Low-salt diet increases mRNA expression of aldosterone-regulated transporters in the intermediate portion of the endolymphatic sac.

The endolymphatic sac is a small sac-shaped organ at the end of the membranous labyrinth of the inner ear. The endolymphatic sac absorbs the endolymph, in which the ion balance is crucial for inner ear homeostasis. Of the three sections of the endolymphatic sac, the intermediate portion is the center of endolymph absorption, particularly sodium transport, and is thought to be regulated by aldosterone. Disorders of the endolymphatic sac may cause an excess of endolymph (endolymphatic hydrops), a histological observation in Meniere's disease. A low-salt diet is an effective treatment for Meniere's disease, and is based on the assumption that the absorption of endolymph in the endolymphatic sac abates endolymphatic hydrops through a physiological increase in aldosterone level. However, the molecular basis of endolymph absorption in each portion of the endolymphatic sac is largely unknown because of difficulties in gene expression analysis, resulting from its small size and intricate structure. The present study combined reverse transcription-quantitative polymerase chain reaction and laser capture microdissection techniques to analyze the difference of gene expression of the aldosterone-controlled epithelial Na+ channel, thiazide-sensitive Na+-Cl- cotransporter, and Na+, K+-ATPase genes in the three individual portions of the endolymphatic sac in a rat model. A low-salt diet increased the expression of aldosterone-controlled ion transporters, particularly in the intermediate portion of the endolymphatic sac. Our findings will contribute to the understanding of the physiological function of the endolymphatic sac and the pathophysiology of Meniere's disease.

Functional maintenance of calcium store by ShcB adaptor protein in cerebellar Purkinje cells.

Intracellular Ca2+ levels are changed by influx from extracellular medium and release from intracellular stores. In the central nervous systems, Ca2+ release is involved in various physiological events, such as neuronal excitability and transmitter release. Although stable Ca2+ release in response to stimulus is critical for proper functions of the nervous systems, regulatory mechanisms relating to Ca2+ release are not fully understood in central neurons. Here, we demonstrate that ShcB, an adaptor protein expressed in central neurons, has an essential role in functional maintenance of Ca2+ store in cerebellar Purkinje cells (PCs). ShcB-knockout (KO) mice showed defects in cerebellar-dependent motor function and long-term depression (LTD) at cerebellar synapse. The reduced LTD was accompanied with an impairment of intracellular Ca2+ release. Although the expression of Ca2+ release channels and morphology of Ca2+ store looked intact, content of intracellular Ca2+ store and activity of sarco/endoplasmic reticular Ca2+-ATPase (SERCA) were largely decreased in the ShcB-deficient cerebellum. Furthermore, when ShcB was ectopically expressed in the ShcB-KO PCs, the Ca2+ release and its SERCA-dependent component were restored. These data indicate that ShcB plays a key role in the functional maintenance of ER Ca2+ store in central neurons through regulation of SERCA activity.

[Brain and Neuronal Aging: Aged Brain Controls via Gene Expression Fidelity and Master Regulatory Factors].

Providing plausible strategies for brain aging protection should be a critical concern for countries with large elderly populations including Japan. Age-related cognitive impairments and movement disorders, such as Alzheimer's and Parkinson's diseases, are caused by neurodegeneration that primarily initiates in the hippocampus and the midbrain substantia nigra, respectively. Neurons are postmitotic, and therefore, the accuracy of cellular metabolism should be crucial for maintaining neural functions throughout their life. Thus accuracy of protein synthesis is a critical concern in discussing mechanisms of aging. The essence of the so-called "error catastrophe theory" of aging was on the fidelity of ribosomal translation and/or aminoacylation of tRNA. There is evidence that reduced protein synthesis accuracy results in neurodegeneration. Similarly, reduced proteostasis via autophagy and proteasomes in aging is crucial for protein quality control and well documented as a risk for aging. In both neurodegeneration and protein quality controls, various proteins are involved in their regulation, but recent evidence suggests that repressor element-1 silencing transcription factor (REST) could be a master regulatory protein that is crucial for orchestrating the neural protecting events in human brain aging. REST is induced in the aged brain, and protects neurons against oxidative stress and protein toxicity. Interestingly, REST is identical with neuron-restrictive silencer factor (NRSF), the master regulator of neural development. Thus NRSF/REST play important roles in both neurogenesis and neurodegeneration. In this review, I summarize the interesting scientific crossover, and discuss the potential use of NRSF/REST as a pharmaceutical target for controlling aging, particularly in relation to brain aging.

Loss of nuclear REST/NRSF in aged-dopaminergic neurons in Parkinson's disease patients.

Parkinson's disease (PD) is the second most common neurodegenerative disease. Lewy bodies and pale bodies in dopaminergic neurons in the substantia nigra are pathological hallmarks of PD. A number of neurodegenerative diseases demonstrate aggregate formation, but how these aggregates are associated with their pathogenesis remains unknown. It has been reported that repressor element-1 silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) is induced in the nuclei of aged neurons, preserves neuronal function, and protects against neurodegeneration during aging through the repression of cell death-inducing genes. The loss of REST is associated with Alzheimer's disease pathology. However, its function in dopaminergic neurons remains unknown. Here we demonstrated that REST enters the nucleus of aged dopaminergic neurons. On the other hand, REST is partially sequestrated in Lewy bodies and is mostly absent from the nucleus of neurons in brains with PD and dementia with Lewy bodies (DLB). Dopaminergic neuron-specific autophagy-deficient mice exhibit REST accumulation in aggregates. Defects in the protein quality control system induce REST mRNA expression; its gene product mainly appears in aggregates. Our results suggest that Lewy pathology disturbs normal aging processes in dopaminergic neurons by sequestering REST and the loss of REST may associate with the PD pathology.

Tricellulin Expression and its Deletion Effects in the Endolymphatic Sac.

OBJECTIVES: Tricellulin is a tight junction (TJ)-forming protein that participates in the sealing function of tricellular TJs. Tricellulin-knockout (Tric-/-) mice show progressive hearing loss with degeneration of hair cells in the cochlea without physiological or physical disorders. In the present study, we investigated the tricellulin expression and its deletion effects in the endolymphatic sac (ES) using Tric-/- mice. MATERIALS AND METHODS: The ES epithelia from wild-type (WT) mice were laser-microdissected, and RT-PCR was performed. The ES sections from Tric-/- and WT mice were immunostained with an anti-tricellulin antibody. Hematoxylin and eosin staining was performed for morphological examination. The inner ear of Tric-/- mice was perfused with biotinylation reagents, and the ES sections were observed for tracer permeability assay after applying streptavidin-Alexa Fluor 488 conjugate. RESULTS: The tricellulin expression was confirmed by RT-PCR and by immunohistochemistry in the WT ES. The ES in Tric-/- mice showed normal morphology and revealed no biotin leakage from the lumen. CONCLUSION: The ES in Tric-/- mice showed no changes in morphology or disruption in macromolecular barrier function. The effects of solute leakages in the ES of Tric-/- mice may be very limited and compensatable, or that the ES epithelia may have other sealing system covering the lack of tricellulin.

N-Acyldopamine induces aggresome formation without proteasome inhibition and enhances protein aggregation via p62/SQSTM1 expression.

Accumulation of ubiquitinated protein aggregates is a common pathology associated with a number of neurodegenerative diseases and selective autophagy plays a critical role in their elimination. Although aging-related decreases in protein degradation properties may enhance protein aggregation, it remains unclear whether proteasome dysfunction is indispensable for ubiquitinated-protein aggregation in neurodegenerative diseases. Here, we show that N-oleoyl-dopamine and N-arachidonyl-dopamine, which are endogenous brain substances and belong to the N-acyldopamine (AcylDA) family, generate cellular inclusions through aggresome formation without proteasome inhibition. Although AcylDA itself does not inhibit proteasome activity in vitro, it activates the rearrangement of vimentin distribution to form a vimentin cage surrounding aggresomes and sequesters ubiquitinated proteins in aggresomes. The gene transcription of p62/SQSTM1 was significantly increased by AcylDAs, whereas the transcription of other ubiquitin-dependent autophagy receptors was unaffected. Genetic depletion of p62 resulted in the loss of ubiquitinated-protein sequestration in aggresomes, indicating that p62 is a critical component of aggresomes. Furthermore, AcylDAs accelerate the aggregation of mutant huntingtin exon 1 proteins. These results suggest that aggresome formation does not require proteasome dysfunction and AcylDA-induced aggresome formation may participate in forming cytoplasmic protein inclusions.

Tau Fibril Formation in Cultured Cells Compatible with a Mouse Model of Tauopathy.

Neurofibrillary tangles composed of hyperphosphorylated tau protein are primarily neuropathological features of a number of neurodegenerative diseases collectively termed tauopathy. To understand the mechanisms underlying the cause of tauopathy, precise cellular and animal models are required. Recent data suggest that the transient introduction of exogenous tau can accelerate the development of tauopathy in the brains of non-transgenic and transgenic mice expressing wild-type human tau. However, the transmission mechanism leading to tauopathy is not fully understood. In this study, we developed cultured-cell models of tauopathy representing a human tauopathy. Neuro2a (N2a) cells containing propagative tau filaments were generated by introducing purified tau fibrils. These cell lines expressed full-length (2N4R) human tau and the green fluorescent protein (GFP)-fused repeat domain of tau with P301L mutation. Immunocytochemistry and super-resolution microscopic imaging revealed that tau inclusions exhibited filamentous morphology and were composed of both full-length and repeat domain fragment tau. Live-cell imaging analysis revealed that filamentous tau inclusions are transmitted to daughter cells, resulting in yeast-prion-like propagation. By a standard method of tau preparation, both full-length tau and repeat domain fragments were recovered in sarkosyl insoluble fraction. Hyperphosphorylation of full-length tau was confirmed by the immunoreactivity of phospho-Tau antibodies and mobility shifts by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). These properties were similar to the biochemical features of P301L mutated human tau in a mouse model of tauopathy. In addition, filamentous tau aggregates in cells barely co-localized with ubiquitins, suggesting that most tau aggregates were excluded from protein degradation systems, and thus propagated to daughter cells. The present cellular model of tauopathy will provide an advantage for dissecting the mechanisms of tau aggregation and degradation and be a powerful tool for drug screening to prevent tauopathy.

Hormonal changes following a low-salt diet in patients with Ménière's disease.

OBJECTIVE: A low-salt diet has been the main treatment modality for Ménière's disease (MD) since the 1930s, although the mechanisms behind this therapy have not yet been elucidated. Salt reduction is associated with a physiological increase in plasma aldosterone concentration. Several experimental reports have suggested that aldosterone may increase endolymph absorption in the inner ear, particularly in the endolymphatic sac. Therefore, aldosterone elevations due to a low-salt diet may increase endolymph absorption in the endolymphatic sac. In this study, urinary sodium excretion, plasma aldosterone, and other hormones were measured during low-salt diet therapy in patients with MD. METHODS: We included 13 patients with unilateral definite MD diagnosed at the Kagawa University Hospital. A national registered dietitian provided nutritional guidance initially for 14 enrolled patients with MD and prescribed them a low-salt diet (2g Na/day). Twenty-four hour urine was sampled at baseline, at 2, 4, 6, and 8 weeks, and at 6, 12, 18, and 24 months after initiating the low-salt diet. Urine osmotic pressure, and Na, K, and Cl levels were measured, and 24-h urinary Na, K, and Cl excretion was estimated. Aldosterone, cortisol, hormones (including anti-diuretic hormone), Na, K, and Cl in the blood were measured, alongside plasma osmotic pressure. A total of 13 patients followed the low salt diet therapy for more than 2 years, while one patient dropped out. RESULTS: Group 1 (n=7) included patients with a mean urinary sodium excretion amount lower than 3g/day and Group 2 (n=6) included those with more than 3g/day. Vertiginous states of all Group 1 patients comprised complete control (Class A, 100%), while Group 2 patients included Class A (four patients, 66%), Class C (one patient, 17%), and Class D (one patients, 17%). Plasma aldosterone concentrations significantly increased during the 2-year low-salt diet; concentrations in Group 1 tended to be higher than that in Group 2. Hearing improvements after 2 years in Group 1 were significantly better than that in Group 2. The plasma concentration of the hormones except aldosterone was not significantly changed during 2-year low-salt diet. CONCLUSION: A low-salt diet was an effective treatment for patients with Ménière's disease. This treatment will have a greater effect, when sodium intake is reduced to less than 3g/day. A low-salt diet may induce an increase in the plasma aldosterone concentration that can activate ion transport and absorbing endolymph in the endolymphatic sac.

Ion transport its regulation in the endolymphatic sac: suggestions for clinical aspects of Meniere's disease.

Ion transport and its regulation in the endolymphatic sac (ES) are reviewed on the basis of recent lines of evidence. The morphological and physiological findings demonstrate that epithelial cells in the intermediate portion of the ES are more functional in ion transport than those in the other portions. Several ion channels, ion transporters, ion exchangers, and so on have been reported to be present in epithelial cells of ES intermediate portion. An imaging study has shown that mitochondria-rich cells in the ES intermediate portion have a higher activity of Na+, K+-ATPase and a higher Na+ permeability than other type of cells, implying that molecules related to Na+ transport, such as epithelial sodium channel (ENaC), Na+-K+-2Cl- cotransporter 2 (NKCC2) and thiazide-sensitive Na+-Cl- cotransporter (NCC), may be present in mitochondria-rich cells. Accumulated lines of evidence suggests that Na+ transport is most important in the ES, and that mitochondria-rich cells play crucial roles in Na+ transport in the ES. Several lines of evidence support the hypothesis that aldosterone may regulate Na+ transport in ES, resulting in endolymph volume regulation. The presence of molecules related to acid/base transport, such as H+-ATPase, Na+-H+ exchanger (NHE), pendrin (SLC26A4), Cl--HCO3- exchanger (SLC4A2), and carbonic anhydrase in ES epithelial cells, suggests that acid/base transport is another important one in the ES. Recent basic and clinical studies suggest that aldosterone may be involved in the effect of salt-reduced diet treatment in Meniere's disease.

The difference in endolymphatic hydrostatic pressure elevation induced by isoproterenol between the ampulla and the cochlea.

OBJECTIVE: The purpose of the study was to investigate the difference in the responses of endolymphatic hydrostatic pressure to isoproterenol, ß-adrenergic receptor agonist, between pars superior and pars inferior. METHODS: The hydrostatic pressure of endolymph and perilymph and endolymphatic potential in the ampulla and the cochlea during the intravenous administration of isoproterenol were recorded using a servo-null system in guinea pigs. RESULTS: The hydrostatic pressure of endolymph and perilymph in the ampulla and cochlea was similar in magnitude. Isoproterenol significantly increased hydrostatic pressure of ampullar and cochlear endolymph and perilymph with no change in the ampullar endolymphatic potential and endocochlear potential, respectively. The isoproterenol-induced maximum change of endolymphatic hydrostatic pressure in ampulla was significantly (p<0.01) smaller than that in the cochlea. In ears with an obstructed endolymphatic sac, the action of isoproterenol on endolymphatic hydrostatic pressure in the ampulla disappeared like that in the cochlea. CONCLUSION: Isoproterenol elevates endolymphatic hydrostatic pressure in different manner between the vestibule and the cochlea.

Involvement of the neuronal phosphotyrosine signal adaptor N-Shc in kainic acid-induced epileptiform activity.

BDNF-TrkB signaling is implicated in experimental seizures and epilepsy. However, the downstream signaling involved in the epileptiform activity caused by TrkB receptor activation is still unknown. The aim of the present study was to determine whether TrkB-mediated N-Shc signal transduction was involved in kainic acid (KA)-induced epileptiform activity. We investigated KA-induced behavioral seizures, epileptiform activities and neuronal cell loss in hippocampus between N-Shc deficient and control mice. There was a significant reduction in seizure severity and the frequency of epileptiform discharges in N-Shc deficient mice, as compared with wild-type and C57BL/6 mice. KA-induced neuronal cell loss in the CA3 of hippocampus was also inhibited in N-Shc deficient mice. This study demonstrates that the activation of N-Shc signaling pathway contributes to an acute KA-induced epileptiform activity and neuronal cell loss in the hippocampus. We propose that the N-Shc-mediated signaling pathway could provide a potential target for the novel therapeutic approaches of epilepsy.

Usefulness of multislice-CT using multiplanar reconstruction in the preoperative assessment of the ossicular lesions in the middle ear diseases.

OBJECTIVE: The aim of the study is to evaluate the usefulness of multislice computed tomography (MSCT) using multiplanar reconstruction (MPR) in obtaining preoperative information on the ossicular lesions of middle ear diseases by comparing the ossicular findings of MPR images with the operative findings. METHODS: Sixty-two ears and 10 ears with preoperative middle ear diseases underwent 4- and 64-detector row CT of the temporal bone in Kagawa University Hospital, respectively. MPR images of three ossicles were created at the planes parallel to the long axis of ossicles. RESULTS: The findings of the three ossicles in MPR images were compatible with their operative findings in approximately 91% of 72 ears with various middle ear diseases. There was no significant difference in the coincidence rate of both findings between 4- and 64-detector row CT scanners. The ears with no soft tissue shadows around the ossicles had the coincidence rate of 96-100% in each ossicular part, whereas the coincidence rate was lower in the ears with soft tissue shadows around the ossicles. CONCLUSION: MPR imagings of the ossicles provide accurate preoperative information on the ossicular lesions in middle ear diseases. The 4-detector CT is still a useful device for imaging of the ossicles.

Deletion of Tricellulin Causes Progressive Hearing Loss Associated with Degeneration of Cochlear Hair Cells.

Tricellulin (also known as MARVELD2) is considered as a central component of tricellular tight junctions and is distributed among various epithelial tissues. Although mutations in the gene encoding tricellulin are known to cause deafness in humans (DFNB49) and mice, the influence of its systemic deletion in vivo remains unknown. When we generated tricellulin-knockout mice (Tric(-/-)), we found an early-onset rapidly progressive hearing loss associated with the degeneration of hair cells (HCs); however, their body size and overall appearance were normal. Tric(-/-) mice did not show any morphological change pertaining to other organs such as the gastrointestinal tract, liver, kidney, thyroid gland and heart. The endocochlear potential (EP) was normal in Tric(-/-) mice, suggesting that the tight junction barrier is maintained in the stria vascularis, where EP is generated. The degeneration of HCs, which occurred after the maturation of EP, was prevented in the culture medium with an ion concentration similar to that of the perilymph. These data demonstrate the specific requirement of tricellulin for maintaining ion homeostasis around cochlear HCs to ensure their survival. The Tric(-/-) mouse provides a new model for understanding the distinct roles of tricellulin in different epithelial systems as well as in the pathogenesis of DFNB49.

Mdm20 Modulates Actin Remodeling through the mTORC2 Pathway via Its Effect on Rictor Expression.

NatB is an N-terminal acetyltransferase consisting of a catalytic Nat5 subunit and an auxiliary Mdm20 subunit. In yeast, NatB acetylates N-terminal methionines of proteins during de novo protein synthesis and also regulates actin remodeling through N-terminal acetylation of tropomyosin (Trpm), which stabilizes the actin cytoskeleton by interacting with actin. However, in mammalian cells, the biological functions of the Mdm20 and Nat5 subunits are not well understood. In the present study, we show for the first time that Mdm20-knockdown (KD), but not Nat5-KD, in HEK293 and HeLa cells suppresses not only cell growth, but also cellular motility. Although stress fibers were formed in Mdm20-KD cells, and not in control or Nat5-KD cells, the localization of Trpm did not coincide with the formation of stress fibers in Mdm20-KD cells. Notably, knockdown of Mdm20 reduced the expression of Rictor, an mTORC2 complex component, through post-translational regulation. Additionally, PKCαS657 phosphorylation, which regulates the organization of the actin cytoskeleton, was also reduced in Mdm20-KD cells. Our data also suggest that FoxO1 phosphorylation is regulated by the Mdm20-mTORC2-Akt pathway in response to serum starvation and insulin stimulation. Taken together, the present findings suggest that Mdm20 acts as a novel regulator of Rictor, thereby controlling mTORC2 activity, and leading to the activation of PKCαS657 and FoxO1.

Prox1 expression in the endolymphatic sac revealed by whole-mount fluorescent imaging of Prox1-GFP transgenic mice.

This study describes a technical breakthrough in endolymphatic sac research, made possible by the use of the recently generated Prox1-GFP transgenic mouse model. Whole-mount imaging techniques through the decalcified temporal bone and three-dimensional observations of Prox1-GFP mouse tissue revealed the positive labeling of the endolymphatic sac in adult stage, and allowed, for the first time, the GFP-based identification of endolymphatic sac epithelial cells. Prox1 expression was observed in all parts of the endolymphatic sac epithelia. In intermediate portion of the endolymphatic sac, mitochondria-rich cells did not express Prox1, although ribosome-rich cells showed strong GFP labeling. The anatomical relationship between the endolymphatic sac and the surrounding vasculature was directly observed. In the endolymphatic sac, expression of Prox1 may suggest progenitor cell-like pluripotency or developmental similarity to systemic lymphatic vessels in other organs. This whole-mount imaging technique of the endolymphatic sac can be combined with other conventional histological, sectioning, and labeling techniques and will be very useful for future endolymphatic sac research.

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'-[F]-fluorothymidine (F-FLT) uptake parameters and those of F-FDG to predict the clinical outcome of head and neck squamous cell carcinoma treated with chemoradiotherapy. METHODS: A total 53 patients undergoing pretreatment F-FLT PET/CT and F-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, F-FLT SUVmax, MTV, TLP, F-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, F-FLT SUVmax, MTV, TLP, and F-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, F-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 F-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 F-FLT PET/CT volume-based metabolic parameters are superior prognostic predictors to those of F-FDG PET/CT. F-FLT SUVmax and MTV can provide important prognostic information for patients with head and neck squamous cell carcinomas administered with chemoradiotherapy.

Retrieval of ruptured medial rectus muscle with an endoscopic endonasal orbital approach. A case report and indication for surgical technique.

INTRODUCTION: Rupture of the extraocular muscle is extremely rare, and a traumatic event is especially uncommon. Although retrieval of an injured MRM is usually performed by an anterior approach by an ophthalmologist, missing muscles in the orbital retrobulbar space are sometimes difficult to identify. This is the first report to demonstrate direct muscle to muscle anastomosis by an endoscopic endonasal orbital approach by a single otolaryngologist. CASE REPORT: A 67-year-old man presented with left medial rectus muscle (MRM) rupture due to a traffic accident 4 months after injury. The MRM was completely ruptured, and the muscle was repaired by an endoscopic endonasal orbital approach. After surgery, his eye abduction was improved in the primary position, and adduction ability was markedly restored on right gaze without diplopia. CONCLUSIONS: Our endonasal endoscopic approach provides excellent access to the MRM in the orbital retrobulbar space and avoids a facial scar. We could suture both ends of the muscle together by an endonasal endoscopic approach and could obtain a good result without any complications.

Clinical outcomes of nedaplatin and S-1 treatment with concurrent radiotherapy in advanced head and neck cancer.

CONCLUSION: Nedaplatin and S-1 treatment with concurrent radiotherapy was effective, with acceptable toxicities. This regimen does not require extensive intravenous hydration and continuous infusion. Nedaplatin and S-1 may contribute to better clinical outcomes and improve quality of life for patients. OBJECTIVES: We retrospectively analyzed the clinical efficacy and toxicity of concurrent chemoradiotherapy with nedaplatin and S-1 for head and neck squamous cell cancer. METHODS: Forty-six patients with oropharyngeal, hypopharyngeal, and laryngeal cancer were treated with S-1 on days 1 through 14 and nedaplatin on day 1 every 4 weeks for two cycles of radiotherapy. Therapeutic responses and adverse events were assessed. RESULTS: Primary site tumors and neck lymph nodes exhibited complete response rates of 91% and 64.3%, respectively. The 4-year relapse-free survival and overall survival rates were 76.2% and 85.3%, respectively. The main grade 3 and 4 toxicities were mucositis (30%), leukopenia (30%), anorexia (22%), dermatitis (15%), and thrombocytopenia (9%).

Predictive value of SUV-based parameters derived from pre-treatment (18)F-FLT PET/CT for short-term outcome with head and neck cancers.

OBJECTIVE: The aim of this study was to investigate the predictive potential of pre-treatment 3'-deoxy-3'-[18F]-fluorothymidine (FLT) uptake parameters for short-term outcome of primary head and neck squamous cell cancer (HNSCC) patients. PATIENTS AND METHODS: A total of 32 patients undergoing pre-treatment FLT positron emission tomography/computed tomography (PET/CT) from May 2010 to May 2013 were evaluated. Semi-quantitative assessment was used to determine mean, peak and maximum standardized uptake values (SUVmean, SUVpeak and SUVmax), metabolic tumor volume (MTV) and total lesion proliferation (TLP). Clinicopathologic factors and PET/CT parameters were analyzed for their association with 2-year loco-regional control (LRC) and overall survival (OS). RESULTS: The mean (± SD) SUVmean, SUVpeak, SUVmax, MTV and TLP were 5.97 ± 3.16, 6.71 ± 3.75, 10.05 ± 5.37, 7.31 ± 8.05 and 44.95 ± 52.82, respectively. In univariate analyses, N category was associated with OS (P = 0.037). Increased MTV ≥13 ml was associated with decreased LRC and OS (P < 0.0001). TLP ≥69.3 g was also linked with both LRC and OS (P = 0.009 and 0.015, respectively). Regarding SUVs, only the SUVpeak was associated with LRC and OS (P = 0.035 and 0.049, respectively). CONCLUSIONS: Pre-treatment MTV is the most useful parameter with FLT PET/CT. TLP and SUVpeak may also provide important prognostic information for patients with HNSCCs.

Effects of D-allose in combination with docetaxel in human head and neck cancer cells.

In this study we investigated the combined effects of docetaxel and d-allose in HSC3 human oral carcinoma cells. The dose enhancement ratios at the 25% survival level were 1.3 and 1.71 for combined treatment with 10 or 25 mM D-allose, respectively. Apoptosis was significantly increased by addition of D-allose. Additionally, a synchronous increase in the G(2)/M-phase population was observed after docetaxel plus D-allose treatment. In vivo experiments revealed that docetaxel plus D-allose was more effective than either agent alone. Thus, D-allose enhanced the anticancer effects of docetaxel, and combined treatment may be useful to achieve clinical efficacy with reduced toxicity.