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Objective Substernal goiters are classified as primary or secondary intrathoracic goiters. Here, we report the diagnosis, symptoms, treatment, and postoperative complications of 44 substernal goiters (2 primary mediastinal goiter and 42 secondary mediastinal goiters). Methods A retrospective chart review of 351 patients undergoing thyroidectomy at the Department of Otolaryngology-Head and Neck Surgery of the Tokyo Metropolitan Tama Medical Center. Between 2009 and 2015, 44 patients underwent surgery for substernal goiter. Results The frequency of primary and secondary mediastinal goiters was 0.5% and 11.9%, respectively. The preoperative symptoms were neck mass, dyspnea, and dysphagia. Eight patients were asymptomatic. Thirty-nine patients had benign masses and 5 patients had malignant masses. Most patients were operated on for adenomatous goiters (52.2%). In ten cases beyond the aortic arch, the tumors were benign and there were eight cases of adenomatous goiter. All patients underwent a successful transcervical incision without sternotomy. Even the primary intrathoracic goiters were extracted after total thyroidectomy via the cervical approach without complications. Although one case showed unilateral recurrent nerve paralysis as a postoperative complication, phonetic function improved in 6 postoperative months. No instances of postoperative bleeding or definitive hypoparathyroidism occurred, and tracheostomy was not performed in any of the cases. Conclusion The cervical approach was safely performed in almost all substernal goiters without an extracervical procedure. Selected cases of primary mediastinal goiter may be excised via the cervical approach.

Objective To evaluate the progression of peripheral vestibular dysfunction in patients with an A-to-G point mutation at nucleotide pair 3243 in mitochondrial DNA (A3243G mutation). Study design Retrospective patient series. Setting Tertiary referral center. Patients Six unrelated patients with an A3243G mutation (four mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; and two maternally inherited diabetes and deafness; five females and one male; average age 41 ± 11.3 yr old), who underwent repeated vestibular examinations, were included (average interval between the first and second examinations: 5.7 ± 2.1 yr). Intervention Diagnostic. Main outcome measure Results of caloric testing and cervical vestibular evoked myogenic potential testing in response to air-conducted sound were analyzed. Results All the patients except one, who was already completely deaf in both ears at the first examination, showed progression of hearing loss (average 4.0 ± 6.3 dB per year). Five of the six patients had vestibular symptoms at the first examination. The other patient developed dizziness later. Caloric responses were abnormal in four patients at the first examination and in five patients at the second examination. Cervical vestibular evoked myogenic potential responses were bilaterally absent in three patients at the first examination and in five patients at the second examination. Conclusions The A3243G mutation causes progression of peripheral vestibular dysfunction as well as that of hearing loss.

Photodynamic therapy (PDT) is a promising treatment modality for malignant tumors in a light-selective manner. To improve the PDT efficacy, numerous kinds of nanocarriers have been developed to deliver photosensitizers (PSs) selectively into the tumor through leaky tumor-associated vasculature. However, the corresponding prolonged retention of the nanocarrier in the bloodstream may lead to unfavorable photochemical damage to normal tissues such as skin. Here, we report an organic-inorganic hybrid nanocarrier with a pH-responsive on/off switch of PDT efficacy. This hybrid nanocarrier is constructed by hydrothermal synthesis after simple mixing of calcium/phosphate ions, chlorin e6 (amphiphilic low molecular weight PS), and poly(ethylene glycol)-b-poly(aspartic acid) (PEG-PAsp) copolymers in an aqueous solution. The hybrid nanocarrier possesses a calcium phosphate (CaP) core encapsulating the PSs, which is surrounded by a PEG shielding layer. Under physiological conditions (pH 7.4), the nanocarrier suppressed the photochemical activity of PS by lowering the access of oxygen molecules to the incorporated PS, while PDT efficacy was restored in a pH-responsive manner because of the dissolution of CaP and eventual recovery of access between the oxygen and the PS. Owing to this switch, the nanocarrier reduced the photochemical damage in the bloodstream, while it induced effective PDT efficacy inside the tumor cell in response to the acidic conditions of the endo-/lysosomes.

The aim of this study was to evaluate the oncological efficacy of tyrosine kinase inhibitors (TKIs) as first-line molecular-targeted therapy for Japanese patients with metastatic renal cell carcinoma (mRCC) in a routine clinical setting. This study included a total of 271 consecutive Japanese patients with TKI-naive mRCC, including 172 patients who received sorafenib and 99 who received sunitinib for ≥2 months as a first-line molecular-targeted agent. The prognostic outcomes of these patients were retrospectively assessed. During the observation period (median, 19 months), 126 patients (46.5%) succumbed to the disease and the median overall survival (OS) for the entire cohort was 33.1 months. The univariate analysis identified the Memorial Sloan-Kettering Cancer Center (MSKCC) classification, C-reactive protein (CRP) level, lymph node metastasis, bone metastasis, liver metastasis, histological subtype and sarcomatoid characteristics as significant predictors of OS. Of these factors, only the MSKCC classification, CRP level and liver metastasis were found to be independently associated with OS in the multivariate analysis. Furthermore, there were significant differences in OS according to the positivity for these 3 independent risk factors (i.e., negative for all factors vs. positive for a single factor vs. positive for 2 or 3 factors). These findings suggest that the introduction of TKIs as first-line molecular-targeted agents resulted in favorable cancer control outcomes in Japanese mRCC patients and that the prognosis of these patients may be stratified by 3 potential parameters, including the MSKCC classification, CRP level and liver metastasis.

Autophagy is one of the major causes of drug resistance. For example, the angiogenesis inhibitor bevacizumab shows only transient and short-term therapeutic effects, whereas long-term therapeutic benefits are rarely observed, probably due to hypoxia-induced autophagy. Nitric oxide (NO) is an important molecule with multiple functions, and it has recently been reported to function as a regulator of autophagy. Therefore, a reasonable therapeutic strategy for overcoming drug resistance by NO would involve it being directly delivered to the tumor. Here, we investigated the inhibitory effect of NO on autophagy by using a macromolecular NO donor S-nitrosated human serum albumin (SNO-HSA) with a high degree of NO loading and tumor targeting potential. In colon 26 (C26) cells, SNO-HSA significantly suppressed hypoxia-induced autophagy by inhibiting the phosphorylation of JNK1 and the expression of its downstream molecule Beclin1. The effect of SNO-HSA was also confirmed in vivo by combining it with Bev. In C26-bearing mice, significant suppression of tumor growth as well as lung metastasis was achieved in the combination group compared to the SNO-HSA or bevacizumab alone group. Similar to the in vitro experiments, the immunostaining of tumor tissues clearly showed that SNO-HSA inhibited the autophagy of tumor cells induced by bevacizumab treatment. In addition to other known antitumor effects of SNO-HSA, that is, the induction of apoptosis and the inhibition of multidrug efflux pumps, these data may open alternate strategies for cancer chemotherapy by taking advantage of the ability of SNO-HSA to suppress autophagy-mediated drug resistance and enhance the efficacy of chemotherapy.

Multifrequency tympanometry (MFT) is the measurement of the impedance of the middle ear transmission system at a wide range of frequencies from 200 Hz to 2 kHz. A potential use of MFT as a new diagnostic tool for detecting endolymphatic hydrops has recently been reported. However, its clinical usefulness for diagnosing Ménière’s disease (MD) remains unclear. To evaluate the clinical usefulness of MFT as a new qualitative and diagnostic test for MD, we performed MFT in 70 patients with unilateral or bilateral MD and in 29 normal control subjects. The width of double peaks in the admittance tympanograms (Y width) at 2 kHz and the resonance frequency (RF) were analyzed, and receiver operating characteristic (ROC) curves were constructed. The Y width in MD-affected ears was significantly greater than that in control ears (p < 0.001). The RF in MD-affected ears was significantly lower than that in control ears (p < 0.01). Neither the Y width nor RF had a significant relationship with hearing levels or the results of caloric and vestibular myogenic potential testings. The area under the ROC curve was 0.71 for the Y width and 0.66 for the RF. At the optimal cutoff points, the sensitivity and specificity of the Y width were 47.3 and 86.8%, respectively, and those of the RF were 41.3 and 84.2%, respectively. These results indicated that MFT is significantly associated with the presence of MD, but its diagnostic accuracy is only modest. MFT is a simple, noninvasive test, which should be considered as a complementary test in the diagnosis of MD.

Objective: To evaluate the function of the superior and inferior vestibular nerve systems in children with profound sensorineural hearing loss, and to assess the influence of dysfunction of each vestibular nerve system on the development of gross motor function. Study Design: Retrospective study. Setting: A tertiary referral center. Methods: Eighty-nine children (age range: 20–97 months) with profound sensorineural hearing loss who were due to undergo cochlear implant surgery were recruited. Function of the superior vestibular nerve system was evaluated by the damped rotation test and the caloric test, whereas functions of the inferior vestibular nerve systems were evaluated by the vestibular evoked myogenic potential (VEMP) test. Gross motor development was assessed using the age of acquisition of head control and independent walking. Results: Among the children able to complete the vestibular function tests, abnormalities were found in 20% (16 of 84 children) in the damped rotation test, 41% (31 of 75 children) in the caloric test and 42% (26 of 62 children) in the VEMP test. Children who showed abnormal responses in the vestibular function tests showed significantly delayed acquisition of head control (p < 0.05) and independent walking (p < 0.05) in comparison with children with normal responses. The children who showed abnormal responses in all 3 vestibular tests showed the greatest delay in acquisition of gross motor function in comparison with the other groups. Conclusions: Children with profound hearing loss tend to have dysfunction in the superior as well as the inferior vestibular nerve systems. Both the superior and inferior vestibular nerve systems are important for the development of gross motor function in children.

Objective:To investigate whether both cervical and ocular vestibular myogenic potentials (cVEMPs and oVEMPs) to air-conducted sound (ACS) and bone-conducted vibration (BCV) can help to differentiate vestibular migraine (VM) and Menière’s disease (MD).Study Design:Retrospective study.Settings:A tertiary referral center.Subjects and Methods:Twenty-eight patients with VM, 28 patients with definite unilateral MD, and 28 age-matched controls were included. Cervical VEMPs to 500 Hz ACS (cVEMPs-air) and 500 Hz BCV (cVEMPs-bone), oVEMPs to 500 Hz ACS (oVEMPs-air) and 500 Hz BCV (oVEMPs-bone), and caloric tests were performed. Results of these vestibular function tests were compared between the groups.Results:The prevalence of abnormality was significantly higher in VM than in controls only for the caloric test ( P < .05). Asymmetry ratios (ARs) for cVEMPs-air and oVEMPs-air were significantly larger in VM than in controls ( P < .05). Between VM and MD, the prevalence of abnormality was significantly different only for oVEMPs-air. The ARs for oVEMPs-air and caloric test asymmetries were significantly smaller in VM than in MD ( P < .05).Conclusions:Among the vestibular function tests, oVEMPs-air may be most helpful for the differentiation of VM from MD as a group.

Human serum albumin (HSA) is the most abundant circulating protein and its S-nitrosated form serves as a reservoir of nitric oxide (NO). Previously, we prepared poly-S-nitrosated HSA (Poly-SNO-HSA) by incubation with Traut's Reagent and isopentyl nitrite and evaluated its potential as a novel anticancer agent through apoptosis involving the caspase-3 pathway. Recently, NO donors such as nitroglycerin were reported to revert the resistance to anticancer agents. Therefore, now we have evaluated the effect of the above type of Poly-SNO-HSA on the resistance to doxorubicin (dx) in human myelogenous leukemic cells (K562 cells). P-gp expression and dx accumulation in K562 and dx-resistant K562 cells (K562/dx cells) were quantified using Western blot and FACS analysis, respectively. Compared with parent K562 cells, higher expression of P-gp and lower accumulation of dx were shown in K562/dx cells. Poly-SNO-HSA caused increased dx accumulation in K562/dx cells by decreasing the expressions of P-gp and HIF-1α. Other experiments with the guanylate cyclase inhibitor ODQ and 8-Br-cGMP revealed that also a cGMP signaling pathway is involved in the Poly-SNO-HSA induced increase in dx accumulation. Furthermore, in vivo studies showed that co-treatment with Poly-SNO-HSA enhanced the anticancer effect of dx in K562/dx cells-bearing mice. Thus, in addition to its proapoptotic effect Poly-SNO-HSA can in an efficient manner revert drug resistance both in vitro and in vivo, and two pathways for this effect have been identified.

Inferior vestibular neuritis (IVN) is a relatively minor subtype of vestibular neuritis (VN) and its clinical characteristics are unique.To clarify clinical characteristics of IVN in comparison with conventional VN.This was a retrospective case series review. Caloric responses and cervical vestibular evoked myogenic potential (cVEMP) responses were measured in 71 patients with VN. The patients were classified into three groups: (1) IVN group, who showed only asymmetrical cVEMP responses; (2) superior VN (SVN) group, who showed only asymmetrical caloric responses; (3) total VN (TVN) group, who showed asymmetrical responses in both tests. The clinical records of time course of subjective symptoms (duration of attack, duration of hospitalization, and time to remission) were reviewed and other profiles (age, sex, affected side, acute symptoms, and sequelae) were evaluated.Of the 71 patients with VN, 13 (18%) were classified as having IVN. The mean age and time to remission of patients with IVN (44.2 ± 4.8 years, 0.9 ± 0.5 months) were significantly lower and shorter, respectively, than those of patients with TVN (57.3 ± 2.5 years, 4.9 ± 4.7 months). There were no significant differences in other symptoms and profiles among the three groups. No patients with IVN showed benign paroxysmal positional vertigo as a sequela.

The primary afferent neurons of the vestibular ganglion convey sensory information from hair cells in the semicircular canals and otolith organs to the vestibular nuclei, the adjacent brainstem and the cerebellum. The intrinsic firing properties of vestibular ganglion cells (VGCs) are heterogeneous and have been classified into phasic, intermediate and tonic firing types on the basis of their response to injected depolarizing currents. A previous study from our group showed that the proportion of phasic discharging VGCs decreased during the first postnatal weeks. Moreover, α-dendrotoxin (α-DTX), a Kv1 potassium channels antagonist, turned neuron phasic firing to tonic, thus suggesting that these channels play an important role in the developmental changes of VGCs firing patterns. Here, by using immunohistochemistry, Western blotting and quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR), we explored the change in the expression of α-DTX-sensitive K(+) channels, Kv1.1, Kv1.2 and Kv1.6 in rat VGCs during early postnatal periods. We showed that expression of Kv1.6 protein is down-regulated together with expression of Kv1.6 mRNA after postnatal day 7 in rat VGCs whereas expression of Kv1.1 and Kv1.2 proteins did not change during the same developmental period. Our results suggest that down-regulation of the Kv1.6 protein and mRNA may be associated with maturation of excitable properties of primary vestibular neurons.

International audience; We have developed a new fluorescent binuclear Zn(II) complex for the detection of neurofibrillary tangles (NFTs) of hyperphosphorylated tau proteins, a representative hallmark of Alzheimer's disease (AD). The probe 1 incorporates a fluorescent BODIPY unit and two Zn(II)-2,2'-dipicolylamine (Dpa) complexes as a binding site for phosphorylated amino acid residues. Using fluorescence titration to evaluate the binding and sensing properties of 1 toward several phosphorylated peptide segments derived from hyperphosphorylated tau protein, we found that 1 binds preferentially to peptides presenting phosphorylated groups at the i and i+4 positions with dissociation constants (K(d)) in the micromolar range. Fluorescence titration with an artificially prepared aggregate of the phosphorylated tau protein (p-Tau) revealed that 1 binds strongly to p-Tau (EC(50) = 9 nM). In contrast, the interactions of 1 were weaker toward artificially prepared aggregates of the nonphosphorylated tau protein (n-Tau; EC(50) = 80 nM) and Abeta(1-42) fibrils (EC(50) = 650 nM). Histological imaging of a hippocampus tissue section obtained from an AD patient revealed that 1 fluorescently visualizes deposits of NFTs and clearly discriminates between NFTs and the amyloid plaques assembled from amyloid-beta peptides, confirming our strategy toward the rational design of a molecular probe for the selective fluorescence detection of NFTs in brain tissue sections.

Multiple system atrophy (MSA) is a progressive neurodegenerative disease that is characterized by varying degrees of parkinsonism and cerebellar, corticospinal, and autonomic dysfunction. Vocal cord abductor paralysis (VCAP) is considered a sign of a poor prognosis in MSA, because it is a life-threatening complication that may cause nocturnal sudden death. This case report presents a patient who was treated for Parkinson's disease, and complained of dizziness and sleep apnea. We examined VCAP using fiberoptic laryngoscopy as the possible cause of sleep apnea. VCAP usually occurs in the advanced stages of MSA and is accompanied by a worsening of other symptoms. Optokinetic nystagmus was severely impaired and the caloric test response was bilaterally absent. Objective findings such as VCAP and abnormal neuro-otological results led to the diagnosis of MSA.

Objectives After tuberculous pleurisy, lymphadenitis arising from cervical lesion is the second most common form of extrapulmonary tuberculosis. It is generally treated with antituberculosis agents, but some patients resist chemotherapy. In such cases, surgical resection is often considered as an alternative treatment. This study aims to evaluate the therapeutic outcome of cervical tuberculous lymphadenitis and the future course of treatment of this disease. Methods We retrospectively reviewed the clinical charts of patients diagnosed at the Tokyo Metropolitan Tama Medical Center between 2009 and 2015 and identified 38 cases of cervical tuberculous lymphadenitis. Precisely 798 patients were registered for primary tuberculosis at our institution during the same period. Results Patient ages ranged from 21 to 85 years (average: 58.9 years), and the male-to-female ratio was 1:1.2. The range of tuberculosis progression was as follows: 30 (78.9%) in only the cervical lymph node, 3 in the other (axillary, mediastinal, and abdominal) lymph nodes, 1 in the lung and vertebrae lumbales, 2 in the lung, and 1 in the pleural membrane. All 38 patients were initially treated with antituberculous drugs at the Department of Pulmonary Medicine based on guidelines for tuberculosis cases in Japan. In seven cases, the antituberculous drugs were replaced due to side effects. Four cases involved a single drug-resistant strain, and one case involved a double drug-resistant strain. Thirty-three (86.8%) cases were cured by chemotherapy alone. The three patients resistant to chemotherapy were successfully treated through neck dissection. Thirty-six cases (94.7%) were cured by chemotherapy or chemotherapy and surgery. Conclusion Local therapy could prove effective in cervical tuberculous lymphadenitis patients who exhibit an inadequate response to drugs. The role of neck dissection in cervical tuberculous lymphadenitis remains an important consideration.

Protein phosphorylation is ubiquitously involved in living cells, and it is one of the key events controlling protein-protein surface interactions, which are essential in signal transduction cascades. We now report that the small molecular receptors bearing binuclear Zn(II)-Dpa can strongly bind to a bis-phosphorylated peptide in a cross-linking manner under neutral aqueous conditions when the distance between the two Zn(II) centers can appropriately fit in that of the two phosphate groups of the phosphorylated peptide. The binding property was quantitatively determined by ITC (isothermal titration calorimetry), induced CD (circular dichroism), and NMR. On the basis of these findings, we demonstrated that these types of small molecules were able to effectively disrupt the phosphoprotein-protein interaction in a phosphorylated CTD peptide and the Pin1 WW domain, a phosphoprotein binding domain, at a micromolar level. The strategy based on a small molecular disruptor that directly interacts with phosphoprotein is unique and should be promising in developing a designer inhibitor for phosphoprotein-protein interaction.

We developed a new fluorescence assay system for GSK3beta-catalyzed kinase reaction using the BODIPY-based fluorescent chemosensor. This system exploits the selective sensing property of the chemosensor for a (i, i+4) bis-phosphorylated peptide, which allows us to conveniently detect the phosphorylation reaction with a fluorescence increase in a real-time fashion.

We examine developmental changes in the responsiveness of rat vestibular ganglion neurons (VGNs) to two neurotrophic factors (NTFs), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) and investigate the protective effects of these NTFs against ototoxic drugs during postnatal development in dissociated cultures. VGNs were obtained from rats on postnatal days (P) 1, 3, 7 and 14. BDNF facilitated neuronal survival as well as neurite sprouting of VGNs obtained from younger rats (P1 and P3), whereas these effects were not observed in older rats (P7 and P14). BDNF was also effective in facilitating neurite extension in VGNs at each of the postnatal ages. NT-3 also facilitated neuronal survival and neurite extension of VGNs from younger rats but these effects were significantly smaller than those of BDNF (p 0.05). The protective effects of BDNF and NT-3 against ototoxic drugs, gentamicin and cisplatin, were also age-dependent: they were effective for neuronal survival, neurite sprouting and neurite extension in VGNs from younger rats, whereas these effects tended to disappear in VGNs from older rats. Analysis of the changes in the expression of the receptors of NTFs revealed that expression of TrkB and TrkC proteins and their mRNA did not change during the developmental period, whereas expression of p75(NTR) protein was down-regulated together with that of p75(NTR) mRNA during the developmental period. Developmental changes in the responsiveness to exogenous NTFs in VGNs, which is not caused by the changes of their receptors but probably caused by changes in the intracellular signaling pathways, should be taken into consideration in the prevention of neuronal degeneration caused by ototoxic drugs.

OBJECTIVE To clarify the origin and pathways of ocular vestibular evoked myogenic potentials (oVEMPs) to air-conducted sound (ACS), we compared the results of oVEMPs with ACS, with oVEMPs with bone-conducted vibration (BCV), cervical VEMPs (cVEMPs) with ACS, and the caloric test in patients with unilateral vestibular schwannoma (VS). STUDY DESIGN Retrospective review. SETTING Tertiary referral center. PATIENTS Forty-five patients with untreated unilateral VS. MAIN OUTCOME MEASURE Each patient underwent vestibular tests, including oVEMPs to ACS, oVEMPs to BCV, cVEMPs to ACS, and caloric tests. The correlations among these tests were evaluated. RESULTS Of the 45 patients recruited, 28 patients (63%) showed reduced or absent oVEMPs to ACS solely on the affected side. There were no significant differences in abnormal response ratios among oVEMPs to ACS, oVEMPs to BCV, cVEMPs to ACS, or the caloric test. The results of oVEMPs to ACS had a significant correlation with those of oVEMPs to BCV and the caloric test (p 0.05). CONCLUSION These findings support the hypothesis that oVEMP in response to ACS are predominantly mediated by the superior vestibular nerve and probably reflect the function of the utricle.

Ocular vestibular evoked myogenic potentials (oVEMPs) to binaural air-conducted stimulation (ACS) may provide a convenient way of assessing the crossed vestibulo-ocular reflex in patients with vestibular dysfunction as well as in healthy subjects.To investigate the clinical feasibility of using oVEMPs in response to binaural ACS to assess normal subjects and patients with vestibular dysfunction.The study investigated 24 normal subjects (14 men and 10 women, aged from 23 to 60 years) and 14 patients with unilateral peripheral vestibular dysfunction. Each subject underwent oVEMP testing in response to monaural ACS and binaural ACS (500 Hz tone burst, 135 dBSPL).In normal subjects, bilateral oVEMPs were elicited in 75% of subjects in response to monaural ACS and in 91% in response to binaural ACS. Asymmetry ratios (ARs) of the responses to binaural ACS were significantly smaller than those of the responses to monaural ACS (p0.01). In patients with unilateral vestibular dysfunction, there were no significant differences in the amplitude, latency, or AR of the responses between monaural and binaural ACS. Approximately 30% of patients showed reduced ARs to binaural ACS relative to monaural ACS, primarily due to contamination by uncrossed responses elicited in healthy ears.

To characterize the impact of sorafenib treatment on health-related quality of life (HRQL) in Japanese patients with mRCC.We performed a prospective observational study including 85 consecutive patients undergoing radical nephrectomy who were diagnosed as having mRCC refractory to cytokine therapy and subsequently treated with sorafenib for at least 3 months. HRQL in these patients was assessed using the Medical Outcomes Study 36-Item Short Form (SF-36).Before treatment all eight scores in the 85 patients were significantly inferior to those in the age-matched control population in Japan. Three months after sorafenib treatment, one score (mental health) in the 85 patients was significantly higher than what it was before treatment. Three scores (body pain, role limitations because of emotional problems, mental health) in patients who had some degree of tumour shrinkage were significantly better than those in the remaining patients, while there were no significant differences in all but one score (social function) between patients with and without severe AEs. Furthermore, there were no significant differences in any scores 3, 6 and 12 months after sorafenib treatment in 26 patients who could be followed for at least 12 months.Despite non-randomized study including a comparatively small number of patients, the findings of the present study suggest that sorafenib treatment may not impair HRQL in patients with mRCC, and HRQL in patients receiving sorafenib is likely to be affected by the efficacy rather than AEs during treatment.

We rarely encounter patients with proptosis, however, it is known that inflammation and extension of paranasal sinus tumors may cause this condition. We should consider the diseases that may cause proptosis to facilitate the diagnosis. Recently, we treated proptosis in 2 cases, one with inflammatory myofibroblastic tumor (IMT) and the other with malignant lymphoma. As these 2 diseases show various clinical features and these features frequently overlap, it is difficult to differentiate between IMT and malignant lymphoma without pathological examinations. In this study, we review the relevant literature reports and discuss the difficulties in establishing a clinicopathological diagnosis and present a slight distinction in magnetic resonance imaging.

To compare the surgical margin (SM) status between open and laparoscopic radical prostatectomy (RRP and LRP, respectively) specimens.Surgical specimens from 137 patients undergoing LRP and 220 patients undergoing RRP for clinically localized prostate cancer were included in the analysis. SM status in each resected specimen, including the number of positive SM as well as their location, was examined.The incidence of positive SM in the LRP group was significantly greater than that in the RRP group. Despite the lack of significant difference in the proportion of solitary positive SM between these two groups, the proportion of multiple positive SM in the LRP group was significantly greater than that in the RRP group. There was no significant difference in the incidence of anterior positive SM between the two groups, while the incidences of positive SM at the apex, posterior site and bladder neck in the LRP group were significantly greater than those in the RRP group. Furthermore, there were no significant preoperative parameters predicting positive SM in the LRP group. On the other hand, the biopsy Gleason score and clinical T stage were identified as significant predictors of positive SM in the RRP group, of which the biopsy Gleason score was independently related to the presence of positive SM.Clinical T stage and Gleason score could be useful predictors of SM status following RRP, while positive SM in LRP specimens were detected irrespective of preoperative parameters, suggesting the need for an effort for further refining the LRP procedure.

The objectives of this study were to retrospectively examine the outcomes of adjuvant cisplatin-based combination chemotherapy following radical cystectomy in patients with invasive bladder cancer in order to identify parameters predicting the prognosis of these patients.This study included a total of 51 patients with muscle invasive bladder cancer who underwent radical cystectomy between January 1995 and December 2004, and subsequently received at least two cycles of either MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) or MVP-CAB (methotrexate, doxorubicin, vincristine, cyclophosphamide, bleomycin and cisplatin) chemotherapy in an adjuvant setting because of the presence of diseases corresponding to pT3/4 and/or pN1/2 without clinical evidence of metastasis. The significance of several clinicopathological factors as predictors of disease recurrence and cancer-specific death was evaluated using univariate and multivariate analyses.During the observation period of this study (median, 26.5 months), disease-recurrence and cancer-specific death were observed in 21 and 16 patients, respectively. The 5-year recurrence-free and cancer-specific survival rates were 48.6% and 54.1%, respectively. Among several factors examined in this series, lymph node metastasis and concomitant carcinoma in situ (CIS) were identified as significant predictors of both disease-recurrence and cancer-specific death, and these were also independently associated with disease-recurrence and cancer-specific death.Adjuvant cisplatin-based combination chemotherapy for patients with extravesically extended bladder cancer following radical cystectomy resulted in comparatively unsatisfactory outcome concerning cancer-control; accordingly, it would be necessary to develop a more efficacious therapeutic strategy for such patients, particularly for those with lymph node metastasis and/or concomitant CIS.

The objective of this study was to investigate risk factors for intravesical recurrence in patients with superficial bladder cancer without concomitant carcinoma in situ (CIS).In this series, we analyzed data from patients with newly diagnosed superficial Ta or T1 transitional cell carcinoma (TCC) of the bladder without concomitant CIS who underwent complete transurethral resection (TUR) without any adjuvant intravesical instillation therapies. Multivariate analysis was used to determine significant risk factors affecting intravesical recurrence after TUR. Differences in clinicopathological features between primary and recurrent tumors were also characterized.Among 341 patients undergoing TUR of Ta or T1 bladder cancer, 187 diagnosed as having concomitant CIS and/or treated with adjuvant intravesical therapy were excluded, and the remaining 154 were evaluated. Intravesical recurrence was detected in 64 of the 154 patients, showing a 5-year recurrence-free survival rate of 58.3%. Among several factors examined, only tumor size was significantly associated with intravesical recurrence. Multivariate analysis identified tumor size as an independent predictor for intravesical recurrence irrespective of other parameters including age, gender, multiplicity, growth pattern, grade and stage. Recurrent tumors were significantly smaller and of a lower grade and lower stage than primary tumors, despite the absence of differences in growth pattern and the multiplicity between them.These findings suggest that primary tumor size could be used as a potential risk factor for predicting intravesical recurrence following TUR of superficial TCC of the bladder without concomitant CIS, and that the pathological characteristics of recurrent tumors are more favorable than those of primary tumors.

The objective of the present study was to characterize the clinicopathological features of histologically defined papillary renal cell carcinoma (RCC).The present study included a total of 35 patients who were treated by radical surgery and subsequently diagnosed as having papillary RCC between April 1995 and June 2004. Clinicopathological data of these patients were retrospectively reviewed according to the previously reported classification system (Mod. Pathol. 1997; 10: 537-44).Of these 35 patients, 23 (65.7%) and 12 (34.3%) were diagnosed as type 1 and type 2 papillary RCC, respectively. Despite the lack of significant differences in clinical parameters between these two groups, including age, gender, clinical stage and metastasis, the incidence of symptomatic disease in patients with type 2 papillary RCC was significantly higher than that in those with type 1 papillary RCC. Pathological examinations demonstrated that there were no significant differences between these two groups in pathological stage, tumor grade or vascular invasion. Furthermore, there was no significant difference between these two groups in overall or recurrence-free survival.Although the present study included a small number of patients with short follow-up period, the clinicopathological features including prognoses were almost similar between patients with type 1 and type 2 papillary RCC; therefore, careful postoperative follow-up should be considered for patients with papillary RCC irrespective of morphological subtype.

In the research field of molecular recognition, selective recognition and sensing of phosphorylated protein surfaces is strongly desirable both for elucidation of protein−protein recognition at the molecular level and for regulation of signal transduction through protein surfaces. Here we describe a new strategy for molecular recognition of a multi-phosphorylated peptide using intrapeptide cross-linking on the basis of coordination chemistry. The present artificial receptor can selectively bind to doubly phosphorylated peptide through multiple-point interactions and fluorescently sense the binding event with an association constant of more than 106 M-1 in neutral aqueous solution.

The first fluorescent chemosensors toward a native phosphorylated peptide are successfully synthesized. Dinuclear zinc(II)-dipicolylamine-based anthracene (1, 2) can selectively recognize and sense phosphorylated species with an increase in the fluorescence intensity. We also demonstrated that these artificial receptors fluorometrically detect a phosphorylated peptide with high affinity (>107 M-1) in aqueous solution.

[Background and purpose] We previously reported that the efficacy of photodynamic therapy (PDT) with dendrimer phthalocyanine-loaded micelles (DPc/m). However, monitoring of this photosensitizer by the clue of fluorescence is quite difficult because of the low intrinsic fluorescence originating from phthalocyanine, thus other fluorescence dye such as Alexa is required for the monitoring. For resolving this problem, we developed a novel micelle-based photosensitizer loading dendrimer porphyrin (DP). The DP-loaded micelles (DP/m) intensely emit fluorescence from porphyrin without an additional fluorescence labeling. The aim of this study was to verify practical effectiveness of DP/m by comparing that of DP on PDD and PDT. [Materials and Methods] For in vitro cytotoxicity tests, rat bladder carcinoma cells (AY-27) were incubated with DP/m for 4 h and were exposed to laser light (635 nm, 100 J/cm2). One day after PDT, cell viability was measured by WST-8 assay. Distribution of DP/m in cellular organelles was investigated using fluorescence markers of cellular organelles by a confocal laser scanning microscope. In addition, we examined in vivo fluorescence imaging using an orthotopic bladder tumor model established by inoculating AY27 cells in female Fischer F344 rats via transurethral catheterization. Four hours after intravenous administration of DP/m, the bladders were extracted and fluorescence image was obtained of bladder. [Results] DP and DP/m without light irradiation were basically non-toxic (low dark toxicity), showing cell viability being > 85% at the concentration up to 17 μM. However, photoirradiated DP and DP/m induced the high level of cytotoxicity: survival rate was less than 5%. PDT using DP/m showed an approximately 15 times of cytotoxicity when compared with PDT using DP. The results suggested that DP/m highly accumulate in cancer cells and can provide a significant photodynamic effect leading to cell damage. Confocal laser scanning microscopic studies showed that DP/m exhibited preferential accumulation in lysosomes through endocytosis and retention in the cells. When DP/m were injected (i.v.) into the bladder tumor animal models, fluorescence from the DP/m were clearly visualized in accordance with tumor distribution. We detected fluorescence even when a size of tumor was less than 1 mm, thus enabling optical imaging with excellent contrast between tumor and surrounding normal tissue. A study of PDT in vivo is now carried out. [Conclusion] We developed dendrimer porphyrin-loaded micelles (DP/m), which were effective for both PDD and PDT. An excellent detection of tumor was achieved owing to the intense fluorescence of DP/m and highly accumulation in tumors. The preferable DP/m uptake in tumors resulted in effective phototoxicity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3469. doi:1538-7445.AM2012-3469

Introduction: Photodynamic diagnosis (PDD) and therapy (PDT) have been clinically used for the early phase cancer of hollow organs. We are advancing the photomedicine to the next stage, in which treatment is carried out immediately after the detection of lesions. For achieving the simultaneous diagnosis and treatment, we established a novel DDS-type photoactivatable agent, micelle-based photosensitizer loading dendrimer porphyrin (DP/M). A micelle-based shell structure is expected to be selectively accumulated in tumors. An intensely emitted fluorescence from porphyrin can be used for lesion detection and a highly quantum yield of porphyrin promises an effective PDT. Apart from the agent, we recently developed a fluorometric system equipped with an ultrathin endoscope that has a spatial resolution of 15,000 pixels even with a diameter of 0.8 mm. The aim of this study was to verify practical effectiveness of the novel photosensitizer combined with the endoscopic fluorometric system for simultaneous diagnosis and treatment. In this study, we targeted esophageal cancer because satisfactory results are not always obtained with conventional therapies and an endoscopic approach is applicable. Materials and Methods: A rat orthotopic esophageal tumor model was established in female Fischer F344 rats by orally administered with NMBuA (N-Nitroso Methylbutylamine) solved in drinking water. After intravenous administration of DP/M, PDD was carried out using the endoscopic fluorometric system (ex. 405 nm, em. > 630 nm). After the detection of lesions, tumors were irradiated using a diffuser tip fiber connected to a 635nm LD laser. Results: About 6 weeks after the administration of NMBuA, polypoid tumors were observed in the esophagus. Pathological analysis revealed that proliferated polymorphonuclear cells were seen: a part of which reached the muscular layer of mucosa. A selective accumulation of DP/M in the tumors was confirmed with the endoscopic fluorometric system. This modality enabled repeated observations of tumors without sacrifice. The following PDT provided a promising result. Conclusions: DP/M combined with the endoscopic fluorometric system brought the simultaneous diagnosis and treatment for the orthotopic rat esophagus tumor models. Acknowledgment: This research is granted by the Japan Society for the Promotion of Science (JSPS) through the “Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program),” initiated by the Council for Science and Technology Policy (CSTP). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3468. doi:1538-7445.AM2012-3468