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

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

Artificial Intelligence-Guided Segmentation and Path Planning Software for Transthoracic Lung Biopsy.

PURPOSE: To validate the sensitivity and specificity of a 3-dimensional (3D) convolutional neural network (CNN) artificial intelligence (AI) software for lung lesion detection and to establish concordance between AI-generated needle paths and those used in actual biopsy procedures. MATERIALS AND METHODS: This was a retrospective study using computed tomography (CT) scans from 3 hospitals. Inclusion criteria were scans with 1-5 nodules of diameter ≥5 mm; exclusion criteria were poor-quality scans or those with nodules measuring <5mm in diameter. In the lesion detection phase, 2,147 nodules from 219 scans were used to develop and train the deep learning 3D-CNN to detect lesions. The 3D-CNN was validated with 235 scans (354 lesions) for sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) analysis. In the path planning phase, Bayesian optimization was used to propose possible needle trajectories for lesion biopsy while avoiding vital structures. Software-proposed needle trajectories were compared with actual biopsy path trajectories from intraprocedural CT scans in 150 patients, with a match defined as an angular deviation of <5° between the 2 trajectories. RESULTS: The model achieved an overall AUC of 97.4% (95% CI, 96.3%-98.2%) for lesion detection, with mean sensitivity of 93.5% and mean specificity of 93.2%. Among the software-proposed needle trajectories, 85.3% were feasible, with 82% matching actual paths and similar performance between supine and prone/oblique patient orientations (P = .311). The mean angular deviation between matching trajectories was 2.30° (SD ± 1.22); the mean path deviation was 2.94 mm (SD ± 1.60). CONCLUSIONS: Segmentation, lesion detection, and path planning for CT-guided lung biopsy using an AI-guided software showed promising results. Future integration with automated robotic systems may pave the way toward fully automated biopsy procedures.

Incidence of pancreatic injury and pancreatitis in patients treated with immune checkpoint inhibitors.

OBJECTIVES: Immune checkpoint inhibitors (ICIs) are being increasingly used to treat advanced malignancies. ICI-induced pancreatic injury (ICI-PI), which is an immune-related adverse event that may be a risk factor for ICI-associated pancreatitis, is not well documented in the literature. METHODS: Consecutive patients who received ICIs for advanced malignancies from August 2015 through October 2022 were analyzed with regard to the incidence of ICI-PI based on the Common Terminology Criteria for Adverse Events and ICI-associated pancreatitis. The imaging, clinical, and pathological findings of ICI-associated pancreatitis were also assessed. RESULTS: This study enrolled 843 patients. In multivariable analyses, dual or simultaneous immunotherapy and ≥10 cycles of ICI administration were significant predictive factors for all grades of pancreatic injury, including grade ≥ 3. Notably, patients who received simultaneous immunotherapy exhibited a higher incidence of grade ≥ 3 pancreatic injuries compared to those receiving asynchronous immunotherapy in univariable analysis (p = 0.032). One-fifth of the patients (16/70) with grade ≥ 3 pancreatic injuries had imaging evidence of pancreatitis similar to mild acute pancreatitis. ICI-associated pancreatitis was observed in 5.7% (48/843) of patients, including 1.8% (15/843) with moderate-to-severe pancreatitis (grade ≥ 2). Symptomatic cases (0.36%, 3/843) were treated with steroids with favorable outcomes. Immunohistochemistry for CD4 and CD8 revealed greater infiltration of CD8+ than CD4+ lymphocytes. CONCLUSION: Simultaneous immunotherapy and dual immunotherapy are risk factors for ICI-PI. Although most patients diagnosed with ICI-PI and ICI-associated pancreatitis were asymptomatic and had a low mortality likelihood, long-term outcomes, including endocrine and exocrine function should be carefully monitored.

Three-compartment spectral diffusion analysis for breast cancer magnetic resonance imaging.

RATIONALE AND OBJECTIVES: To examine the diagnostic performance of a three-compartment diffusion model with the fixed cut-off diffusion coefficient (D) using magnetic resonance spectral diffusion analysis for differentiating between invasive ductal carcinoma (IDC) and ductal carcinoma in situ (DCIS) and compare the conventional apparent D (ADC), and mean kurtosis (MK), with the tissue D (DIVIM), perfusion D (D*IVIM), and perfusion fraction (fIVIM) calculated by conventional intravoxel incoherent motion. PATIENTS AND METHODS: This retrospective study included women who underwent breast MRI with eight b-value diffusion-weighted imaging between February 2019 and March 2022. Spectral diffusion analysis was performed; very-slow, cellular, and perfusion compartments were defined using cut-off Ds of 0.1 × 10-3 and 3.0 × 10-3 mm2/s (static water D). The mean D (Ds, Dc, Dp, respectively) and fraction F (Fs, Fc, Fp, respectively) for each compartment were calculated. ADC and MK values were also calculated; receiver operating characteristic analyses were performed. RESULTS: Histologically confirmed 132 ICD and 62 DCIS (age range 31-87 [53 ± 11] years) were evaluated. The areas under the curve (AUCs) for ADC, MK, DIVIM, D*IVIM, fIVIM, Ds, Dc, Dp, Fs, Fc, and Fp were 0.77, 0.72, 0.77, 0.51, 0.67, 0.54, 0.78, 0.51, 0.57, 0.54, and 0.57, respectively. The AUCs for the model combining very-slow and cellular compartments and the model combining the three compartments were 0.81 each, slightly and significantly higher than for ADC, DIVIM, and Dc (P = 0.09-0.14); and MK (P < 0.05), respectively. CONCLUSION: Three-compartment model analysis using the diffusion spectrum accurately differentiated IDC from DCIS; however, it was not superior to ADC and DIVIM. The diagnostic performance of MK was lower than that of the three-compartment model.

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

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

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

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

A rare case of long-term survival from metachronous bilateral adrenal metastasis of lung adenocarcinoma after combined surgical removal and immunochemotherapy.

Introduction: The prognosis of adrenal metastasis from non-small cell lung cancer is very poor. A recent report described the efficacy of the surgical removal of adrenal metastasis when solitary. However, metachronous bilateral adrenal metastasis is extremely rare, and a treatment strategy has not been established. Case presentation: Herein, we describe a 52-year-old Asian male who presented with a right adrenal metastasis of non-small cell lung cancer 8 months after immunochemotherapy and surgical resection of the lung. He underwent combined systemic treatment and a laparoscopic right adrenalectomy; however, after 9 months, a metachronous left adrenal metastasis emerged. A subsequent laparoscopic left adrenalectomy and systemic treatment led to long-term progression-free survival. Conclusion: The appropriate surgical indication and combined systemic treatment of a metachronous bilateral adrenal metastasis in non-small cell lung cancer may extend the prognosis.

A case of metastatic treatment-emergent small cell/neuroendocrine prostate cancer with BRCA2 mutation diagnosed by liver biopsy.

Introduction: Treatment-emergent small cell/neuroendocrine prostate cancer occurs predominantly in advanced or metastatic castration-resistant prostate cancer that arises when prostate adenocarcinoma is transformed after androgen deprivation therapy. The clinical course for the pathogenesis involved or associated genetic information have not been clearly elucidated. Case presentation: A Japanese male, 63-year-old, underwent a para-aortic lymph biopsy due to sudden severe bilateral leg edema, with a final diagnosis of stage IV prostate adenocarcinoma. He was initially responsive to upfront abiraterone with androgen deprivation therapy; however, relapse occurred in the liver and bone 10 months after initial treatment, with serum neuron-specific enolase elevation and without prostate-specific antigen elevation. Pathological findings of liver tumor revealed treatment-emergent small cell/neuroendocrine prostate cancer. FoundationOne® CDx was used for cancer-related gene profiling of liver tumor specimen; a BRCA2 mutation was identified. Conclusion: Early detection of this transformation and pathological diagnosis can improve patient survival when genetic mutations, including BRCA 1/2.

Erratum to "Ependymoma of the broad ligament mimicking an ovarian surface epithelial tumor" [Radiology Case Reports 16 (2021) 210-214].

[This corrects the article DOI: 10.1016/j.radcr.2020.10.046.].

Continuous monitoring of postirradiation reoxygenation and cycling hypoxia using electron paramagnetic resonance imaging.

Reoxygenation has a significant impact on the tumor response to radiotherapy. With developments in radiotherapy technology, the relevance of the reoxygenation phenomenon in treatment efficacy has been a topic of interest. Evaluating the reoxygenation in the tumor microenvironment throughout the course of radiation therapy is important in developing effective treatment strategies. In the current study, we used electron paramagnetic resonance imaging (EPRI) to directly map and quantify the partial oxygen pressure (pO2 ) in tumor tissues. Human colorectal cancer cell lines, HT29 and HCT116, were used to induce tumor growth in female athymic nude mice. Tumors were irradiated with 3, 10, or 20 Gy using an x-ray irradiator. Prior to each EPRI scan, magnetic resonance imaging (MRI) was performed to obtain T2-weighted anatomical images for reference. The differences in the mean pO2 were determined through two-tailed Student's t-test and one-way analysis of variance. The median pO2 60 min after irradiation was found to be lower in HCT116 than in HT29 (9.1 ± 1.5 vs. 14.0 ± 1.0 mmHg, p = 0.045). There was a tendency for delayed and incomplete recovery of pO2 in the HT29 tumor when a higher dose of irradiation (10 and 20 Gy) was applied. Moreover, there was a dose-dependent increase in the hypoxic areas (pO2  < 10 mmHg) 2 and 24 h after irradiation in all groups. In addition, an area that showed pO2 fluctuation between hypoxia and normoxia (pO2  > 10 mmHg) was also identified surrounding the region with stable hypoxia, and it slightly enlarged after recovery from acute hypoxia. In conclusion, we demonstrated the reoxygenation phenomenon in an in vivo xenograft model study using EPRI. These findings may lead to new knowledge regarding the reoxygenation process and possibilities of a new radiation therapy concept, namely, reoxygenation-based radiation therapy.

Survival Outcome after Reduced-Port Laparoscopic Radical Cystectomy for Bladder Cancer: Long-Term Follow-Up Analysis.

INTRODUCTION: This study had two objectives: (i) to evaluate oncological outcomes in a long-term follow-up of patients with bladder cancer after reduced-port laparoscopic radical cystectomy (RP-LRC) and (ii) to assess the effect of modified Glasgow prognostic scores (mGPS) on patient outcomes. METHODS: Consecutive patients (n = 100) who received RP-LRC between March 2012 and December 2018 at our institution and affiliated hospital were retrospectively reviewed. Preoperative serum albumin and C-reactive protein levels were determined. Patients were grouped based on clinical T stage (≤cT2: n = 75, ≥cT3: n = 25) using pooled cumulative data. Oncological outcomes and mGPS as a prognostic biomarker were analyzed retrospectively. Kaplan-Meier curves displayed recurrence and survival rates. Univariate and multivariate Cox regression analyses evaluated potential prognostic factors for recurrence-free survival (RFS) and cancer-specific survival (CSS). RESULTS: Patient characteristics between the two groups were statistically similar for preoperative hematological and mGPS status, blood loss level, rate of allogeneic transfusion, and pneumoperitoneum time. After a median follow-up period of 55 months, 40/100 patients experienced disease relapse. RFS and CSS for ≤cT2 were significantly less than for ≥cT3 (p < 0.001, p < 0.05, respectively). Distant metastasis occurred in 30 patients with similar distributions of relapse sites between T-stage cohorts. Median RFS for mGPS 1/2 were 18.9 (95% confidence interval [CI]: 8.8-not assessed [NA]) and 35.0 (95% CI: 8.7-NA) months, respectively, significantly worse than for mGPS 0 (median NA, 95% CI: NA-NA); CSS was similar. Univariate and multivariate analyses revealed ≥cT3 stage, worse clinical N stage, and poor mGPS status were significant prognostic factors for short RFS and CSS. CONCLUSIONS: A large proportion of bladder cancer patients who undergo RP-LRC experience relapse, with ≥cT3 stage, worse clinical N stage or poor mGPS status identified as significant prognostic factors. Our findings may contribute to improved surgical procedures for such patients.

Utilization of an Occlusion Balloon Catheter during Stent-Graft Placement to Treat Postsurgical Visceral Arterial Hemorrhage.

The utility of occluding the bleeding artery using an occlusion balloon catheter during stent-graft placement for visceral artery bleeding was evaluated. Stent-graft placement for visceral artery bleeding was performed using a balloon catheter in 6 patients. All bleeding occurred after biliary or pancreatic surgery. Since 1 patient underwent the procedure twice, 7 procedures were assessed in total. Technical success, procedure-related adverse events, and 30-day mortality rates were evaluated. Technical success was defined as the placement of the stent-graft at the target site and the resolution of extravasation or pseudoaneurysm. In all procedures, stent-graft placement was successfully performed (technical success rate, 100%). Focal liver infarction occurred in 2 of 7 patients (29%), but did not require further treatment and was considered a minor adverse event. The 30-day mortality rate was 0%. In conclusion, the use of an occlusion balloon in the feeding artery facilitated successful stent-graft repair of hemorrhage from visceral arteries.

Testicular seminoma arising from infertile testes 6 years after microdissection testicular sperm extraction.

INTRODUCTION: In Western countries, the risk of a testicular germ cell tumor in men with male factor infertility is greater than in the general population. However, Japanese data on this risk are lacking. Additionally, the clinical course for the pathogenesis involved has not been clearly characterized. CASE PRESENTATION: A 35-year-old Japanese male underwent a right orchiectomy because of a mass in his right scrotum. He had a previous history of microdissection testicular sperm extraction undertaken 6 years ago. The final diagnosis of the right scrotal mass was a stage I seminoma. However, a relapse occurred in the left inguinal lymph node 2 years after surgery and the patient was consequently treated with systemic chemotherapy. Pathological analysis of a microdissection testicular sperm extraction sample yielded a germ cell neoplasia in situ in the right testis. CONCLUSION: In Japan, men who seek an evaluation for infertility might be more likely to develop testicular germ cell tumor.

Rare case of immunoglobulin G4-related disease arising in gonadal glands with long-term remission without steroid treatment: Discussion and literature review.

INTRODUCTION: Immunoglobulin G4-related disease embraces a wide range of extra-pancreatic manifestations. However, localized pathogenesis in gonadal glands, including testes or seminal vesicles, is rare. The clinical course and therapeutic strategy for this disease have not been clearly characterized. CASE PRESENTATION: A 61-year-old Asian male had a left orchiectomy and right seminal vesicle biopsy because of a mass in the left testis and right seminal vesicle. Histological findings showed an infiltration of immunoglobulin G4-positive plasma cells in the respective tissues and met immunoglobulin G4-related disease diagnostic criteria. No recurrence and exacerbation have been observed after 12 years' follow-up without any clinical intervention. To date, immunoglobulin G4-related disease in gonadal tissue is rare. This is the first case with mass-forming lesions in both the testis and seminal vesicle. CONCLUSION: Based on the clinical course of our case and the literature, for patients with accurately diagnosed inactive gonadal immunoglobulin G4-related disease, watchful waiting is a feasible clinical treatment option.

Detection of metabolic change in glioblastoma cells after radiotherapy using hyperpolarized 13 C-MRI.

Dynamic nuclear polarization (DNP) of 13 C-labeled substrates enables the use of magnetic resonance imaging (MRI) to monitor specific enzymatic reactions in tumors and offers an opportunity to investigate these differences. In this study, DNP-MRI chemical shift imaging with hyperpolarized [1-13 C] pyruvate was conducted to evaluate the metabolic change in glycolytic profiles after radiation of two glioma stem-like cell-derived gliomas (GBMJ1 and NSC11) and an adherent human glioblastoma cell line (U251) in an orthotopic xenograft mouse model. The DNP-MRI showed an increase in Lac/Pyr at 6 and 16 h after irradiation (18% ± 4% and 14% ± 3%, respectively; mean ± SEM) compared with unirradiated controls in GBMJ1 tumors, whereas no significant change was observed in U251 and NSC11 tumors. Metabolomic analysis likewise showed a significant increase in lactate in GBMJ1 tumors at 16 h. An immunoblot assay showed upregulation of lactate dehydrogenase-A expression in GBMJ1 following radiation exposure, consistent with DNP-MRI and metabolomic analysis. In conclusion, our preclinical study demonstrates that the DNP-MRI technique has the potential to be a powerful diagnostic method with which to evaluate GBM tumor metabolism before and after radiation in the clinical setting.

Novel case of androgen receptor-positive cancer of unknown primary without serum prostate-specific antigen elevation that became progression free in the long term after primary combined androgen blockade.

INTRODUCTION: The prognosis of cancer of unknown primary is very poor. Such a prognosis can be improved by characterizing primary characteristics and developing tailored site-specific therapy, especially for androgen receptor-positive adenocarcinoma. However, in such cases without elevated prostate-specific antigen, the efficacy of androgen deprivation therapy is unclear. CASE PRESENTATION: Herein, we report a case that presented with a retroperitoneal cancer of unknown primary that was confirmed as an androgen receptor-positive adenocarcinoma without prostate-specific antigen elevation. Pelvic magnetic resonance imaging did not reveal any suspicious cancer lesions in the prostate. Furthermore, malignant cells were not present in a prostate biopsy specimen. In spite of the prostate-specific antigen level, on the basis of immunohistochemical analyses, including NKX3.1, the patient was first treated with androgen deprivation therapy, leading to long-term progression-free survival. CONCLUSION: Early androgen deprivation therapy based on immunohistochemical analyses might lead to a good outcome in androgen receptor-positive adenocarcinoma cancer of unknown primary patients regardless of prostate-specific antigen level.

Effects of a combined treatment regimen consisting of Hsp90 inhibitor DS-2248 and radiation in vitro and in a tumor mouse model.

BACKGROUND: Heat shock protein 90 (HSP90) is a molecular chaperone that is responsible for the conformational maintenance of several client proteins that play important roles in DNA damage repair, apoptosis following radiation, and resistance to radiation therapy. DS-2248 (tricyclic pyrazolopyrimidine derivative) is a newly-developed, orally available inhibitor of HSP90 with low adverse effects. We investigated the combined effects of radiation and DS-2248 in vitro and in vivo. METHODS: SCCVII squamous cell carcinoma cells and tumors transplanted in C3H/HeN mice were used. In vitro combined effects of X-ray radiation and DS-2248 were investigated using a colony assay. Phosphorylated histone H2AX (γH2AX) was quantified after 2-Gy irradiation with or without 24-hour pretreatment with DS-2248. The mice bearing SCCVII tumors received oral DS-2248 10 times over 2 weeks and received local irradiation with doses of 1, 2, 3, and 4 Gy delivered 6 times over 2 weeks. Then, tumor volumes were measured. RESULTS: Radiation plus pretreatment with 50 nM DS-2248 for 24 hours produced synergistic effects on SCCVII cells. γH2AX foci persisted after radiation for longer periods (6 and 24 hours) in DS-2248-treated cells than in control cells. In vivo, the combined effects appeared to be additive when 5 or 10 mg/kg DS-2248 was combined with total radiation doses of 6-18 Gy, but the effect was considered supra-additive when 15 mg/kg of DS-2248 was combined with a total dose of 24 Gy. CONCLUSIONS: The combined effects of DS-2248 and radiation were additive at low drug and radiation doses, but may have been supra-additive at higher doses. Inhibition of slow repair of DNA double strand breaks (i.e., homologous recombination) was considered to contribute to this combined effect.

Ependymoma of the broad ligament mimicking an ovarian surface epithelial tumor.

We report a case of ependymoma of the broad ligament occurring in a 21-year-old woman. CT and MRI findings showed a 40-mm-diameter, well-demarcated cystic mass with a lobulated solid component in the right pelvis. The solid component showed heterogeneous intermediate signal intensity on T2-weighted image and prolonged mild contrast enhancement. The tumor was resected and confirmed as ependymoma based on the histologic findings along with its immunohistochemical profile. To our knowledge, this is the first report of an adnexal ependymoma describing the precise radiological characteristics that resembled those of borderline or malignant epithelial ovarian tumors.

Co-imaging of the tumor oxygenation and metabolism using electron paramagnetic resonance imaging and 13-C hyperpolarized magnetic resonance imaging before and after irradiation.

To examine the relationship between local oxygen partial pressure and energy metabolism in the tumor, electron paramagnetic resonance imaging (EPRI) and magnetic resonance imaging (MRI) with hyperpolarized [1-13C] pyruvate were performed. SCCVII and HT29 solid tumors implanted in the mouse leg were imaged by EPRI using OX063, a paramagnetic probe and 13C-MRI using hyperpolarized [1-13C] pyruvate. Local partial oxygen pressure and pyruvate metabolism in the two tumor implants were examined. The effect of a single dose of 5-Gy irradiation on the pO2 and metabolism was also investigated by sequential imaging of EPRI and 13C-MRI in HT29 tumors. A phantom study using tubes filled with different concentration of [1-13C] pyruvate, [1-13C] lactate, and OX063 at different levels of oxygen confirmed the validity of this sequential imaging of EPRI and hyperpolarized 13C-MRI. In vivo studies revealed SCCVII tumor had a significantly larger hypoxic fraction (pO2 < 8 mmHg) compared to HT29 tumor. The flux of pyruvate-to-lactate conversion was also higher in SCCVII than HT29. The lactate-to-pyruvate ratio in hypoxic regions (pO2 < 8 mmHg) 24 hours after 5-Gy irradiation was significantly higher than those without irradiation (0.76 vs. 0.36) in HT29 tumor. The in vitro study showed an increase in extracellular acidification rate after irradiation. In conclusion, co-imaging of pO2 and pyruvate-to-lactate conversion kinetics successfully showed the local metabolic changes especially in hypoxic area induced by radiation therapy.

Quantitative imaging of pO2 in orthotopic murine gliomas: hypoxia correlates with resistance to radiation.

Hypoxia is considered one of the microenvironmental factors associated with the malignant nature of glioblastoma. Thus, evaluating intratumoural distribution of hypoxia would be useful for therapeutic planning as well as assessment of its effectiveness during the therapy. Electron paramagnetic resonance imaging (EPRI) is an imaging technique which can generate quantitative maps of oxygen in vivo using the exogenous paramagnetic compound, triarylmethyl and monitoring its line broadening caused by oxygen. In this study, the feasibility of EPRI for assessment of oxygen distribution in the glioblastoma using orthotopic U87 and U251 xenograft model is examined. Heterogeneous distribution of pO2 between 0 and 50 mmHg was observed throughout the tumours except for the normal brain tissue. U251 glioblastoma was more likely to exhibit hypoxia than U87 for comparable tumour size (median pO2; 29.7 and 18.2 mmHg, p = .028, in U87 and U251, respectively). The area with pO2 under 10 mmHg on the EPR oximetry (HF10) showed a good correlation with pimonidazole staining among tumours with evaluated size. In subcutaneous xenograft model, irradiation was relatively less effective for U251 compared with U87. In conclusion, EPRI is a feasible method to evaluate oxygen distribution in the brain tumour.