiotherapy (CIRT). From 2010 to 2015, 131 patients with prostate adenocarcinoma treated with CIRT (57.6 Gy relative biological effectiveness (RBE) in 16 fractions) alone were recruited. PSA was measured at 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54, and 60 months post-CIRT. PSA bounce was defined as PSA increase over a cutoff followed by spontaneous decrease to or below the pre-bounce nadir. PSA failure was determined using the Phoenix criteria (nadir + 2.0 ng/mL). As a result, non-failure-associated temporary increase in PSA exhibited two distinct patterns, namely a classical bounce and a surge at one month. PSA bounce of &sup3, 0.2 ng/mL was observed in 55.7% of the patients. Bounce amplitude was &lt, 2.0 ng/mL in 97.6% of cases. Bounce occurred significantly earlier than PSA failure. Younger age was a significant predictor of bounce occurrence. Bounce positivity was a significant predictor of favorable 5-year PSA failure-free survival. Meanwhile, a PSA surge of &sup3, 0.2 ng/mL was observed in 67.9% of patients. Surge amplitude was significantly larger than bounce amplitude. Larger prostate volume was a significant predictor of PSA surge occurrence. PSA surge positivity did not significantly predict PSA failure. In summary, PSA bounce was distinguishable from PSA failure with regard to timing of occurrence and amplitude (earlier and lower for bounce, respectively). These data are useful for post-CIRT surveillance of prostate cancer patients.

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine neoplasm. Although surgical resection is the first-line treatment for primary MCCs, the characteristics of this disease (i.e., high prevalence in the elderly and in the head and neck region) generate a considerable number of inoperable cases. Radiation therapy shows potential as a definitive treatment alternative to surgery. In definitive radiation therapy for non-resected MCC, 60-66 Gy administered in 2 Gy per fraction and five fractions per week is recommended. However, such frequent visits to the hospital can be a great burden to elderly patients and family members. In this report, we present the case of an 89-year-old patient with MCC (cT2N0M0, stage IIA) of the left cheek. The patient was treated with radiation therapy using a mild hypofractionated schedule (57 Gy provided in 3 Gy per fraction and three fractions per week) targeting the gross tumor. The treatment led to complete tumor remission with well-tolerated acute toxicities at three months post-irradiation. This case indicates that a mild hypofractionated irradiation schedule may achieve tumor control in MCC patients who are inoperable and who cannot make frequent hospital visits.

Background This study aimed to explain the dynamics of prostate-specific antigen (PSA) levels in patients with prostate cancer who were treated with carbon ion radiotherapy (CIRT) and neoadjuvant androgen-deprivation therapy (ADT). Methods Eighty-five patients with intermediate-risk prostate cancer who received CIRT and neoadjuvant ADT from December 2015 to December 2017 were analyzed in the present study. The total dose of CIRT was set at 51.6 Gy (relative biological effectiveness) delivered in 12 fractions over 3 weeks. The PSA bounce was defined as a ≥0.4 ng/ml increase of PSA levels from the nadir, followed by any decrease. PSA failure was defined using the Phoenix criteria. Results The median patient age was 68 (range, 48–81) years. The median follow-up duration was 33 (range, 20–48) months. The clinical T stage was T1c, T2a, and T2b in 27, 44, and 14 patients, respectively. The Gleason score was 6 in 3 patients and 7 in 82 patients. The median pretreatment PSA level was 7.37 (range, 3.33–19.0) ng/ml. All patients received neoadjuvant ADT for a median of 6 (range, 2–117) months. PSA bounces were observed in 39 patients (45.9%), occurring a median of 12 (range, 6–30) months after CIRT. PSA failure was observed in eight patients (9.4%), occurring a median of 21 (range, 15–33) months after CIRT. The 3-year PSA failure-free survival rate was 88.5%. No clinical recurrence was observed during the follow-up period. Younger age and lower T stage were significant predictors of PSA bounce. Younger age was a significant predictor of PSA failure. Conclusions In this study, we identified the significant predictors of the occurrence of PSA bounce and failure. Further follow-up is needed to reveal the clinical significance of PSA dynamics.

Purpose The aim of this study was to investigate the efficacy of combination therapy with intravenously injected microglia (MI) and radiation therapy (RT) for malignant glioma in rats. Methods and Materials Transgenic rats expressing v-erbB and spontaneously developing malignant glioma were used. The rats were divided into 4 groups: control (n = 19), RT alone (n = 10), MI alone (n = 9), and combination MI and RT (MI + RT) (n = 10). Cranial x-ray irradiation (8 Gy per fraction; once per week) was performed at 50 and 51 weeks of age. Cultured rat microglial cells (5 × 106 cells/rat) were intravenously injected via the tail vein within 30 minutes after RT. Results No evidence of side effects, including thrombosis or graft-versus-host disease, was noted. Rats treated with RT alone, MI alone, MI + RT, and control survived 60.9, 56.3, 66.0, and 56.1 weeks, respectively. The survival period of MI + RT was significantly longer than that of control (P = .014), MI alone (P = .027), and RT alone (P = .049). Immunohistochemical analysis showed a significantly higher number of tumor-infiltrated MI in the RT alone (P = .041) and MI + RT groups (P = .014) compared with the control. Significantly more CD8-positive lymphocytes were observed in the MI + RT group (P = .049) compared with the control. A positive correlation was found between the number of MI and CD8-positive lymphocytes (R2 = 0.556). A positive correlation was also found between CD8-positive lymphocytes and survival periods (R2 = 0.460). Conclusions MI + RT increased infiltrated MI and CD8-positive T cells and prolonged survival in transgenic rats that spontaneously developed malignant glioma. Combined immunocellular therapy and RT may provide a novel treatment strategy for malignant glioma.

Inguinal hernia should be repaired prior to photon radiotherapy for prostate cancer to avoid exposing the radiosensitive intestinal tract potentially included in hernia sac.

Herein, we investigate the long-term clinical outcomes for cervical cancer patients treated with in-room computed tomography–based brachytherapy. Eighty patients with Stage IB1–IVA cervical cancer, who had undergone treatment with combined 3D high-dose rate brachytherapy and conformal radiotherapy between October 2008 and May 2011, were retrospectively analyzed. External beam radiotherapy (50 Gy) with central shielding after 20–40 Gy was performed for each patient. Cisplatin-based chemotherapy was administered concurrently to advanced-stage patients aged ≤75 years. Brachytherapy was delivered in four fractions of 6 Gy per week. In-room computed tomography imaging with applicator insertion was performed for treatment planning. Information from physical examinations at diagnosis, and brachytherapy and magnetic resonance imaging at diagnosis and just before the first brachytherapy session, were referred to for contouring of the high-risk clinical target volume. The median follow-up duration was 60 months. The 5-year local control, pelvic progression-free survival and overall survival rates were 94%, 90% and 86%, respectively. No significant differences in 5-year local control rates were observed between Stage I, Stage II and Stage III–IVA patients. Conversely, a significant difference in the 5-year overall survival rate was observed between Stage II and III–IVA patients (97% vs 72%; P = 0.006). One patient developed Grade 3 late bladder toxicity. No other Grade 3 or higher late toxicities were reported in the rectum or bladder. In conclusion, excellent local control rates were achieved with minimal late toxicities in the rectum or bladder, irrespective of clinical stage.

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neuroendocrine neoplasia. Surgical resection is the first-line therapeutic option, and radiation therapy is an alternative treatment for inoperable cases. Herein, we report a case of primary MCC (cT2N0M0, stage IIA) of the head and neck region. This case was misdiagnosed as a metastatic tumor and referred to the department of radiation oncology for palliative irradiation. Additional immunohistochemical analysis confirmed the diagnosis of MCC, and the tumor was treated with definitive radiation therapy (66 Gy in 33 fractions), leading to complete in-field control. This case indicates that even in patients with suspected metastatic tumors referred for palliative treatment, patient characteristics and pathology should be carefully examined to avoid missing potentially controllable primary tumors. In such cases, MCC, although rare, should be included in the differential diagnosis of head and neck lesions.

Background/aim The aim of this study was to evaluate the efficacy and safety of hypofractionated intensity-modulated radiotherapy (IMRT) for intermediate- and high-risk prostate cancer. Patients and methods Seventy-five consecutive patients with intermediate- and high-risk prostate cancer treated with IMRT (63 Gy/21 fractions/7 weeks) between 2010 and 2013 were retrospectively analyzed. PSA relapse and adverse events were determined based on the Phoenix criteria and the Common Terminology Criteria for Adverse Events v4.0, respectively. Results The 5-year PSA relapse-free rate, clinical relapse-free rate, and overall survival rate for all patients was 92.1%, 95.1%, and 92.9%, respectively. The incidence of late grade 2 gastrointestinal- and genitourinary-toxicity at 5 years was 1.3% and 17.1%, respectively. No grade 3 or greater toxicities were observed. Conclusion These data indicate that hypofractionated IMRT (63 Gy in a total of 21 fractions with 3 fractions per week) is effective and safe for intermediate- and high-risk prostate cancer.

Cardiac metastasis of uterine cervical cancer with antemortem diagnosis is extremely rare. Therefore, its landscape epidemiology has not been well elucidated to date. In the present study, a case of solitary cardiac metastasis of uterine cervical cancer diagnosed antemortem is reported, and a review of the currently available literature (which includes 18 cases of cardiac metastasis of uterine cervical cancer) is conducted. In January 2013, a 78-year-old woman with squamous cell carcinoma (SCC) of the uterine cervix (International Federation of Gynecology and Obstetrics stage IIIb) underwent definitive radiotherapy at Gunma University Hospital (Gunma, Japan). Follow-up examination at 5 months after completion of the treatment indicated no evidence of recurrence or metastasis. In April 2014, the patient reported epigastric discomfort and general malaise. Electrocardiogram suggested myocardial dysfunction. Transthoracic echocardiography revealed the presence of a mass occupying the right ventricle and pericardial effusion. Cine magnetic resonance imaging demonstrated a filling defect in the right ventricle, and transcatheter biopsy confirmed SCC. The patient was diagnosed with a solitary cardiac metastasis of uterine cervical cancer. Despite aggressive medical therapy, the patient succumbed to disease 31 days after admission to hospital. A review of the current literature revealed that 84% of cases of cardiac metastasis develop within 2 years of completion of the initial treatment, and that electrocardiogram and echocardiography reveal findings of myocardial dysfunction and the presence of a mass in the right ventricle, respectively. A treatment strategy for cardiac metastasis of uterine cervical cancer has not been standardized thus far, and the prognosis is very poor, as the majority of patients succumbed to disease within 1 year. In summary, the current case and the literature review conducted in the present study suggest that: i) Cardiac metastasis should be included in the differential diagnosis in cases with nonspecific complaints such as epigastric discomfort and general malaise when patients have a history of uterine cervical cancer, particularly within the previous 2 years; and ii) electrocardiogram and echocardiography are convenient and effective modalities for the diagnosis of cardiac metastasis of uterine cervical cancer.

Creatine riboside (CR) is a novel metabolite of cancer metabolism. It is a urinary diagnostic biomarker of lung and liver cancer risk and prognosis. The level of CR is highly positive correlated in tumor and urine indicating that it is derived from human lung and liver cancers. A precise and sensitive ultra-pressure liquid chromatography-tandem mass spectrometry (UPLC-ESI-MS/MS) method was developed and validated for simultaneous quantification of the noninvasive biomarker CR, along with creatinine riboside (CNR), and their precursors creatine and creatinine, utilizing the labeled internal standard creatine riboside-(13)C,(15)N(2) (CR-(13)C,(15)N(2)). Chromatography was carried out on a hydrophilic interaction chromatography column under a gradient mobile phase condition. MRM transitions were monitored for CR (264.1 > 132.1, m/z), CNR (246.1 > 113.9, m/z), creatine (132.0 > 72.0, m/z), creatinine (114.0 > 85.8, m/z) and CR-(13)C,(15)N(2) (267.1 > 134.9, m/z) with a 11.0 min run time in the positive mode ionization. The calibration plot of the method was linear over the concentration range of 4.50–10,000 nM. Method validation was performed according to regulatory guidelines established for sensitivity, selectivity, calibration curve, stability at different storage conditions, reinjection reproducibility, ruggedness with acceptable accuracy, and precision. This assay was applied for the quantification of CR along with CNR, creatine and creatinine in a subset of urine and serum samples from the National Cancer Institute – Maryland (NCI-MD) cohort population controls and lung cancer cases. It can be standardized and used in multiple laboratories for cancer diagnosis and determining the efficacy of cancer therapy and monitoring cancer recurrence.

Key Clinical Message Leptomeningeal metastasis (LM) of uterine cervical cancer is extremely rare. A 54‐year‐old woman with uterine cervical cancer treated with surgery and radiotherapy developed LM manifesting as ptosis 17 years later. Although rare, LM should be considered in patients with a history of uterine cervical cancer presenting with cranial nerve symptoms.

Key Clinical Message Interstitial pneumonia (IP) sometimes precedes collagen vascular disease (CVD) onset. A patient with bladder cancer and mild IP received pelvic irradiation and experienced unexpectedly severe urinary toxicity followed by polymyositis onset and fatal IP exacerbation. Careful observation for “alarm adverse effects” of radiotherapy in IP patients may help predicting CVD onset.

Background The skin is considered a critical organ at risk in carbon ion radiotherapy (CIRT) for locally advanced malignant bone and soft tissue tumors (MBSTs). The predictive factors for acute skin reactions after CIRT have not been investigated. The present study aimed to identify these factors and evaluate the correlation between the severity of acute skin reactions and skin dose parameters. Methods CIRT with total doses of 64.0–70.4 Gy (relative biological effectiveness [RBE]) was administered to 22 patients with MBSTs. The skin-tumor distance (STD), maximum skin total dose (Dmax), and area of the skin receiving a total dose of X Gy (RBE) were evaluated. Results All patients developed acute skin reactions after CIRT, including Grades 1 and 2 dermatitis in 15 (71%) and 6 (29%) patients, respectively. There was a significant difference in the STD between the two groups (P = 0.007), and the cut-off value of STD for predicting Grade 2 acute skin reactions was 11 mm. There was a significant difference in Dmax between the groups (P

To compare the incidence and degree of hematological toxicity between innovator and generic cisplatin formulations, decreases in white blood cell (WBC) count (leukopenia) and platelet counts (thrombocytopenia) were retrospectively examined, using the Common Toxicity Criteria for Adverse Events ver. 4.0, in patients with uterine cervical cancer treated with concurrent chemoradiotherapy using innovator (innovator group, n = 22) or generic (generic group, n = 22) cisplatin formulations. There were no significant differences in patient characteristics except in the technique of external irradiation; larger numbers of patients in the innovator and generic groups were irradiated using the parallel-opposed two-field technique and the four-field box technique, respectively (P = 0.00012), which is in line with the historical progress of external beam radiation therapy. The numbers of patients showing Grade 1, 2, 3 and 4 leukopenia were 1 (4.5%), 14 (64%), 7 (32%) and 0 (0.0%) in the innovator group, and 1 (4.5%), 6 (27%), 13 (59%) and 2 (9.0%) in the generic group, respectively. The number of patients showing Grade 3–4 leukopenia was significantly greater in the generic group than in the innovator group (P = 0.034). There was no significant relationship between the incidence of Grade 3–4 leukopenia and the technique of external irradiation. There were no significant differences in the incidence and degree of thrombocytopenia between the two groups. These results indicate the possibility that the generic cisplatin formulation may have a different toxicity profile compared to the innovator formulation in terms of the incidence of leukopenia.

Carbon ion radiotherapy holds great promise for cancer therapy. Clinical data show that carbon ion radiotherapy is an effective treatment for tumors that are resistant to X-ray radiotherapy. Since 1994 in Japan, the National Institute of Radiological Sciences has been heading the development of carbon ion radiotherapy using the Heavy Ion Medical Accelerator in Chiba. The Gunma University Heavy Ion Medical Center (GHMC) was established in the year 2006 as a proof-of-principle institute for carbon ion radiotherapy with a view to facilitating the worldwide spread of compact accelerator systems. Along with the management of more than 1900 cancer patients to date, GHMC engages in translational research to improve the treatment efficacy of carbon ion radiotherapy. Research aimed at guiding patient selection is of utmost importance for making the most of carbon ion radiotherapy, which is an extremely limited medical resource. Intratumoral oxygen levels, radiation-induced cellular apoptosis, the capacity to repair DNA double-strand breaks, and the mutational status of tumor protein p53 and epidermal growth factor receptor genes are all associated with X-ray sensitivity. Assays for these factors are useful in the identification of X-ray-resistant tumors for which carbon ion radiotherapy would be beneficial. Research aimed at optimizing treatments based on carbon ion radiotherapy is also important. This includes assessment of dose fractionation, normal tissue toxicity, tumor cell motility, and bystander effects. Furthermore, the efficacy of carbon ion radiotherapy will likely be enhanced by research into combined treatment with other modalities such as chemotherapy. Several clinically available chemotherapeutic drugs (carboplatin, paclitaxel, and etoposide) and drugs at the developmental stage (Wee-1 and heat shock protein 90 inhibitors) show a sensitizing effect on tumor cells treated with carbon ions. Additionally, the efficacy of carbon ion radiotherapy can be improved by combining it with cancer immunotherapy. Clinical validation of preclinical findings is necessary to further improve the treatment efficacy of carbon ion radiotherapy.

Carbon ion radiotherapy shows great potential as a cure for X-ray-resistant tumors. Basic research suggests that the strong cell-killing effect induced by carbon ions is based on their ability to cause complex DNA double-strand breaks (DSBs). However, evidence supporting the formation of complex DSBs in actual patients is lacking. Here, we used advanced high-resolution microscopy with deconvolution to show that complex DSBs are formed in a human tumor clinically treated with carbon ion radiotherapy, but not in a tumor treated with X-ray radiotherapy. Furthermore, analysis using a physics model suggested that the complexity of radiotherapy-induced DSBs is related to linear energy transfer, which is much higher for carbon ion beams than for X-rays. Visualization of complex DSBs in clinical specimens will help us to understand the anti-tumor effects of carbon ion radiotherapy.

Lung cancer is the leading cause of cancer-related death worldwide. With the advent of low-dose computed tomography screening, it is expected that the number of lung cancers diagnosed at an early stage will rise sharply. The recommended treatment for stage I non-small cell lung cancer (NSCLC) patients is tumor resection, which may be followed by chemotherapy in patients with pathologically high-risk, margin-negative stage IB tumors. Still, up to 30% surgically treated stage I patients experience recurrence leading to death. Therefore, biomarkers that molecularly categorize stage I patients after tumor resection and stratify high-risk patients who may benefit from adjuvant chemotherapy would lead to improved clinical management. We previously conducted metabolomic profiling of urines collected from 469 NSCLC patients and 536 population controls using ultraperformance liquid chromatography coupled to mass spectrometry (UPLC-MS) and found that creatine riboside, a novel metabolite identified by the study, is significantly elevated in stage I and II NSCLC patients compared to controls. We also found that creatine riboside levels are 19-fold higher in tumor tissues compared to adjacent normal lung tissues (P This abstract is also being presented as Poster A18. Citation Format: Takahiro Oike, Yasuyuki Kanke, Amelia Parker, Majda Haznadar, Kristopher W. Krausz, Elise D. Bowman, Ana I. Robles, Frank J. Gonzalez, Curtis C. Harris. Diagnostic and prognostic utility of urinary creatine riboside for early stage non-small cell lung cancer [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr PR02.

Uterine cervical cancer/Radiotherapy/Small bowel/Pelvic insufficiency fracture/Common iliac lymph node region. The purpose of this study was to compare dose red uction to the small bowel and sacral bone by twofield and four-field techniques when the common iliac lymph node region is excluded from the radiation field in external beam radiotherapy of uterine cervical cancer. Thirteen patients with cervical cancer were entered into the study. Conventional treatment plans based on bony landmarks were made with parallelopposed two-field technique (C2F) and four-field box technique (C4F). Modified C2F (M2F) and C4F (M4F) plans of excluding the common iliac lymph node region from the conventional radiation fields were created in reference to the bifurcations of pelvic arteries in computed tomography images. For each patient, the dose volume histograms for the small bowel and sacral bone resulting from the C2F, C4F, M2F, and M4F plans were compared. The volumes were obtained at 10 levels of prescribed dose, at increments of 10%, from 5 Gy to 50 Gy. By sparing both small bowel and sacral bone, the M2F and M4F plans were s ignificantly better than the C2F and C4F plans at any dose level (p < 0.05), respectively. In addition, the M4F plan was significantly better than the M2F plan in sparing both small bowel at 10–50% of the prescribed dose (p < 0.05) and sacral bone at 40–100% of the prescribed dose (p < 0.05). The present study suggests that modified treatment planning could be useful for selected patients for reducing small bowel complications and insufficiency fracture after radiotherapy.

Liver cancer is third leading cause of cancer-related deaths worldwide. A tremendous burden of this disease is evident in that there is an estimated rise in liver cancer incidence from 39,239 in 2016 to 95,374 by 2020. This bleak statistic serves as a motivation to search for early diagnosis biomarkers, especially considering that the 5-year relative survival rate for people with localized disease is ~30.5%, and for regional stage is only 10.7%. Hepatocellular Carcinoma (HCC) is the most common primary malignant tumor of the liver, and is considered to be the third leading cause of all cancer-related deaths and fifth common cancer worldwide. Hepatitis virus B and C infections, fatty and alcoholic liver disease are established risk factors for developing HCC. Cholangiocarcinoma (CCA) is the second most common primary hepatic malignancy. Liver fluke, a chronic parasitic disease of the bile ducts, is a risk factor for developing CCA; otherwise not enough is known about the etiology of this form of liver cancer. We initially conducted a pilot study in the NCI-MD cohort comprising 98 HCC cases, 101 high risk subjects and 95 controls, to evaluate whether previously identified urinary metabolite biomarkers of lung cancer were also predictive of liver cancer, given preliminary evidence that they were universally elevated in several cancer types. Thus, we leveraged ultraperformance liquid chromatography coupled to tandem mass-spectrometry (UPLC-MS/MS) for quantitation of creatine riboside, N-acetylneuraminic acid, cortisol sulfate, and a lipid molecule designated as 561+. This study resulted in findings that all four aforementioned metabolites are significantly increased in HCC cases compared to both, population controls and, more importantly, high risk subjects. We next evaluated whether our previously described findings from the NCI-MD liver case-control study validate in the TIGER-LC cohort (n=370 cases, 471 high risk subjects, 251 controls), where CCA is highly prevalent. We confirmed that indeed the four metabolites were significantly increased in HCC cases compared to both, controls and high risk subjects in TIGER-LC. Most importantly, we also showed that these metabolites are also deregulated in CCA, as their levels are significantly elevated in CCA cases when compared to both, controls and high risk subjects. Furthermore, we showed in the Receiver Operating Characteristic (ROC) analysis a robust ability of the four-metabolite profile to classify both, HCC (AUC=0.75) and CCA (AUC=0.81) compared to high risk subjects. Additionally, the four-metabolite profile performed better in classifying CCA than a clinically utilized CCA tumor marker, CA19-9, and their combination led to a significantly improved classifier (AUC=0.88, P=9.4E-7). Currently, we are investigating a number of pesticides and herbicides used in the areas of Thailand from where TIGER-LC subjects were recruited, to investigate whether these putative carcinogens participate in the etiology of CCA. Citation Format: Majda Haznadar, Kristopher W. Krausz, Christopher M. Diehl, Elise D. Bowman, Anuradha S. Budhu, Jittiporn Chaisaingmongkol, Siritida Rabibhadana, Marshonna Forgues, Takahiro Oike, Mathuros Ruchirawat, Frank J. Gonzalez, Xin W. Wang, Curtis C. Harris. Urinary metabolites are diagnostic biomarkers of liver cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2500. doi:10.1158/1538-7445.AM2017-2500

The mammalian target of rapamycin (mTOR) correlates with cell survival under hypoxia and regulates hypoxia-inducible factor-1α (HIF-1α), a key protein in hypoxia-related events. However, the role of mTOR in radio-resistance has not been fully investigated. Therefore, the effect of mTOR on the radio-resistance of cancer cells under hypoxia was evaluated using the mTOR inhibitor temsirolimus. Clonogenic survival was examined in the A549 human lung adenocarcinoma cell line under normoxia or hypoxia, with or without temsirolimus. An oxygen enhancement ratio (OER) was calculated using the D(10) values, the doses giving 10% survival. Western blotting was performed to investigate the effect of temsirolimus on mTOR and the HIF-1α pathway under normoxia and hypoxia. A549 cells showed a radio-resistance of 5.1 and 14.2 Gy, as indicated by D(10) values under normoxia and hypoxia, respectively; the OER was 2.8. The cell survival rates under hypoxia and with temsirolimus remarkably decreased compared with those under normoxia. The D(10) values of the cells under normoxia and hypoxia were 4.8 and 5.4 Gy, respectively (OER = 1.1). mTOR expression was suppressed by temsirolimus under both normoxia and hypoxia. HIF-1α expression decreased under hypoxia in the presence of temsirolimus. These results suggest that temsirolimus can overcome the radio-resistance induced by hypoxia. When the fact that mTOR acts upstream of HIF-1α is considered, our data suggest that the restoration of radiation sensitivity by temsirolimus under hypoxia may be associated with the suppression of the HIF-1α pathway. Temsirolimus could therefore be used as a hypoxic cell radio-sensitizer.

Background Interstitial brachytherapy (ISBT) is an optional treatment for locally advanced gynecological tumours for which conventional intracavitary brachytherapy (ICBT) would result in suboptimal dose coverage. However, ISBT with Martinez Universal Perineal Interstitial Template (MUPIT), in which ~10-20 needles are usually applied, is more time-consuming and labor-intensive than ICBT alone, making it a burden on both practitioners and patients. Therefore, here we investigated the applicability of a combined intracavitary/interstitial (IC/IS) approach in image-guided adaptive brachytherapy for bulky and/or irregularly shaped gynecological tumours for which interstitial brachytherapy (ISBT) was performed. Methods Twenty-one consecutive patients with gynecological malignancies treated with computed tomography-guided ISBT using MUPIT were analyzed as cases for this dosimetric study. For each patient, the IC/IS plan using a tandem and 1 or 2 interstitial needles, which was modeled after the combined IC/IS approach, was generated and compared with the IS plan based on the clinical ISBT plan, while the IC plan using only the tandem was applied as a simplified control. Maximal dose was prescribed to the high-risk clinical target volume (HR-CTV) while keeping the dose constraints of D2cc bladder

Glioblastoma multiforme is the most common adult primary brain tumor that is associated with very poor survival. The current standard therapy for newly diagnosed glioblastoma multiforme includes surgical resection and a combination of radiotherapy and chemotherapy with temozolomide. This treatment strategy leads to better overall survival; however, majority of tumor recurrences occur within the irradiated field. To overcome this problem, dose intensification is being tested in the management of glioblastoma multiforme. In recent years, technological development of radiotherapies, such as intensity-modulated radiation therapy, stereotactic radio surgery, stereotactic radiation therapy, boron neutron capture therapy, and particle beam therapy, has improved dose distribution. Several prospective studies using these radiotherapies have shown that dose escalation is feasible and appears to be effective. Although the number of patients with glioblastoma multiforme in each study was not large, the survival times in these studies tended to be better than in those with standard dosing schedules. Dose escalation radiotherapy could be a hopeful strategy for patients with glioblastoma multiforme. In this review, we review advances in current radiotherapies for patients with newly diagnosed glioblastoma multiforme.

Recently, it has become clear that acute hypoxia affecting radioresistance exists widely in tumor tissues. Concurrently, hypoxia-inducible factor-1α (HIF-1α) is recognized as an essential transcriptional factor, enabling cells to survive through hypoxia. However, it is unclear as to whether HIF-1α plays a direct role in the radioresistance caused by acute hypoxia. Therefore, in this study, we investigated the in vitro response of the human lung adenocarcinoma cell line, A549, to ionizing radiation in an experimental model that imitates acute hypoxia in the presence and absence of HIF-1α expression, using the HIF-1α inhibitor 5-[1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol (YC-1). Cells were treated with or without 10 μM YC-1 for 2 h. Cells were exposed to either 95% N(2) and 5% CO(2) (hypoxic condition of

This study was conducted to investigate the feasibility and survival benefits of combined treatment with radiotherapy and temozolomide (TMZ), which has been covered by the national health insurance in Japanese patients with glioblastoma since September 2006. Between September 2006 and December 2011, 47 patients with newly diagnosed and histologically confirmed glioblastoma received radiotherapy for 60 Gy in 30 fractions. Among them, 45 patients (TMZ group) received concomitant TMZ (75 mg/m(2)/day, every day) and adjuvant TMZ (200 mg/m(2)/day, 5 days during each 28-days). All 36 of the glioblastoma patients receiving radiotherapy between January 1988 and August 2006 were analyzed as historical controls (control group). All patients were followed for at least 1 year or until they died. The median survival was 15.8 months in the TMZ group and 12.0 months in the control group after a median follow-up of 14.0 months. The hazard ratio for death in the TMZ group relative to the control group was 0.52 (P