Multidimensional voice evaluation in pretreatment glottic carcinoma.

It is generally accepted that, in glottic carcinoma, the voice will deteriorate, even in the early stages. This paper reports the degree of hoarseness and multidimensional vocal evaluation of glottic carcinoma patients. Forty-seven male glottic carcinoma patients and a control group of 13 normal subjects were included in this study involving psychoacoustic evaluation by doctors, acoustic analysis, phonogram, maximum phonation time and stroboscopy before treatment. A normal voice or mild hoarseness by psychoacoustic evaluation was found in 35% of cases with T1 and T2 glottic carcinoma. Patients with psychoacoustically inferior vocalization had high scores on acoustic analysis, small phonogram areas, and short maximum phonation time. Stroboscopy revealed attenuation or disappearance of the mucosal wave on the tumor side in all cases, whether the acoustic analysis data were within or beyond the normal limits. We identified two conditions offering superior vocalization in glottic carcinoma patients: (1) the lesion should be unilateral, and (2) the lesion should be flat with no protrusion. We should evaluate patients with glottic carcinoma not only with vocal examination but also using stroboscopy before biopsy.

Irradiation impairment of umami taste in patients with head and neck cancer.

BACKGROUND: Previous studies have reported the alteration of the four basic tastes (sweet, salty, sour and bitter) in patients with head and neck cancer (HNC) during radiotherapy. However, there has been no investigation on the function of umami taste, a novel basic taste recognized recently, during head and neck irradiation. OBJECTIVE: To investigate the recognition threshold of umami and the four basic tastes at different irradiation dose intervals during radiotherapy for head and neck cancer. METHODS: In 30 patients with malignant neoplasm of head and neck, objective taste thresholds were examined by use of a whole-mouth method at pre-radiotherapy, irradiation doses at 15, 30, 45, and 60 Gy, respectively. Subjective taste loss and some distresses were recorded simultaneously. RESULTS: Sweet, sour, salty, and bitter tastes showed temporarily and slightly increased thresholds during the treatment, but no statistical difference was found between the threshold at pre-radiotherapy and that at 15, 30, 45, and 60 Gy in any taste quality (all P > 0.05). Significantly impaired threshold of umami taste was revealed at 30 Gy (P < 0.05) and remained throughout the following treatment (at 45 and 60 Gy, both P < 0.01). Subjective taste impairment, appetite loss and satisfaction with the current state tended to deteriorate significantly during the irradiation. Mean body weight of the patients experienced a continuous loss, decreasing from an average of 60.4 kg before treatment to 57.3 kg at 60 Gy (P < 0.01). Scores of satisfaction with current state showed a significant correlation with umami taste thresholds (P = 0.035). CONCLUSION: The clinical impairment pattern of umami taste is different from that of the other four basic tastes in HNC patients during radiotherapy. Impaired umami taste acuity plays an important role in impacting the quality of life of the patients irradiated to the head and neck.

[Treatment of hypopharyngeal carcinomas--an institutional analysis of the results of FAR radiochemotherapy, radical resection, and free jejunum flap reconstruction and the indication of neck dissection].

The treatment results of 65 patients with hypopharyngeal carcinomas treated at our institute between 1995 and 2000 were analyzed. In general, concurrent radiochemotherapy (RCT), consisting of intravenous 5-FU injection, intra-muscular vitamin A injection, and radiation (FAR therapy) was used as an initial treatment for advanced hypopharyngeal carcinomas and early hypopharyngeal carcinomas. Tumor responses were evaluated at the time of radiation doses of 30Gy. Patients who showed a complete response (CR) subsequently received curative radiation doses of 60 to 70Gy. Patients who did not show a CR underwent radical surgery consisting of pharyngo-laryngo-cervical esophagectomy, neck dissection for positive cervical nodes and/or the primary tumor sides, and reconstruction using a free jejunum flap. The disease-specific 5-year survival rates were 92%, 55%, 35% and 49% for stage I/II, III, IV and all cases, respectively. Eight out of 9 patients with stage I/II disease who showed a CR after receiving 30Gy of RCT survived with an intact larynx after definitive RCT. All the patients with stage II/III disease who underwent radical surgery after receiving 30Gy of RCT did not have a recurrence, whereas the 5-year survival rate of patients with stage IV disease who underwent RCT and radical surgery was 45%. Seventeen out of 19 patients with clinically negative cervical nodes on the opposite side of their primary tumors showed no nodal metastasis after RCT without neck dissection. This result suggests that elective neck dissection after RCT is not necessary. To improve the treatment results for hypopharyngeal carcinomas, early detection of this disease is prerequisite. In addition, the clinical diagnosis of highly malignant cases and new molecular-targeted therapies based on an analysis of distant metastasis mechanisms should be developed to overcome the poor prognosis of advanced hypopharyngeal carcinomas.

[Laminin gamma2 chain expression in squamous cell carcinomas of the tongue and its clinical relevance].

Laminin gamma2 chain (LNgamma2) expression and its clinical relevance were examined in squamous cell carcinomas of the tongue. When tumor cells were attached to each other and showed expansive growth, LNgamma2 was expressed only in the peripheral cells of the tumor nests (peripheral expression). In contrast, when tumor cells showed infiltrative growth diminishing cell-cell adhesion, LNgamma2 expression was diffusely observed in almost all of the cells (diffuse expression). Patients with caricinoma cells of the primary lesions showing peripheral LNgamma2 expression were classified as the peripheral expression type, whereas patients with carcinoma cells showing diffuse LNgamma2 expression at least in part of the invasive fronts were classified as the diffuse expression type. Among 30 patients with tongue carcinomas of more than stage II, 19 patients were the peripheral expression type and 11 patients were the diffuse expression type. The 3-year disease-specific survival rates for the peripheral type and diffuse type were 64% and 34%, respectively. LNgamma2 may play an important role in growth and invasion of tongue carcinomas. In particular, it seems likely that the diffuse LNgamma2 expression in carcinoma cells has a significant relevance to the malignant characteristics of infiltrative carcinoma cells. In addition, LNgamma2 expression may be a useful prognostic factor for the patients with carcinomas of the tongue.

Immunoregulatory role of ocular macrophages: the macrophages produce RANTES to suppress experimental autoimmune uveitis.

Murine experimental autoimmune uveitis (EAU) is a model of human uveitis. Ocular-infiltrating macrophages play a crucial role in the generation of tissue damage in EAU. In fact, several chemokines are actually produced in the inflamed eye. The aim of this study was to elucidate the role of ocular macrophage-derived chemokines in EAU. C57BL/6 mice were immunized with human interphotoreceptor retinoid binding protein peptide 1-20, and the EAU severity was scored at multiple time points based on microscopic fundus observations (retinal vascular dilatation and exudates) and histological examinations. The peak inflammatory response was observed 1 wk (day 16) after the beginning of macrophage infiltration to the eye (day 9). Ocular-infiltrating cells were enriched or depleted of macrophages by magnetic beads and analyzed by real-time RT-PCR for chemokine mRNA production. We found that only the macrophage-enriched cells from the eye produced RANTES, and thus proposed that macrophage-derived RANTES facilitated the ocular inflammations. In contrast to our postulate, neutralization of RANTES by specific Ab in vivo on days 9 and 13 exacerbated EAU. We also found that the ratio of ocular CD4/CD8 T cells was markedly increased after treatment. As a result, RANTES neutralization might exacerbate EAU by modulating the type of T cell subsets recruited to the eye. In conclusion, our data provide insight into the immunoregulatory role of macrophages and RANTES in the pathogenesis of ocular inflammation. Not all macrophage-derived chemokines cause local inflammation, since RANTES produced by ocular macrophages appears to suppress EAU.

A rapid speech synthesizing software on a PDA for Japanese with speech impairments.

We developed a Japanese-language, rapid synthesizing software application for use on a personal digital assistant. It has an unrestricted vocabulary and can synthesize words and sentences within 3 s. Eight hundred common sentences and words are preregistered. By touching the first character at the head of a preregistered sentence or word from an on-screen Kana (Japanese alphabet) chart, the user can select the sentence or word to be spoken. Characters on the Kana chart can also be input sequentially. Two Japanese subjects with speech impairments rated the device highly for its portability and quick response. Whereas communication previously had to be done by writing or sign language, it was easy for listeners with or without specialized training in communication with persons with speech impairments to understand the output from this device, making conversation easier which, in turn, improved the quality of life and social activity of these persons with speech impairments.

Follicular dendritic cell sarcoma of the neck; a case report and literature review.

Follicular dendritic cell (FDC) sarcomas, also known as dendritic reticulum cell tumors, are uncommon neoplasms arising from antigen-presenting cells in B-lymphofollicles of nodal and extra-nodal sites. It is considered as an intermediate grade malignancy since it has significant recurrent and metastatic potential. We report a case of FDC sarcoma arising in the neck. A 56-year-old female presented with a left neck tumor. Neck dissection was performed. Microscopically, the tumor showed spindle-shaped stromal cells with large oval and polygonal nuclei. Immunohistologically, the cells were positive for CD21 and CD35, consistent with FDC sarcomas. Adjuvant chemotherapy of cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) was given. Literature review provides the current information for the diagnosis and treatment of this unusual tumor.

[Postpartum hypercalcemia in a patient with previous thyroid carcinoma: a report of 2 cases].

We report postpartum hypercalcemia in 2 patients with previous thyroid carcinoma who had undergone total thyroidectomy and total parathyroidectomy and required vitamin D and calcium therapy to control hypoparathyroidism. Postpartum, they required less vitamin D and calcium for satisfactory control. While lactating, they maintained normal serum calcium without supplementary vitamin D or calcium. Transient remission of hypoparathyroidism symptoms has been observed during lactation. Some studies have shown that parathyroid-related protein (PTHrP) is produced by breast tissue, having an endocrine-like effect. We discuss the mechanism of postpartum hypercalcemia.

Transcutaneous PCO(2) monitoring with hyperventilation during phonation in vocal cord paralysis.

OBJECTIVE: Hyperventilation during phonation is one of the causes of fatigue in-patients with vocal disorders. METHODS: The transcutaneous (tc) PCO(2) during phonation in 8 normal subjects and 12 patients with unilateral vocal cord paralysis was measured. Cases were further divided into two groups by the degree of the tcPCO(2) decrease during phonation. Patients with a tcPCO(2) decrease less than 3.4 mmHg during phonation were classified as group 1 (G1). Patients with a tcPCO(2) decrease larger than or equal to 3.4 mmHg during phonation were classified into group 2 (G2). RESULTS: The average changes in tcPCO(2) in the G1 cases was not significantly different from that in normal subjects. The decrease in tcPCO(2) during phonation in the six G2 cases was 10.7+/-6.2 mmHg, and was significantly different from that in normal subjects (P<0.01, t-test). The decrease of tcPCO(2) during phonation in both G1 and G2 cases improved significantly after surgical treatment. Easy fatigability during phonation in two G1 cases and five G2 cases improved. CONCLUSIONS: The decrease in tcPCO(2) during phonation in cases of unilateral vocal cord paralysis is well correlated with easy fatigability. It is clinically useful to classify cases into two groups using the criteria of a less than 3.4 mmHg or larger than or equal to 3.4 mmHg decrease in tcPCO(2). These results also suggest that hyperventilation is one major cause for easy fatigability during phonation in cases with unilateral vocal cord paralysis. TcPCO(2) changes during phonation are useful in evaluating hyperventilation and the effect of treatment.

[Analysis of the regulatory mechanism of the rat cerebellum on the motor coordination in the time and space domain].

To elucidate the mechanism of the cerebellum on the regulation of coordinated movement in time and space domain, ninety-six Purkinje cell complex spike was simultaneously recorded utilizing ninety-six glass micro pipette electrodes. The complex activity of the bilateral cerebellum was symmetrically synchronized. Furthermore, the medial cells fired first, then the lateral cells fired succeedingly. These results suggest that the time domain of the motor coordination was regulated by the symmetrical firing pattern of the bilateral cerebellum Purkinje cell activity.

"FAR" chemoradiotherapy improves laryngeal preservation rates in patients with T2N0 glottic carcinoma.

BACKGROUND: The appropriate treatment approach for patients with T2N0 laryngeal cancer remains highly controversial. Because radiotherapy alone is associated with a high risk of local recurrence, we have developed a triple combination treatment approach consisting of 5-fluorouracil (250 mg/day, i.v.), vitamin A (50,000 unit/day, i.m.) and external radiation (2.0 Gy/day), which we have termed "FAR therapy." METHODS: Patients with T2N0 glottic carcinoma were initially treated with 15 days of FAR therapy, which included a cumulative radiation dose of 30Gy (i.e., "30 Gy of FAR therapy"). Those patients who demonstrated a complete response either clinically or pathologically continued to receive further FAR therapy, with up to 60-70 Gy. All other patients received laryngectomy without any additional treatment. RESULTS: Ninety-five patients were treated according to this program, and most of the patients (98%) were able to complete this treatment course. Eighty-eight patients (93%) were treated with FAR therapy alone. The local control and ultimate local control rates were 91% (85 of 93), and 99% (92 of 93), respectively. The cumulative 5-year voice preservation and complete laryngeal preservation rates were 91% and 87%, respectively. The cumulative 5-year disease-specific survival rate was 97%. CONCLUSIONS: Because a high rate of laryngeal preservation was achieved without compromising disease-specific survival, our treatment approach based on FAR therapy may be promising for the treatment of patients with T2N0 glottic carcinoma.

Taste dysfunction in irradiated patients with head and neck cancer.

Taste disorders caused by radiation therapy for head and neck cancer are common. This prospective study of 40 patients with head and neck cancer assessed changes in taste sensations during radiation therapy. The relationship between the time course and the degree of taste disorder was studied. The taste recognition threshold and supra-threshold taste intensity performance for the four basic tastes were measured using the whole-mouth taste method before, during, and after radiation therapy. Bitter taste was affected most. An increase in threshold for sweet taste depended upon whether the tip of tongue was included within the radiation field. The slope of the taste intensity performance did not change during or after radiotherapy. The pattern of salivary dysfunction was different from that of taste dysfunction. The main cause of taste disorders during radiation support the hypothesis that taste dysfunction is due to damage to the taste buds in the radiation field.

Pre- and postsynaptic ATP-sensitive potassium channels during metabolic inhibition of rat hippocampal CA1 neurons.

Presynaptic and postsynaptic membrane activities during experimental metabolic inhibition were analysed in mechanically dissociated rat hippocampal neurons using nystatin-perforated and conventional whole-cell patch clamp recordings. NaCN, an inhibitor of mitochondrial ATP synthesis, induced an outward current across the postsynaptic soma membrane. This current was blocked by tolbutamide, a sulfonylurea, which blocks ATP-sensitive K+ (KATP) channels. The presynaptic effect of metabolic inhibitors such as NaCN, NaN3, or glucose-free solution was to increase the frequency of GABAergic miniature inhibitory postsynaptic currents (mIPSCs). Tolbutamide had no effect on this increase in mIPSC frequency induced by metabolic inhibition. Diazoxide, a KATP channel opener, evoked a similar somatic outward current in a dose-dependent manner. In addition, diazoxide decreased the frequency of mIPSCs in a dose-dependent fashion. Both these pre- and postsynaptic effects of diazoxide were reversed by tolbutamide, suggesting the existence of KATP channels on both pre- and postsynaptic membranes. These results confirm the presence of KATP channels on both the pre- and postsynaptic membranes but indicate that the channels have significantly different sensitivities to metabolic inhibition.

Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma.

The precise mechanism responsible for the frequent overexpression of cyclinD1 in human head and neck squamous cell carcinoma (HNSCC) is not known. In view of the fact that signal transducers and activators of transcription 3 (Stat3) is often activated in HNSCC cells, we examined the effects of Stat3 on cyclin D1 expression and cell proliferation in the YCU-H891 HNSCC cell line that displays constitutive activation of Stat3. Expression of a dominant negative Stat3 construct in YCU-H891 cells inhibited proliferation, cyclin D1 promoter activity, and cellular levels of cyclin D1 mRNA and protein. The levels of the antiapoptotic Bcl-2 and Bcl-X(L) proteins were also inhibited. In 51 primary tumor samples from patients with squamous cell carcinoma of the p.o. tongue, there was a significant correlation between increased levels of the activated form of Stat3, phosphorylated-Stat3, and increased levels of cyclin D1 (P < 0.0001). Increased tumor levels of phosphorylated-Stat3 were also associated with lower survival rates (P < 0.01). This study provides the first evidence that in HNSCC, constitutive activation of Stat3 plays a causative role in overexpression of cyclin D1, and in clinical studies, Stat3 activation may provide a novel prognostic factor. Furthermore, agents that target Stat3 may be useful in the treatment of HNSCC.

The roles of JNK1 and Stat3 in the response of head and neck cancer cell lines to combined treatment with all-trans-retinoic acid and 5-fluorouracil.

We have used a combination of vitamin A (all-trans-retinyl palmitate), 5-fluorouracil (5-FU) and radiation to treat human head and neck squamous cell carcinoma (HNSCC). This chemoradiotherapy is called "FAR therapy." In this study we examined the effects of all-trans-retinoic acid (ATRA), the active metabolite of vitamin A, and ATRA plus 5-FU on two HNSCC cell lines (YCU-N861 and YCU-H891) to gain insight into the molecular mechanisms of FAR therapy. ATRA at 1 mM (the order of concentration found in HNSCC tumors treated with FAR therapy) inhibited cell proliferation and caused G1 cell cycle arrest in both cell lines. This was associated with a decrease in cyclin D1, an increase in p27(Kip1) and a reduction in the hyperphosphorylated form of retinoblastoma protein (pRB). With YCU-N861 cells, ATRA also caused a decrease in Bcl-2 and Bcl-X(L) and an increase in Bax. Both ATRA and 5-FU activated c-Jun N-terminal kinase (JNK) 1 and the combination of both agents resulted in additive or synergistic activation of JNK1, and also enhanced the induction of apoptosis. The YCU-H891 cells, in which the epidermal growth factor receptor (EGFR)-signal transducer and activator of transcription 3 (Stat3) pathway is constitutively activated, were more resistant to treatments with ATRA, 5-FU and the combination of both agents than YCU-N861 cells. A dominant negative Stat3 construct strongly enhanced the cellular sensitivity of this cell line to 5-FU but not to ATRA. In addition there is evidence that activation of Stat3 is associated with cellular resistance to radiation in HNSCC. Therefore, the addition to FAR therapy of agents that inhibit activation of the Stat3 pathway may enhance the clinical response of patients with HNSCC to FAR therapy.

Mutation analysis of human cytokeratin 8 gene in malignant rhabdoid tumor: a possible association with intracytoplasmic inclusion body formation.

The rhabdoid cell, which is typically observed in malignant rhabdoid tumor (MRT) and other malignant neoplasms, has an eosinophilic cytoplasm containing a spheroid perinuclear inclusion body. This distinct cell is known to act as a highly aggressive indicator in many types of malignant tumors and is characterized by aggregates of intermediate filaments, comprising both vimentin and cytokeratin (CK) 8, which is mainly expressed in simple-type epithelium such as liver and intestine. To clarify the cause of the inclusion body formation, we analyzed the alteration of the complete human CK8 gene (KRT 8: 1724 base pairs) in seven samples of MRT (three from frozen materials and four from cultured cell lines) by reverse-transcriptase polymerase chain reaction, followed by direct sequencing. In addition, the two cell lines, Huh7 and HeLa, which lacked rhabdoid feature, six pediatric malignant tumors, including three cases of primitive neuroectodermal tumor (PNET) and three of Wilms' tumor; and 15 normal liver tissue (as a control) were also analyzed. All MRT samples had missense mutations in the human KRT 8 gene, i.e., Arg89 --> Cys (5/7); Arg --> Cys251 (3/7); Glu267 --> Lys (6/7); Ser290 --> Ile, Met; (7/7) and Arg301 --> His(4/7), none of which was detected in any control samples. Among these mutations, the most noteworthy findings were that Arg89 belongs to the H1 subdomain of the head domain and that Arg251 belongs to the short nonhelical linker segment, or L1-2. Both these mutations are noted for their relationships to lateral protofilament-protofilament interactions. In addition, Ser290 has been previously reported to be a phosphorylation site, which has been recognized to play an important role in filament organization, leading to conformational change of the CK8 filaments. In conclusion, mutated codons of CK8 gene in MRT were located in the important region involved in the conformational change of intermediate filament.

Serum squamous cell carcinoma antigen is a useful biologic marker in patients with inverted papillomas of the sinonasal tract.

BACKGROUND: Inverted papilloma (IP) is a frequent benign sinonasal tumor that is characterized histologically by squamous metaplasia, epithelial acanthosis, and hyperplasia of the nasal epithelium. Because of its high recurrence rate and malignant transformation potential, careful long-term follow up is necessary. METHODS: The purpose of the current report was to study the expression of squamous cell carcinoma (SCC) antigen in sinonasal IPs and to evaluate the usefulness of SCC antigen as a biologic marker for the follow-up of patients with sinonasal IP. The expression of SCCA1 in three sinonasal IP cases, three sinonasal SCC cases, and cases of normal nasal epithelium were examined by Western blot analysis, and the SCCA1 expression pattern in 31 IP specimens and 4 carcinoma in IP specimens were evaluated immunohistochemically. The serum levels of SCC antigen in 11 patients with sinonasal IP also were analyzed. RESULTS: SCCA1 was overexpressed in all three sinonasal IP tissues compared with sinonasal SCC tissues or normal nasal epithelium. SCCA1 cytoplasmic immunoreactivity was detected in the suprabasal epidermal keratinocytes of all 31 sinonasal IP cases. In the four carcinoma in IP specimens, SCCA1 expression in the papillomatous lesion was more intense than in the cancerous lesion. The serum SCC antigen level was high in 10 of 11 patients with IP (91%) and significantly decreased after surgical resection of the tumors. CONCLUSIONS: The results of the current study indicate that SCCA1 frequently is overexpressed and may play a biologic role in the development of sinonasal IPs. Serum SCC antigen may be a useful biologic marker in patients with sinonasal IP.