Objective Although radiotherapy is an important treatment strategy for head and neck cancers, it induces tumor repopulation which adversely affects therapeutic outcome. In this regard, fractionated radiotherapy is widely applied to prevent tumor repopulation. Evaluation of tumor proliferative activity using 18 F-fluorothymidine (FLT), a noninvasive marker of tumor proliferation, may be useful for determining the optimal timing of and dose in the repetitive irradiation. Thus, to assess the potentials of FLT, we evaluated the sequential changes in intratumoral proliferative activity in head and neck cancer xenografts (FaDu) using FLT. MethodsFaDu tumor xenografts were established in nude mice and assigned to control and two radiation-treated groups (10 and 20 Gy). Tumor volume was measured daily. 3 H-FLT was injected intravenously 2 hrs before sacrifice. Mice were sacrificed 6, 24, 48 hrs, and 7 days after the radiation treatment. Intratumoral 3 H-FLT level was visually and quantitatively assessed by autoradiography. Ki-67 immunohistochemistry (IHC) was performed. ResultsIn radiation-treated mice, the tumor growth was significantly suppressed compared with the control group, but the tumor volume in these mice gradually increased with time. In the visual assessment, intratumoral 3 H-FLT level diffusely decreased 6 hrs after the radiation treatment and then gradually increased with time, whereas no apparent changes were observed in Ki-67 IHC. Six hours after the radiation treatment at 10 and 20 Gy, the intratumoral 3 H-FLT level markedly decreased to 45 and 40% of the control, respectively (P < 0.0001, vs control), and 4 then gradually increased with time. In each radiation-treated group, the 3 H-FLT levels at 48 hrs and on day 7 were significantly higher than that at 6 hrs. The Intratumoral 3 H-FLT levels in both treated groups were 68 and 60% at 24 hrs (P < 0.001), 71 and 77% at 48 hrs (P < 0.001), and 83and 81% on day 7 (P = NS) compared with the control group.Conclusion Intratumoral FLT uptake level markedly decreased at 6 hrs and then gradually increased with time. Sequential evaluation of intratumoral proliferative activity using FLT can be beneficial for determining the optimal timing of and dose in repetitive irradiation of head and neck cancer.

An early identification of the tumor response to sorafenib treatment is indispensable for selecting optimal personalized treatment strategies. However, at present, no reliable predictors are clinically available. 18F-fluorothymidine (18F-FLT) positron emission tomography (PET) is used to assess tumor proliferation, since the FLT uptake level reflects thymidine kinase-1 (TK-1) activity. Thus, the present study determined whether FLT was able to evaluate the early tumor response to sorafenib treatment in a human renal cell carcinoma (RCC; A498) xenograft in comparison with the tumor proliferation marker, Ki-67. Mice bearing A498 tumors were assigned to the control and sorafenib-treated groups and the tumor volume was measured every day. [Methyl-3H(N)]-3′-fluoro-3′-deoxythymidine (3H-FLT) was injected 2 h prior to the sacrifice of the mice on days three and seven following the treatment. 3H-FLT autoradiography (ARG) and Ki-67 immunohistochemistry (IHC) were performed using adjacent tumor sections. In the visual assessment, the intratumoral 3H-FLT uptake level diffusely increased following the treatment, while no significant changes were observed in Ki-67 IHC. The intratumoral 3H-FLT uptake levels significantly increased by 2.7- and 2.6-fold on days three and seven following the treatment, while the tumor volume and Ki-67 index did not significantly change. Thus, an increased FLT uptake level was demonstrated following the treatment, which may indicate the suppression of thymidylate synthase (TS) and the compensatory upregulation of TK-1 activity by sorafenib.

We report an advanced case of bisphosphonate-related osteonecrosis of the jaw (BRONJ) in an osteoporotic patient treated with oral risedronate sodium for 2 years. An 80-year-old woman presented to our hospital complaining of pain, swelling and pus discharge in the lower alveolar ridge. Fluorine-18 labeled fluorodeoxyglucose positron emission tomography (FDG-PET) and bone scintigraphy showed definite uptake in the mandible. Under clinical diagnosis of BRONJ, we applied systematic treatments including antibiotic therapy, irrigation, cessation of bisphosphonate, hyperbaric oxygen (HBO) therapy, and debridement of necrotic bone. After pre-operative 20 sessions of HBO therapy, her clinical symptoms disappeared. SUVmax of FDG-PET decreased definitely from 4.5 to 2.5, although magnetic resonance image and bone scintigraphy did not show remarkable changes. After minor surgery with debridement of necrotic bone, she received another ten sessions of HBO therapy. After the treatment, her clinical course was excellent. In conclusion, this report demonstrates FDG-PET may predict the effect of HBO therapy in BRONJ.

Abstract.A mechanistic dissociation exists between tumor starvation and vascular normalization after antiangiogenic therapy. Thus, improved understanding of tumor responses (tumor starvation or vascular normalization) is important for optimizing treatment strategies.18 F-fluoromisonidazole ( 18 F-FMISO) is widely used for imaging tumor hypoxia.To clarify the tumor response to the antiangiogenic drug sorafenib, the present study evaluated the changes in the tumor oxygen state using 18 F-FMISO in mice bearing a renal cell carcinoma xenograft (A498). Mice bearing A498 xenografts were assigned to the control and three sorafenib-treatment groups and administered sorafenib (0, 10, 20 or 40 mg/kg/day, per os) once daily for 3 days. Following one day after the final administration, the mice were injected with 18 F-FMISO and pimonidazole (a hypoxia marker).18 F-FMISO accumulation in the tumor was determined by autoradiography. Immunohistochemistry of pimonidazole and cluster of differentiation (CD)31 (a vascular marker) was also performed. The 18 F-FMISO expression level in the tumor increased sorafenib-dose-dependently, which is consistent with the increase in the number of pimonidazole-positive cells and decrease in the number of microvessels. These findings indicated that the present sorafenib treatment protocol induces 'tumor hypoxia/starvation' in the renal cell carcinoma xenograft (A498) due to its antiangiogenic properties. IntroductionAngiogenesis is an important hallmark of tumor development and metastasis and is a validated target for cancer treatment (1-3). Sorafenib (BAY 43-9006) is an oral multikinase inhibitor with antiangiogenic properties. Currently, sorafenib has been approved for the treatment of metastatic renal cell carcinoma (RCC) and advanced hepatocellular carcinoma, and is under investigation for use in other malignancies in combination with additional chemotherapies (4).Conventionally, antiangiogenic drugs inhibit new vessel formation or destroy the tumor vasculature to reduce blood flow and starve the tumor of nutrients (5). However, numerous preclinical studies demonstrated that anti-vascular endothelial growth factor (VEGF) treatment alters the tumor vasculature towards a more 'mature' or 'normal' phenotype ('vascular normalization'), by attenuation of hyperpermeability, improvement of tumor oxygenation and blood flow and the resultant reduction in tumor hypoxia and interstitial

BackgroundRadiotherapy is an important treatment strategy for head and neck cancers. Tumor hypoxia and repopulation adversely affect the radiotherapy outcome. Accordingly, fractionated radiotherapy with dose escalation or altered fractionation schedule is used to prevent hypoxia and repopulation. 18F-fluoromisonidazole (FMISO) and 18F-fluorothymidine (FLT) are noninvasive markers for assessing tumor hypoxia and proliferation, respectively. Thus, we evaluated the dynamic changes in intratumoral hypoxic and proliferative states following radiotherapy using the dual tracers of 18F-FMISO and 3H-FLT, and further verified the results by immunohistochemical staining of pimonidazole (a hypoxia marker) and Ki-67 (a proliferation marker) in human head and neck cancer xenografts (FaDu).MethodsFaDu xenografts were established in nude mice and assigned to the non-radiation-treated control and two radiation-treated groups (10- and 20-Gy). Tumor volume was measured daily. Mice were sacrificed 6, 24, and 48 hrs and 7 days after radiotherapy. 18F-FMISO, and 3H-FLT and pimonidazole were injected intravenously 4 and 2 hrs before sacrifice, respectively. Intratumoral 18F-FMISO and 3H-FLT levels were assessed by autoradiography. Pimonidazole and Ki-67 immunohistochemistries were performed.ResultsIn radiation-treated mice, tumor growth was significantly suppressed compared with the control group, but the tumor volume in these mice gradually increased with time. Visual inspection showed that intratumoral 18F-FMISO and 3H-FLT distribution patterns were markedly different. Intratumoral 18F-FMISO level did not show significant changes after radiotherapy among the non-radiation-treated control and radiation-treated groups, whereas 3H-FLT level markedly decreased to 59 and 45% of the non-radiation-treated control at 6 hrs (p < 0.0001) and then gradually increased with time in the 10- and 20-Gy-radiation-treated groups. The pimonidazole-positive hypoxic areas were visually similar in both the non-radiation-treated control and radiation-treated groups. No significant differences were observed in the percentage of pimonidazole-positive cells and Ki-67 index.ConclusionIntratumoral 18F-FMISO level did not change until 7 days, whereas 3H-FLT level markedly decreased at 6 hrs and then gradually increased with time after a single dose of radiotherapy. The concomitant monitoring of dynamic changes in tumor hypoxia and proliferation may provide important information for a better understanding of tumor biology after radiotherapy and for radiotherapy planning, including dose escalation and altered fractionation schedules.