Terushige Mori

Enhancement of the radiation effects by D-allose in head and neck cancer cells.

The aim of this study was to investigate the radiosensitizing potential of D-allose in human head and neck cancer cells. HSC-3 cells were treated with or without D-allose for 6 h and then irradiated (2-6 Gy). The combination of D-allose and radiation was more effective than either agent alone. The radiation enhancement ratios at the 37% survival level were 1.61 and 2.11 for 10 mM and 25 mM D-allose treatment, respectively. The combination of D-allose and radiation also reduced the cell proliferation in 3D culture experiments. Although the mRNA expression of TXNIP was not increased by radiation alone, combined use with D-allose markedly elevated TXNIP expression. The combination of D-allose and radiation significantly induced intracellular reactive oxygen species (ROS) and apoptosis compared to that induced by either agent alone. This study shows that D-allose enhances the effect of radiation, suggesting a potential clinical application of combination treatment with D-allose and radiation for head and neck cancer.

Growth inhibition of head and neck carcinomas by D-allose.

An inhibitory effect of D‐allose, a rare sugar, on several cancer cell lines has been reported. This study aimed to investigate the growth inhibition of head and neck squamous cell carcinoma cells by D‐allose.

Expression of the Na+–K+–2Cl− cotransporter in the rat endolymphatic sac

The endolymphatic sac (ES) is a part of the membranous labyrinth that contains the cochlea, vestibular organs, an d semicircular canals, and is believed to absorb endolymphatic fluid. Na(+)-K(+)-2Cl(-) (NKCC) is a cotransporter that occurs as two isoforms (NKCC-1 and NKCC-2). Especially, NKCC-2 is suggested to participate in ES endolymph absorption. In the present study, the expression and cellular localization of NKCC-1 and NKCC-2 in the rat ES wer e examined by RT-PCR and in situ hybridization, respectively. The findings indicate that both NKCC-1 and NKCC-2 are expressed in the rat ES and suggest that NKCC is involved in ES homeostasis. NKCC-2 may be particularly involved in endolymph absorption. This is the first report confirming NKCC expression in the ES.

Expression of thiazide-sensitive Na+–Cl− cotransporter in the rat endolymphatic sac

The endolymphatic sac (ES) is a part of the membranous labyrinth and is believed to absorb endolymph. It has been well-established that the endolymph absorption is dependent on several ion transporters in a manner similar to that in the kidney, and the ES is regulated by hormones such as aldosterone and vasopressin that also affect on the kidney. The thiazide-sensitive Na(+), Cl(-) cotransporter (TSC) is an electroneutral cotransporter specific to the kidney that plays an important role in absorption of NaCl in renal tubules. In the inner ear, TSC expression has never been examined. The expression of TSC in the rat ES was examined by RT-PCR, in situ hybridization and immunohistochemistry. These analyses indicated that TSC genes and proteins were expressed in the rat ES. In contrast, it was not observed in the rat cochlea by RT-PCR. This is the first report confirming the expression of TSC in the ES.

Endolymphatic sac is involved in the regulation of hydrostatic pressure of cochlear endolymph

To clarify the role of the endolymphatic sac (ES) in the regulation of endolymphatic pressure, the effects of isoproterenol, a beta-adrenergic receptor agonist, and acetazolamide, a potent carbonic anhydrase inhibitor, both of which decrease ES direct current potential on cochlear hydrostatic pressure, were examined in guinea pigs. When isoproterenol was applied intravenously, hydrostatic pressures of cochlear endolymph and perilymph were significantly increased with no change in endocochlear potential or the hydrostatic pressure of cerebrospinal fluid. Acetazolamide produced no marked change in the hydrostatic pressure of cochlear endolymph. In ears with an obstructed ES, the action of isoproterenol on the hydrostatic pressure of cochlear endolymph and perilymph was suppressed. These results suggest that the ES may regulate the hydrostatic pressure of the endolymphatic system via the action of the agents such as catecholamines on the ES.

Prognostic value comparison between (18)F-FLT PET/CT and (18)F-FDG PET/CT volume-based metabolic parameters in patients with head and neck cancer.

Purpose The present study compared the potential of pretreatment 3′-deoxy-3′-[18F]-fluorothymidine (18F-FLT) uptake parameters and those of 18F-FDG to predict the clinical outcome of head and neck squamous cell carcinoma treated with chemoradiotherapy. Methods A total 53 patients undergoing pretreatment 18F-FLT PET/CT and 18F-FDG PET/CT from May 2006 to April 2013 were evaluated. The SUVmax, metabolic tumor volume (MTV), total lesion glycolysis, and total lesion proliferation (TLP) were determined semiquantitatively. Associations between clinical factors and PET/CT parameters and prognostic value were analyzed. Results In univariate analyses, 18F-FLT SUVmax, MTV, TLP, 18F-FDG MTV, and total lesion glycolysis correlated with locoregional control (P = 0.02, P = 0.0007, P = 0.0001, P = 0.007, and P = 0.013, respectively). Clinical T stage, 18F-FLT SUVmax, MTV, TLP, and 18F-FDG SUVmax correlated with overall survival (P = 0.012, P = 0.0057, P = 0.0018, P = 0.0012, and P = 0.047, respectively). On multivariate analyses, 18F-FLT TLP was an independent factor for locoregional control (P = 0.002; hazards ratio [HR], 5.13; 95% confidence interval [CI], 1.81-14.54), as were 18F-FLT SUVmax and MTV for overall survival (P = 0.021; HR, 3.47; 95% CI, 1.2–10.01 and P = 0.029; HR, 3.17; 95% CI, 1.12–8.95). Conclusions Pretreatment 18F-FLT PET/CT volume-based metabolic parameters are superior prognostic predictors to those of 18F-FDG PET/CT. 18F-FLT SUVmax and MTV can provide important prognostic information for patients with head and neck squamous cell carcinomas administered with chemoradiotherapy.

Comparison of 18 F-FLT PET and 18 F-FDG PET for detection of cervical lymph node metastases in head and neck cancers

Abstract Conclusion: Despite low uptake of tracer, 3′-deoxy-3′-18F-fluorothymidine (FLT) PET could detect cervical lymph node metastases as well as 2-deoxy-2-18F-fluoro-d-glucose (FDG) PET. Objective: The diagnostic efficacy of FLT PET was compared with that of FDG PET regarding nodal staging of head and neck squamous cell cancers. Methods: Twenty-three patients were examined with FLT PET and FDG PET. PET images were evaluated qualitatively for regions of focally increased metabolism and maximum standardized uptake values (SUV) were calculated for semiquantitative analysis. Results: The mean (± SD) FLT SUV in visualized metastatic lymph nodes was 4.8 ± 2.9 as compared with 6.9 ± 4.9 for FDG SUV (p < 0.001). Significant correlations were found between the area of metastatic lymph nodes and both FLT SUV (r = 0.8; p < 0.0001) and FDG SUV (r = 0.84; p < 0.0001). The false-positive (over-staged) and false-negative (under-staged) rates for lymph node staging by FLT PET were 4% (1/23) and 17% (4/23), respectively. Those for FDG PET were 9% (2/23) and 13% (3/23). All metastatic lymph nodes measuring more than 9 mm in short-axis diameter were correctly detected by FLT PET. However, both FLT and FDG PET had low sensitivity for detecting the lymph node metastases ≤ 9 mm in short-axis diameter and tumor deposits < 5 mm.

In vitro and in vivo effects of D-allose: up-regulation of thioredoxin-interacting protein in head and neck cancer cells.

Objectives: This study was aimed to investigate the relationship between the antiproliferative effects of D-allose and the up-regulation of thioredoxin-interacting protein (TXNIP) in head and neck cancer cells. Methods: For the in vitro study, 5 oral squamous cell carcinoma cell lines (Ca9–22, HSC-3, HSC-4, SAS, and KON) were treated with 25 mmol/L D-allose. For the in vivo study, HSC-3 cells were used in a xenograft model with female athymic nude mice (BALB/c nu/nu; 5 to 6 weeks old). Results: Inhibition of cell growth by D-allose was noted in HSC-3 and Ca9–22 cells, along with significant induction of TXNIP. Although TXNIP up-regulation was also evident, albeit to a lesser extent, in the remaining cell lines, D-allose did not inhibit their growth. With the HSC-3 line, the cell survival fractions decreased and TXNIP expression increased in a D-allose dose—dependent manner. The antiproliferative effects were partially suppressed by concomitant D-glucose treatment, which also reduced TXNIP expression. In the in vivo experiment, the tumor volume at day 15 after D-allose treatment was reduced to 61% of that of the control group. Conclusions: This study showed that D-allose exerts growth inhibitory effects on head and neck cancer cells in vitro and in vivo. The sugar may act as an antiproliferative agent via TXNIP induction and thus may be useful as a novel anticancer drug.

The value of 18F-FLT PET for detecting second primary cancers and distant metastases in head and neck cancer patients.

Objective Diagnostic efficacy of 18F-FLT PET was compared with that of 18F-FDG PET regarding second primary cancers and distant metastases of head and neck squamous cell cancers (HNSCCs). Methods A total of 88 patients with HNSCCs were qualitatively examined with FLT PET and FDG PET for regions of focally increased metabolism. Final diagnoses of second primary cancer and distant metastasis were established on the basis of histological findings or clinical follow-up. Results FDG PET had 1 false-negative finding with lung metastasis, and FLT PET had 4 false-negative findings with 1 liver metastasis, 1 bone metastasis, and 2 lung metastases. There were no false-positive findings with FLT PET in contrast to 9 with FDG PET (1 in lung, 4 in mediastinum, 1 in rectum, and 3 in stomach). Overall accuracy of FDG PET and FLT PET for pretreatment metastasis staging was 92% and 98%, respectively. Five distant metastases in 3 patients occurred after the initiation of chemoradiotherapy. FLT PET missed 2 metastatic lesions (1 in liver and 1 in lung), whereas FDG PET could not discriminate intracranial metastasis because of FDG uptake in the brain. Conclusions FLT PET does not appear to be recommendable to replace FDG PET for pretreatment metastasis staging in HNSCC cases because of its lower sensitivity and higher background activity in the liver and bone marrow. However, it might provide additional diagnostic specificity and biological information.

A new approach for selective rat endolymphatic sac epithelium collection to obtain pure specific RNA

The endolymphatic sac (ES) is an organ that is located in the temporal bone. Its anatomical location makes ES tissue collection without any contamination very difficult, and sometimes accurate molecular analyses of the ES are prevented due to this matter. In the present study, a new selective ES epithelial tissue collection method was attempted using laser capture microdissection to obtain pure ES RNA without any contamination. The validity of this method was demonstrated by RT-PCR with three specific primer pairs against osteocalcin, calponin H1, and NKCC2, which are specific proteins in bone, smooth muscle, and kidney/ES cells, respectively. From the RT-PCR results, the high specificity and sufficient sensitivity of the new method was indicated. It is considered that the new method is optimal for ES collection without contamination and it will be able to contribute to future analyses of the ES.