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Forward bias degradation caused by basal plane dislocations (BPDs) in the substrate is the critical issue in the Sic bipolar devices operated under high current density conditions. In this work, we proposed the calculation model of the current density in the PiN diode using the injection hole density at the buffer/substrate interface to enable the forward bias degradation prediction. We found out the critical current density which occurs stacking faults expansion from BPDs at buffer/substrate interface could be improved by shortening the carrier lifetime of the substrate or densifying the dopant concentration of the buffer layer. In the case of the conversion of BPD to threading edge dislocation (TED) located inside the Sic substrate, we estimated more than twice improvement of critical current density using the BPD-TED conversion effect of the Si-vapor etching process., International Conference on Solid State Devices and Materials (SSDM2019), September 2-5, 2019, Nagoya University, Japan

There is a need to develop practical methods to reduce nitrate–nitrogen loads from recirculating aquaculture systems to facilitate increased food protein production simultaneously with attainment of water quality goals. The most common wastewater denitrification treatment systems utilize methanol-fueled heterotrophs, but sulfur-based autotrophic denitrification may allow a shift away from potentially expensive carbon sources. The objective of this work was to assess the nitrate-reduction potential of fluidized sulfur-based biofilters for treatment of aquaculture wastewater. Three fluidized biofilters (height 3.9 m, diameter 0.31 m; operational volume 0.206 m3) were filled with sulfur particles (0.30 mm effective particle size; static bed depth approximately 0.9 m) and operated in triplicate mode (Phase I: 37–39% expansion; 3.2–3.3 min hydraulic retention time; 860–888 L/(m2 min) hydraulic loading rate) and independently to achieve a range of hydraulic retention times (Phase II: 42–13% expansion; 3.2–4.8 min hydraulic retention time). During Phase I, despite only removing 1.57 ± 0.15 and 1.82 ± 0.32 mg NO3–N/L each pass through the biofilter, removal rates were the highest reported for sulfur-based denitrification systems (0.71 ± 0.07 and 0.80 ± 0.15 g N removed/(L bioreactor-d)). Lower than expected sulfate production and alkalinity consumption indicated some of the nitrate removal was due to heterotrophic denitrification, and thus denitrification was mixotrophic. Microbial analysis indicated the presence of Thiobacillus denitrificans, a widely known autotrophic denitrifier, in addition to several heterotrophic denitrifiers. Phase II showed that longer retention times tended to result in more nitrate removal and sulfate production, but increasing the retention time through flow rate manipulation may create fluidization challenges for these sulfur particles.

The ability to consistently and cost-effectively reduce nitrate-nitrogen loads in effluent from recirculating aquaculture systems would enhance the industry's environmental stewardship and allow improved facility proximity to large markets in sensitive watersheds. Heterotrophic denitrification technologies specifically employing organic carbon found in aquaculture system waste offer a unique synergy for treatment of land-based, closed-containment production outflows. For space-efficient fluidized sand biofilters to be used as such denitrification reactors, system parameters (e.g., influent dissolved oxygen and carbon to nitrogen ratios, C:N) must be evaluated to most effectively use an endogenous carbon source. The objectives of this work were to quantify nitrate removal under a range of C:Ns and to explore the biofilter bacterial community using three replicated fluidized sand biofilters (height 3.9 m, diameter 0.31 m; fluidized sand volume plus biofilm volume of 0.206 m 3 ) operated at a hydraulic retention time of 15 min and a hydraulic loading rate of 188 L/min m 2 at The Conservation Fund Freshwater Institute in Shepherdstown, West Virginia, USA. Nitrate reduction was consistently observed during the biofilter study period (26.9 ± 0.9% removal efficiency; 402 ± 14 g NO 3 -N/(m 3 biofilter d)) although nitrite-N and total ammonium nitrogen concentrations slightly increased (11 and 13% increases, respectively). Nitrate removal efficiency was correlated with carbonaceous oxygen demand to nitrate ratios ( R 2 > 0.70). Nitrate removal rates during the study period were moderately negatively correlated with influent dissolved oxygen concentration indicating it may be possible the biofilter hydraulic retention time was too short to provide optimized nitrate removal. It is reasonable to assume that the efficiency of nitrate removal across the fluidized sand biofilters could be substantially increased, as long as organic carbon was not limiting, by increasing biofilter bed depths (to 6–10 m), and thus hydraulic retention time. These findings provide a low-cost yet effective technology to remove nitrate-nitrogen from effluent waters of land-based closed-containment aquaculture systems.

A continuous water disinfection process can be used to prevent the introduction and accumulation of obligate and opportunistic fish pathogens in recirculating aquaculture systems (RAS), especially during a disease outbreak when the causative agent would otherwise proliferate within the system. To proactively prevent the accumulation of fish pathogens, ozonation and ultraviolet (UV) irradiation processes have been used separately or in combination to treat water in RAS before it returns to the fish culture tanks. The objective of the present study was to determine the process requirements necessary to disinfect the full RAS flow, using ozonation followed by UV irradiation, just before the flow was returned to the fish culture tank(s). We found that a proportional-integral (PI) feed-back control loop was able to automatically adjust the concentration of ozone (O3) generated in the oxygen feed gas (and thus added in the low head oxygenator) in order to maintain the dissolved O3 residual or ORP at a pre-selected set-point. We determined that it was easier and effective to continuously monitor and automatically control O3 dose using an oxidative reduction potential (ORP) probe (in comparison to a dissolved ozone probe) that was located at the outlet of the O3 contact chamber and immediately before water entered the UV irradiation unit. PI control at an ORP set-point of 450 and 525 mv and a dissolved O3 set-point of 20 ppb provided almost complete full-flow inactivation of heterotrophic bacteria plate counts (i.e., producing

The high solubility of carbon dioxide precludes significant desorption within commercial oxygen absorption equipment. This operating characteristic of the equipment limits its application in recirculating water culture systems despite its ability to significantly increase allowable fish loading rates (kg/(L min)). Carbon dioxide (DC) is typically removed by air stripping. This process requires a significant energy input for forced air movement, air heating in cold climates and water pumping. We developed a modification for a spray tower that provides for carbon dioxide desorption as well as oxygen absorption. Elimination of the air-stripping step reduces pumping costs while allowing dissolved nitrogen to drop below saturation concentrations. This latter response provides for an improvement in oxygen absorption efficiency within the spray tower. DC desorption is achieved by directing head-space gases from the spray tower (O 2 , N 2 , CO 2 ) through a sealed packed tower scrubber receiving a 2 N NaOH solution. Carbon dioxide is selectively removed from the gas stream, by chemical reaction, forming the product Na 2 CO 3 . Scrubber off-gas, lean with regard to carbon dioxide but still rich with oxygen, is redirected through the spray tower for further stripping of DC and absorption of oxygen. Make-up NaOH is metered into the scrubbing solution sump on an as needed basis as directed by a feedback control loop programmed to maintain a scrubbing solution pH of 11.4–11.8. The spent NaOH solution is collected, then regenerated for reuse, in a batch process that requires relatively inexpensive hydrated lime (Ca(OH) 2 ). A by-product of the regeneration step is an alkaline filter cake, which may have use in bio-solids stabilization. Given the enhanced gas transfer rates possible with chemical reaction, the required NaOH solution flow rate through the scrubber represents a fraction of the spray tower water flow rate. Further, isolation of the water being treated from the atmosphere (1), allows for an improvement in oxygen absorption efficiency by maintaining DN well below local saturation concentrations (2), minimizes building energy requirements related to heating and ventilation and (3), reduces the potential for pathogen transmittance. We report on the performance of a test scrubber evaluated over a range of NaOH solution temperatures, pH, packing irrigation rates, and gas stream compositions. We also describe our experience with the process in a pilot scale recirculating water (trout) production system.

A model partial-reuse system is described that provides an alternative to salmonid production in serial-reuse raceway systems and has potential application in other fish-culture situations. The partial-reuse system contained three 10m3 circular ‘Cornell-type’ dual-drain culture tanks. The side-wall discharge from the culture tanks was treated across a microscreen drum filter, then the water was pumped to the head of the system where dissolved carbon dioxide (CO2) stripping and pure oxygen (O2) supplementation took place before the water returned to the culture tanks. Dilution with make-up water controlled accumulations of total ammonia nitrogen (TAN). An automatic pH control system that modulated the stripping column fan ‘on’ and ‘off’ was used to limit the fractions of CO2 and unionized ammonia nitrogen (NH3N). The partial-reuse system was evaluated during the culture of eight separate cohorts of advanced fingerlings, i.e., Arctic char, rainbow trout, and an all female brook trout × Arctic char hybrid. The fish performed well, even under intensive conditions, which were indicated by dissolved O2 consumption across the culture tank that went as high as 13mg/L and fish-culture densities that were often between 100 and 148kg/m3. Over all cohorts, feed conversion rates ranged from 1.0 to 1.3, specific growth rates (SGR) ranged from 1.32 to 2.45% body weight per day, and thermal growth coefficients ranged from 0.00132 to 0.00218. The partial-reuse system maintained safe water quality in all cases except for the first cohort—when the stripping column fan failed. The ‘Cornell-type’ dual-drain tank was found to rapidly (within only 1–2min) and gently concentrate and flush approximately 68–88% (79% overall average) of the TSS produced daily within only 12–18% of the tank’s total water flow. Mean TSS concentrations discharged through the three culture tanks’ bottom-center drains (average of 17.1mg/L) was 8.7 times greater than the TSS concentration discharged through the three culture tanks’ side-wall drains (average of 2.2mg/L). Overall, approximately 82% of the TSS produced in the partial-reuse system was captured in an off-line settling tank, which is better TSS removal than others have estimated for serial-reuse systems (approximately 25–50%). For the two cohorts of rainbow trout, the partial-reuse system sustained a production level of 35–45kg per year of fish for every 1L/min of make-up water, which is approximately six to seven times greater than the typical 6kg per year of trout produced for every 1L/min of water in Idaho serial-reuse raceway systems.

Biofilm structure was quantitatively analyzed to detect differences in biofilm structure due to sand size (effective diameter D10 of 0.23 and 0.60 mm) and location within a fluidized-sand filter vessel. Laser scanning confocal microscopy and 3D image analysis were used to quantify biofilm volume per unit sand area, biofilm surface area per unit sand area, and biofilm surface area per biofilm volume. Biofilms from reactor vessels using 0.60 mm sand size had thin, smoother biofilms which was attributed to higher shear environments, in contrast to the thick, rough, porous films that were measured on the 0.23 mm sand samples. The thicknesses of the biofilms in the small sand reactors were affected by their location within the reactor vessel, i.e. films from the base of the reactor in the more highly turbulent zone had thinner biofilms than films on sands that were taken from a higher less turbulent location in the reactor vessel. A major finding of this study was that biofilm surface area per biofilm volume remained fairly constant regardless of sand size and sampling location.

This study examined the adhesive interaction of peripheral blood monocytes with VCAM-1 and analyzed the effect of P-selectin binding to monocytes on the adhesive interaction with VCAM-1 under flow conditions. P-selectin glycoprotein ligand-1 is expressed on most monocytes. Furthermore, most monocytes bind soluble P-selectin derived from platelets. P-selectin binding to monocytes did not alter the amount of expression of α4 integrin on monocytes. However, the mean channel fluorescence value for binding Cy2-conjugated soluble VCAM-1 to P-selectin-bound monocytes was slightly more than that for binding Cy2-conjugated soluble VCAM-1 to untreated monocytes. Under flow conditions, the number of P-selectin-bound monocytes bound to VCAM-1 was much higher than that of untreated monocytes bound to VCAM-1. These bindings were abolished by pretreatment of untreated monocytes and P-selectin-bound monocytes with anti-VCAM-1 mAb or anti-α4 integrin mAb. Furthermore, P-selectin binding to monocytes increased shear resistance and thus increased the adhesive strength of monocytes to VCAM-1. These findings indicate that P-selectin binding to monocytes enhances the adhesive interaction of monocytes with VCAM-1. It is suggested that P-selectin glycoprotein ligand-1/P-selectin interaction and α4 integrin/VCAM-1 interaction can act sequentially in the adhesion cascade that regulates monocyte trafficking to inflammatory and atherosclerotic lesion.

This study examined the adhesive interactions of peripheral blood NK cells with P- and E-selectin and analyzed the effect of IL-12 on the binding of NK cells to these selectins. P-selectin glycoprotein ligand-1 (PSGL-1) is expressed on most resting and IL-12-activated NK cells. However, the percentage of resting NK cells bound to P-selectin-IgG was 15%, and that of activated NK cells bound to P-selectin-IgG was 65%. Furthermore, the number of IL-12-activated NK cells bound to P-selectin-transfected Chinese hamster ovary cells was significantly higher than that of resting NK cells under flow conditions. These interactions were abolished by the incubation of these NK cells with anti-PSGL-1 (PL-1) mAb. Thus, PSGL-1/P-selectin interaction is important in the binding of resting and activated NK cells to P-selectin. NK cells express sialyl-Lewisx (sLex) structure recognized by anti-sLex mAb (KM-93), and IL-12 activation of NK cells increased the mean fluorescence intensity of KM-93-reactive NK cells. Adhesion of IL-12-activated NK cells to E-selectin-transfected Chinese hamster ovary cells was stronger than that of resting NK cells under flow conditions. These interactions were reduced markedly by incubation with anti-sLex mAb. Thus, sLex is the major ligand of resting and activated NK cells for E-selectin. These findings indicate that IL-12 stimulation of NK cells promotes their adhesion activity to endothelial selectins.

Summary The objectives of this study are to develop and evaluate a mechanistic model for gas/liquid two-phase flow in pipelines. A mechanistic model has been developed by combining currently available models and correlations. The approach of the modeling study was based on the work by Xiao et al.1 Modifications have been made on the annular flow model by implementing the currently developed film-thickness-distribution model. An experimental database has been developed for model evaluation. Seventy-five runs of steady-state air/water flow tests in horizontal and slightly inclined pipes were conducted using a large-scale experimental facility. The experimental program was set up in a wide range of experimental conditions to cover the intermittent, dispersed bubble, and annular flow patterns. An evaluation of the model was carried out for each flow pattern, namely, intermittent, dispersed bubble, and annular flow. The comparisons between the measured and calculated pressure drops show good agreement for each flow pattern. Also, overall evaluation revealed that the proposed model provided the best performance among the commonly used empirical correlations, such as Beggs and Brill,2 Mukherjee and Brill,3 and Dukler et al.4

This study examined the adhesive interactions of peripheral blood B cells with TNF-alpha-activated endothelial monolayers, and analyzed the roles of E-selectin, P-selectin, or VCAM-1 molecules expressed on activated HUVEC. B cell interaction occurred on activated HUVEC, but not on resting HUVEC under flow conditions. The majority of peripheral blood B cells expressed P-selectin glycoprotein ligand-1 and alpha4 integrin. However, the expression of cutaneous lymphocyte Ag on B cells was low. Under flow conditions, B cells could bind to P-selectin-coated tubes and VCAM-1-transfected Chinese hamster ovary cells. In contrast, B cells could not bind to E-selectin-coated tubes. Adhesion activity of B cells to P-selectin-coated tubes was weaker than that of T cells. Furthermore, adhesion activity of B cells to VCAM-1-transfected Chinese hamster ovary cells was similar to that of T cells. Treatment of activated HUVEC with anti-VCAM-1 mAb reduced interaction of B cells under flow conditions. However, the treatment of activated HUVEC with anti-P-selectin mAb did not reduce interaction. These data indicated that the interaction of VCAM-1 with alpha4 integrin plays a major role in an initial attachment of B cells to endothelial monolayers under flow conditions.

As part of an EPAs National Onsite Demonstration Project for Small Communities (NODP) -Phase V, The Conservation Funds Freshwater Institute (Shepherdstown, WV) added real-timemonitoring technologies to existing recirculating sand and peat filter treatment systems. The objectives for this monitoring project were to: display real-time wastewater data on the Internet for use as an educational tool; improve the understanding of innovative and alternative systems; evaluate the feasibility of using telemonitoring in management districts with many smallindependent treatment systems; investigate probe maintenance requirements; demonstrate how alternative measurement parameters correlate to conventional indicatorsfor monitoring system performance. The following water quality parameters were measured every half hour: pH, oxidative reductivepotential (ORP), and temperature of the influent to the filters; ORP in the denitrification tank;and pH, dissolved oxygen (DO), and temperature in the effluent pump sumps. In addition, flowmeters monitored flow rates throughout the two systems and pressure sensors recordedbackpressure on the two low pressure pump (LPP) dosing fields. Finally a small weather stationmonitored ambient air temperature, humidity, solar radiation and rainfall. Data was transmittedto a central data logger, recorded, and displayed on a computer screen and a subset of the datawas transmitted for display on the Internet. This paper discusses the challenges encountered and lessons learned while operating this system.System design and installation, operation and maintenance and, data analysis are discussed.

We analyzed an initial step of T cell adhesion to endothelial cells under flow conditions. An initial step in T cell-endothelial cell interactions was characterized either by a rolling phase, or by an immediate arrest without rolling. Anti-E- and P-selectin Abs inhibited T cell rolling on endothelial cells under flow conditions. The rolling velocity of T cells on endothelial cells increased after treatment of endothelial cells with anti-E- or P-selectin Abs. Also, rolling of T cells was observed on E-selectin-transfected CHO cells but not on ICAM-1-transfected CHO cells. Thus, rolling of T cells under flow condition was dependent on E-selectin as well as P-selectin expressed on endothelial cells. In contrast, neither anti-E- nor P-selectin Abs inhibited the immediate arrest of T cells on endothelial cells significantly and anti-ICAM-1 Abs also failed to inhibit the immediate arrest of T cells. Therefore, other adhesion molecules may play an important role in the immediate arrest of T cells under flow conditions. The number of CD45RA- T cells rolling on E-selectin-transfected CHO cells was much higher than that of CD45RA+ T cells.

The DNA ploidy of fresh frozen tissues from head and neck squamous cell carcinomas was determined by flow cytometry, with the aim of investigating whether DNA ploidy correlates with various clinical and pathological parameters. The subjects were 51 patients who had undergone radical surgery in our department. The DNA ploidy pattern was classified into three types, diploid, single aneuploid and multiploid, according to the DNA index and the DNA histogram. This is our original classification. No particular correlation could be detected between the DNA ploidy pattern and sex, age, primary tumor site or disease stage. The degree of tissue differentiation tended to be poorer in aneuploid than in diploid tissues. The efficacy of chemotherapy was higher in aneuploid than in diploid cases. The recurrence rate was significantly lower in diploid than in multiploid cases. When disease stage, degree of histological differentiation, the efficacy of chemotherapy and the DNA ploidy pattern were subjected to multivariate analysis for correlation with prognosis, the DNA ploidy pattern showed the highest correlation. Our results suggest that the DNA ploidy, as analyzed by flow cytometry, can serve as useful prognostic factor.

The distribution and abundance of the calcium binding protein, calbindin D-28k (CB) immunoreactivity in the taste buds of the circumvallate papillae and larynx were compared between normoxic and chronically hypoxic rats (10% O2 for 8 weeks). In the normoxic rats, CB immunoreactivity was observed in some cells and fibers of the intragemmal region of the taste buds in the circumvallate papillae. In contrast, in the subgemmal region of the laryngeal taste buds, fibers but not cells were immunoreactive for CB. In chronically hypoxic rats, CB immunoreactive cells and fibers in the taste buds were decreased in the circumvallate papillae. In the laryngeal taste buds, the density of the subgemmal CB immunoreactive fibers in chronically hypoxic rats was greater than in normoxic rats. It is considered that function of the laryngeal taste buds is different from that of the lingual taste buds, so that laryngeal taste buds may be involved in chemosensation other than taste. The altered density of CB immunoreactive cells and fibers in the lingual and laryngeal taste buds is a predominant feature of hypoxic adaptation, and chronic hypoxic exposure might change the chemical sensitivity of the circumvallate papillae and larynx through the regulation of intracellular Ca2+.

Recently, the Japanese government designated 246 university departments as 21th Century Centers of Excellence (COE's) covering almost all fields of science and technology. Two COE's have been selected for the area relevant to this special session. One is formed by the Brain Science Center and other departments of Tamagawa University, and is led by M. Tsukada with the project title being "Integrative Human Science Program". The other COE is the Department of Brain Science and Systems Engineering of Kyutech, being led by T. Yamakawa. Its project title is "World of Brain Computing Interwoven out of Animals and Robots". Both COE's are engaged in biology experiments as well as engineering and computational studies.

In a preliminary study conducted at The Conservation Fund Freshwater Institute (Shepherdstown, WV, USA), dissolved chitosan was added to a recirculating system to determine if the chitosan would coagulate particulate matter and consequently increase solids removal. The recirculating water became visibly clearer and the culture tank total suspended solids (TSS) concentration dropped from 10.7 to 2.9 mg/L within 2 hours after dosing had been initiated. However, fish showed symptoms of distress and the chitosan treatment was discontinued. In subsequent studies conducted to determine the particle capture mechanism associated with chitosan addition, effluent treated with dissolved chitosan was not returned to the system. The results of two jar test studies indicated that dissolved chitosan did not enhance particle capture by settling or by microscreen filtration when mixed with a fish culture system effluent containing * 10 mg/L of TSS. However, these jar tests indicated that an additional 44% of TSS could be removed from the water that had already passed through a microscreen filter if this water was treated by a mixing and settling step, even without addition of dissolved chitosan. Additional studies using small-scale fluidized-sand biofilters indicated that the reduction in TSS observed in our initial experiment was due to TSS capture in the fluidized sand biofilter. TSS concentrations were reduced from 5.1-7.4 mg/L at the biofilter inlet to 1.7-2.2 Ihg/L at the biofilter outlet. Thus, adding dissolved chitosan to water flowing into a fluidized-sand biofilter turned the biofilter into a novel type of upflow 'sludge blanket clarifier,' which appears to be both non-plugging and relatively simple to operate. In addition, dissolved chitosan did not change nitrification occurring within the fluidized-sand biofilter. Therefore, adding a coagulant (such as dissolved chitosan or a non-toxic polymer) to the flow entering a fluidized sand biofilter has the potential to create a unit process that reduces TSS while simultaneously treating dissolved wastes.

Cases with head and neck squamous cell carcinoma (HNSCC) have clinically advanced tumors. The curative treatments for advanced HNSCC are radiotherapy and/or surgical resection. However, standard treatment alone is less successful for advanced HNSCC. Accordingly, two modalities using chemotherapy are applied as preoperative treatment for HNSCC. First, multi-drug chemotherapy has been administered as neoadjuvant chemotherapy (NAC). As a result during the past 20 years, NAC without a high complete response (CR) rate has never improved the long-term outcome of advanced cases. Therefore, the development of intensive chemotherapy regimen with a high CR rate including taxanes is ongoing. On the other hand, organ preservation modality has been under investigation using combined radiotherapy with NAC regimen with a dose reduction of administered chemotherapeutic drugs or a new chemotherapy regimen including taxanes (concomitant or concurrent chemoradiotherapy). In this strategy, impact chemotherapy with almost the same anti-tumor effect as NAC and with a potential of radiation sensitizer is necessary.

A late phase II clinical study of S-1, a novel oral antitumor agent of fluorinated pyrimidines, in patients with advanced/recurrent head and neck cancer was conducted in 25 institutions across Japan as a multi-institutional cooperative study from August 1995 to March 1998. Out of 59 eligible patients, the objective responses were 4 complete responses (CR) and 13 partial responses (PR). The response rate was 28.8% (17/59, 95% CI: 17.8-42.1%). The response rate in previously treated patients was 28.3% (15/53), whereas that in treatment naive patients was 33.3% (2/6). The response rate in patients with prior chemotherapy was 26.7% (12/45). Major adverse reactions of grade 2 or more were anemia (25.4%, 15/59), leucopenia (22.0%, 13/59), neutropenia (25.4%, 15/59), thrombocytopenia (3.4%, 2/59), anorexia (6.8%, 4/59), nausea/vomiting (1.7%, 1/59), stomatitis (1.7%, 1/59), skin symptoms including eruptions or desquamation (5.1%, 3/59), and malaise (1.7%, 1/59). Grade 4 anemia was observed in one case; however, this returned to the normal level after the termination of drug administration and the blood transfusion. Therefore, this event was confirmed to be reversible. Based on these results, we conclude that S-1 is an active agent for the treatment of advanced/recurrent head and neck cancer.

Nedaplatin (254-S), which is a cisplatin (CDDP) analog, is an effective agent for head and neck squamous cell carcinoma (HNSCC). 254-S is expected to play an important role in neo-adjuvant chemotherapy (NAC) for HNSCC in place of CDDP. We have been using combination chemotherapy including CDDP, 5-FU, MTX and LV. The response rate and CR rate of this 4-drug combined chemotherapy are 87% and 33%. Thirty-six patients with HNSCC were treated with 5-FU, 800 mg/m2/day for 5 days and 254-S, 100 mg/m2 on day 4. Chemotherapy was discontinued in one patient because of allergic shock. Three patients showed a CR and 10 patients showed a PR. The response rate and CR rate of 254-S plus 5-FU chemotherapy were 37.1% and 8.6%. These were inferior to those with the 4-drug combined chemotherapy. Fourteen percent of patients showed grade 3 leukocytopenia, and 17% showed more than grade 3 thrombocytopenia. The effect of combination chemotherapy of 254-S and 5-FU was inferior to that of the previous chemotherapy including CDDP, 5-FU, MTX and LV. Further study or another combination therapy including 254-S will be essential for improving efficacy against HNSCC.

We describe in this paper a therapeutic modality which is based on a self-rescuing concept (SRC) featuring dual activity, i.e., effect-enhancing activity and adverse reaction-reducing activity. We present the theory and practice of S-1, a novel oral fluoropyrimidine anticancer agent designed to enhance anticancer activity and reduce gastrointestinal toxicity through the deliberate combination of the following components: an oral fluoropyrimidine agent, tegafur (FT); a DPD inhibitor (CDHP: 5-chloro-2, 4-dihydroxypyridine) which is about 200-fold more potent than uracil used in UFT; and an ORTC inhibitor (Oxo: potassium oxonate) which is localized in the gastrointestinal tract. We devised a novel oral anticancer agent, S-1, as a combination drug with a molar ratio of 1:0.4:1 for FT, CDHP, and Oxo, respectively. To compare S-1, FT, and UFT in terms of their anticancer activity and adverse reactions, a colon cancer implantation model in rats was used for 4-week consecutive oral administration from the time when the postimplantation tumor weight become about 2 g. The tumor disappeared on day 16 at a given dose of S-1 (as 22.5 mg/kg FT), and the tumor did not reappear for at least three months. Antitumor activity was more marked with S-1 than FT and UFT. Adverse reaction, i.e., stomatitis, depilation, and weight loss, were less frequent in the S-1 group than in the other groups. A clinical pharmacology study examined blood concentrations of 5-FU after twice-a-day administration after meals of S-1 at a dose of 40 mg/m2. Blood concentrations of 5-FU were 60 to 200 ng/ml in all twelve patients examined. Late phase II clinical trials of S-1 were conducted in patients with advanced and recurrent stomach cancers, in the same regimen as for the clinical pharmacology study. It basically consisted in four cycles, each of which comprised 4-week, twice-a-day, consecutive oral administration with a 2-week withdrawal. The overall response rate was 44.6% (45/101). Median survival time (MST) was 224 days. S-1 was given manufacturing approval by the Ministry of Health and Welfare of Japan after a priority review, with indications for advanced and recurrent stomach cancers. A late phase II clinical study of S-1 in patients with advanced/recurrent head and neck cancer was conducted in 59 eligible patients. Objective responses were 4 complete response (CR) and 13 partial response (PR), for a response rate of 28.8% (17/59). MST was 344 days. Grade 4 hemoglobin decrease was observed in one case; however, this returned to normal after the termination of drug administration and blood transfusion. Therefore, this event was confirmed to be reversible. A late phase II clinical trial of S-1 was conducted to evaluate the efficacy and toxicities in patients with metastatic colorectal carcinoma. Sixty-three patients with measurable metastatic colorectal carcinoma were enrolled in this clinical trial. The overall response rate was 35.5% (22/62), and the MST was 378 days. The main adverse reactions were myelosuppression and GI toxicities. The incidence of neutropenia (Grade 3 or 4) was 13%, while the incidence of other adverse reactions was 10% or below. None of 53 outpatients required to be hospitalization due to adverse reactions. Late phase II clinical trials of S-1 are in progress for colorectal cancer, breast cancer and non-small cell lung cancer. To establish the standard therapeutic modality for cancers, including gastrointestinal cancers, in Japan, the conduction of clinical trials combining S-1 and other anticancer drugs holds promise for the future.

In most new cases of head and neck squamous cell carcinoma, especially in the pharynx and oral cavity, the tumors are advanced. Multidisciplinary treatments including chemotherapy in addition to definitive treatments, e.g., surgery and/or radiotherapy, have been applied. However, these treatments have not improved the poor prognosis for advanced head and neck carcinomas. A new curative treatment modality including chemotherapy and having a high complete response rate, e.g., a regimen consisting of taxanes, CDDP and 5-FU, is desirable. In addition, new therapeutic drugs against malignant solid tumors have been developed. The literature on thymidylate synthase inhibitor, dihydropyrimidine dehydrogenase inactivator, p-glycoprotein inhibitor, anti-epidermal growth factor receptor antibody, antiangiogenic drugs, COX-2 inhibitor and retinoids that may be applied in cases of head and neck carcinoma in the future, are reviewed.

Inostamycin is an inhibitor of cytidine 5'-diphosphate 1,2-diacyl-sn-glycerol (CDP-DG): inositol transferase. It significantly reduced epidermal growth factor (EGF)-induced in vitro invasion of the tongue carcinoma cell line, HSC-4, through reconstituted basement membrane Matrigel. Since phosphatidylinositol (PI) 4,5-biphosphate is important for signal transduction through protein kinase C and actin reorganisation, we further examined the effect of inostamycin on production of two matrix metalloproteinases (MMPs), MMP-2 and -9, and on cell motility. Zymographic analysis showed that inostamycin suppressed pro-MMP-2 and pro-MMP-9 levels at a dose-dependent fashion, while MMP-2 activity was not significantly affected. By reverse transcription-polymerase chain reaction, it was found that inostamycin diminished steady state levels of MMP-2 and -9 but not membrane type 1-MMP mRNA expressions. Inostamycin partially blocked both EGF- and phorbol 12-myristate 13-acetate-stimulated pro-MMP-9 production. A cytoplasmic calcium chelator (BAPTA-AM) dramatically elevated pro- MMP-9 and slightly elevated pro-MMP-2 secretions. EGF-stimulated motility of HSC-4 cells was suppressed by inostamycin treatment along with reduction of actin cytoskeletal reorganisation, filopodia formation and cdc42 expression. These results suggested that inostamycin would be useful for an anti-invasive agent in tongue cancer.

Laminin-5 (LN-5), an important basement membrane (BM) protein consisting of laminin alpha3, beta3 and gamma 2 chains, has been suggested to be involved in tumor cell invasion and tissue repair. In this study, the distribution of the LN-5 subunits in atypical adenomatous hyperplasia (AAH) and different types of adenocarcinomas of the lung was examined by immunohistochemical analysis. In AAH and non-sclerosing, well-differentiated adenocarcinomas, the LN gamma 2 chain was frequently detected along with the continuous BMs. These BMs were also positive for both LN alpha3 and beta3 chains, suggesting that LN-5 had been deposited. In contrast, the cytoplasmic staining for the LN gamma 2 chain was frequently observed in tumor cells of sclerosing, well-differentiated adenocarcinomas, as well as of moderately and poorly differentiated adenocarcinomas, without any evidence of co-expression of the LN alpha3 and beta3 chains. This staining pattern of the LN gamma 2 chain was prominent in carcinoma cells invading into interstitial stroma and was associated with the formation of a central scar in the tumor tissues. These results suggest that the LN gamma 2 chain monomer could be an important indicator of progression of lung adenocarcinoma.

A randomized crossover study between azasetron alone and azasetron combined with dexamethasone was performed to investigate the prevention of nausea and vomiting due to chemotherapy including cisplatin in patients with advanced head and neck carcinoma. The results indicated that the combination therapy with dexamethasone was more effective than azasetron alone in preventing nausea on days 1 through 5 after the administration of cisplatin and was significantly superior to azasetron alone on days 2 and 3. In addition, complete response (no vomiting) and the antiemetic and antinausea efficacy of combination therapy with dexamethasone on day 2 was significantly superior compared to azasetron alone. No adverse effect from either antiemetic therapy was observed in this study.

Standard treatment for squamous cell carcinomas in the head and neck consists of surgery and/or radiotherapy. However, this standard treatment alone has not improved the poor prognosis of advanced head and neck carcinomas. A new curative treatment modality for advanced head and neck carcinomas including chemotherapy with an impact is needed. The clinical results of chemotherapy over the past twenty years have shown chemotherapy including cisplatin (CDDP) and 5-fluorouracil (5-FU) to be the most efficacious for advanced cases. In this paper, the problems with this chemotherapy are discussed in terms of predictive factors of the response to this treatment, and the recent clinical results with chemotherapy including CDDP, 5-FU, and other drugs are reviewed. Furthermore, new chemotherapeutic regimens and the clinical results including commonly applied taxanes, e.g., paclitaxel and docetaxel, are reviewed.

The Bcl-2 family of genes includes some important regulators of apoptosis. Among these genes, Bcl-2 and Bax control cell death, thus contributing to both tumor growth and drug sensitivity. We determined the levels of protein and RNA expression of Bcl-2 family in 21 head and neck cancer cell lines. Then using four cell lines, which were KB (Bcl-2+/Bax+), KCC-L871 (Bcl-2+/Bax-), YCU-T891 (Bcl-2-/Bax+) and TC901 (Bcl-2-/Bax-), we investigated the impact of Bcl-2/Bax status on sensitivity to the following chemotherapeutic agents; paclitaxel, cisplatin, vincristine and 5-fluorouracil. Immunohistochemistry and RT-PCR showed that 71% of the cell lines were Bcl-2 positive, 62% were Bax positive, 38% were Bcl-XL positive and 62% were Bcl-XS positive. After treatment with all the chemotherapeutic agents, Bax expression changed from negative to positive in TC901 cells. In KB cells, Bcl-2 expression decreased only after treatment with paclitaxel. YCU-T891 cells were sensitive to all of the drugs. In conclusion, Bcl-2/Bax status was correlated with drug sensitivity and treatment with chemotherapeutic agents induced apoptosis in these cancer cells.

The distribution and abundance of substance P (SP) and calcitonin gene-related peptide (CGRP) immunoreactive nerve fibers in four different regions of the laryngeal mucosa were compared between normoxic and chronically hypoxic rats (10% O2 and 3.0-4.0% CO2 for 3 months). In the chronically hypoxic laryngeal mucosa, the number of SP and CGRP fibers within and just beneath the epithelium, and around the laryngeal gland was increased in comparison with those in the normoxic controls. Especially in the epiglottic and arytenoid regions, the number of intraepithelial SP fibers was increased remarkably. Most intraepithelial SP and CGRP fibers penetrated into the epithelium to extend to the luminal surface. There was no distinct difference in the distribution and abundance of these peptidergic fibers in the mucosa of the normoxic and chronically hypoxic vocal cord regions. These results suggest that the increased density of SP and CGRP fibers within the epithelium of the upper laryngeal mucosa is a predominant feature of hypoxic adaptation, and this may be involved in airway protection, swallowing, and other functions in the chronically hypoxic environment. In addition, the increased SP and CGRP fibers around the laryngeal gland suggest an enhanced mucous secretion, and this may participate in the airway defense mechanism in low O2 conditions.

Histopathologically, about 90% of head and neck carcinomas are squamous cell carcinomas. In this paper, the changes and the recent developments in treatment modalities for squamous cell carcinomas in the head and neck are reviewed. The curative treatments for head and neck carcinomas are radiation and/or surgical resection. The development of diagnostic techniques and the introduction of these curative treatments have contributed to an improvement in the long-term outcome. In terms of surgical procedures, reconstructive surgeries such as free cutaneous and/or muscle flap procedures have been developed and led to extended radical resection, while with curative radiotherapy, the increase in total dose and improvements in radiation field have been made possible. However, there has been a limit regarding significant improvements in prognosis with these curative therapies alone, excluding laryngeal cancer, because of the difficulty of early detection. Since the 1980 s, multi-drug chemotherapy including cisplatin (CDDP) has been administered in advanced cases. First, this chemotherapy was applied as neo-adjuvant chemotherapy (NAC) for previously untreated cases followed by curative surgery or radiotherapy. As a result, chemotherapy including CDDP and 5-fluorouracil has been shown to be the most efficacious with a high complete response (CR) rate. Furthermore, cases with CR have shown better outcomes than those without CR. Curative treatment modalities including impact chemotherapy have been invented and trials have begun with the aim of organ preservation. These include NAC followed by curative radiotherapy, curative radiotherapy with chemotherapy with almost the same anti-tumor effect as NAC and potential a radiation sensitizer (concomitant chemoradiotherapy), and NAC followed by concomitant chemoradiotherapy. These treatment modalities, including impact chemotherapy, are recommendable for the preservation of functions, e. g., swallowing and/or articulation, without worsening the prognosis. Furthermore, maintenance chemotherapy subsequent to curative treatment is advisable for advanced head and neck carcinomas. Besides the future development of the above-mentioned treatment modalities, new treatment modalities taking QOL into consideration for the elder are necessary, and improvements in poor prognoses of cases with complications and those with double cancer which are common in patients with head and neck squamous cell carcinomas is indispensable.

A late phase II clinical study of RP56976 (docetaxel), a new anticancer agent for advanced/recurrent head and neck cancer, was conducted in 29 institutions all over Japan as a multi-institutional cooperative study. Docetaxel was administered by 1 to 2-hour intravenous infusion at a dose of 60 mg/m2 every 3 to 4 weeks. Of 63 patients eligible in this study, 59 were judged as complete cases. Complete response (CR) was observed in 1 patient, partial response (PR) in 13, no change (NC) in 25, and progressive disease (PD) in 20, for an overall response rate of 22.2% (14/63, 95% CI: 12.7-34.5%) in eligible cases, and 23.7% (14/59, 95% CI: 13.6-36.6%) in complete cases. Previously treated patients showed a 17.9% (10/56) response rate, whereas treatment--naive patients showed a 57.1% (4/7) response rate. Among 46 patients who received prior chemotherapy, one CR and 7 PR were observed with a 17.4% response rate. Major hematological toxicities were leucopenia in 95.1% (or = grade 3, 59.7%) and neutropenia in 90.3% (or = grade 3, 79.0%). Other severe toxicities (or = grade 3) included anorexia in 9.7% (6 cases), diarrhea in 3.2% (2 cases), dyspnea in 3.2% (2 cases), and fatigue in 3.2% (2 cases). One patient had a grade 3 interstitial pneumonia; however, symptoms were resolved by the administration of corticosteroids. During this study, one patient died due to multiple organ failure (MOF) caused by disseminated intravascular coagulation (DIC), and this case was reported as a therapy-related death. Based on these results, docetaxel is an active agent for treatment of head and neck cancer.

The recent strategies for advanced head and neck squamous cell carcinoma (HNSCC) were reviewed and compared between Japan and western countries. The curative treatments for advanced HNSCC are radiotherapy and/or surgical resection. These standard treatment modalities are the same in both areas. However, combined treatment, especially including impact chemotherapy, was developed in western countries earlier than in Japan. The organ preservation modality to preserve the organ and physiological function has been under investigation in controlled randomized trials in western countries. Patients with advanced HNSCC, for example, achieving a complete response at the primary lesion after neo-adjuvant chemotherapy followed by curative radiotherapy or concomitant chemoradiotherapy including impact chemotherapy, receive organ-sparing treatment. This strategy for advanced HNSCC in Japan promises to be widespread in future.

Hypopharyngeal carcinoma (HPC) has a poor prognosis. We investigated the expression of cyclin D1 in 34 advanced HPCs, and the value of cyclin D1 expression was evaluated as a predictive marker in terms of the prognosis of HPC, compared with other clinical factors. Using immunohistochemical staining, 20 of 34 patients showed positive immunoreactivity for cyclin D1. The statistical trend of the survival rate was lower in the cyclin D1-positive patients than in the cyclin D-negative ones (p = 0.0805). The predictive factors for the survival rate were effectiveness of neo-adjuvant chemotherapy (F = 8.698) (p = 0.0066), cyclin D1 expression (F = 6.244) (p = 0.0191) and N classification (F = 5.037) (p = 0.0335). The cyclin D1-positive patients had approximately four-fold higher mortality than the cyclin D1-negative ones. These data indicate that the expression of cyclin D1, in advanced patients with hypopharyngeal carcinoma is a useful marker for prognosis.

Histopathologically, about 90% of head and neck cancer is squamous cell carcinoma. The curative treatments for head and neck cancer are conventional radiotherapy and/or surgical resection. Multidisciplinary treatment, including combinations of the curative therapy, chemotherapy and immunotherapy, has been applied for advanced head and neck carcinomas with poor outcomes. Nowadays, chemotherapy is under investigation in the neo-adjuvant, adjuvant and concurrent chemoradiotherapy. In this paper, the treatment approach was reviewed in terms of prognostic factors which have been retrospectively estimated, along with recent developments in treatment modalities of advanced cases.

Vagal paragangliomas are rare tumors and difficult to differentiate from carotid body tumors or schwannomas of the vagus nerve. We present a patient who could be preoperatively diagnosed as having a vagal paraganglioma by ultrasonography and color Doppler sonography.

In developing new anticancer agents, the most important thing is the balancing of antitumor activity and toxicity. To achieve high activity and low toxicity, S-1 was designed, in which tegafur, prodrug of 5-FU, was combined with two classes of modulators. CDHP, inhibitor of 5-FU degradation in liver and Oxo, inhibitor of 5-FU phosphoribosylation in digestive tract, respectively. This cooperative study with 15 nation-wide institutes was conducted to evaluate the antitumor activity and toxicity of S-1 in patients with advanced head and neck cancer from Jan. 1994 to March 1996 in Japan. Out of 26 patients, CR was achieved in 1 and PR in 11 with a response rate of 46.2%, while adverse events of grade 3 were as follows: hemoglobinemia (7.7%), leukocytopenia, neutropenia, stomatitis and anorexia (3.8%), each. Neither grade 4 adverse event nor treatment-related deaths were observed. Based on these findings, it was concluded that S-1 is a useful anticancer agent with the low grade toxicities for treatment of the patients with advanced head and neck cancer, and the effects of CDHP and Oxo found in preclinical studies might be also reflected in these results.

Thirty-seven biopsy specimens from primary sites, 18 surgically removed metastatic neck nodes, and 18 surgically removed primary sites from 37 patients with hypopharyngeal carcinoma (HPC) were evaluated for the presence of Epstein-Barr Virus (EBV) infection by in situ hybridization (ISH) and polymerase chain reaction (PCR). Although some of normal lymphocytes in 6 of 18 metastatic nodes were positive by ISH, there were no positive results from HPC tumor cells themselves. Our results indicate that EBV-infected non-neoplastic cells such as lymphocytes can be a cause of false positivity, if a study were conducted with PCR alone. Because ISH for EBV-encoded early RNAs was highly sensitive, even more sensitive than PCR from paraffin-embedded samples in our study, this method should be the first choice for identification of EBV infection to avoid false positives.

We analyzed the relationship between clinical response to neo-adjuvant chemotherapy including 5-fluorouracil (5-FU) in patients with hypopharyngeal carcinoma (HPC) and thymidylate synthase (TS) expression in their tumors. TS expression was evaluated with immunohistochemical staining techniques on biopsy specimens from HPC patients. TS immunostaining was divided into four levels (TS0-TS3) according to its level and pattern. The relationship between prognosis, tumor size, nodal status, differentiation of tumor cells and TS expression were also investigated. There was a statistically significant association between the level of TS expression and tumor size (p0.01). In terms of the effectiveness of chemotherapy, tumor differentiation, nodal status and prognosis, a statistical difference was not found in TS expression. These results suggest that the level of TS expression may show the degree of tumor proliferation, but may not necessarily be useful to obtain a response to chemotherapy including other drugs, e.g., cisplatin and other derivatives of platinum.

The effects of weekly subcutaneous recombinant human erythropoietin (r-hEPO) administration on anemia during chemotherapy including cisplatin and 5-fluorouracil in patients with head and neck carcinomas were examined. Weekly subcutaneous r-hEPO administration in cancer patients has not been investigated previously. Patients were treated with r-hEPO 100 IU/kg (2 patients), 200 IU/kg (6 patients), or 400 IU/kg (5 patients), or placebo, and effectiveness was evaluated by monitoring hemoglobin concentration changes after administration for 8 weeks. Hemoglobin concentrations in all 3 r-hEPO dosage groups were higher than that in the control group during chemotherapy. All r-hEPO doses produced improvements in the anemia induced by chemotherapy; however, the 400 IU/kg dose was most effective. The requirement for blood transfusions decreased in patients receiving r-hEPO therapy, and no significant side-effects were associated with r-hEPO administration. These results suggest that chemotherapy-induced anemia can be prevented by weekly subcutaneous r-hEPO administration.

Distribution of vasoactive intestinal polypeptide (VIP)-immunoreactive nerve fibers and VIP-receptor (VIP-R)-immunoreactive sites in the human submandibular gland were examined by the peroxidase-antiperoxidase method using the specimens taken from patients that had not received radiotherapy. VIP-immunoreactive fibers were found around both serous and mucous acini, the duct system, and those around the mucous acini were more numerous than those around the serous acini. VIP-R immunoreactivity was restricted to the mucous acini and the intercalated duct segment. The serous acini, striated duct, and excretory ducts lacked VIP-R immunoreactivity. These findings suggest that the mucous acinar cells contain VIP-R, and that VIP-R-mediated VIP action is involved in regulating synthesis of viscous saliva and its release.

In head and neck carcinomas, over 50% of patients present with advanced local and regional disease. Despite curative treatments of radiotherapy and/or surgery for these advanced cases, locoregional control remains a significant problem with locoregional recurrences in up to 50-60% of cases. The prognosis of cases who relapse in the early period after their primary therapy, is poor, because of the poor response to chemotherapy and/or radiation therapy. Furthermore, metastatic recurrences in distant organs and second primaries are other medical problems. Chemotherapy is a key treatment in the management of locally recurrent patients during the early period after curative radiotherapy in primary therapy. Recently, chemotherapy including CDDP has been applied for locally recurrent patients. The response rate or chemotherapy, however, is low with a short duration time. The recent studies in terms of reirradiation for patients with locoregional recurrences were reviewed. Because of radiation therapy given in the primary therapy, reirradiation combined with chemotherapy (chemoradiation) has been used to improve the efficacy and to reduce the cumulative dose of reirradiation. Chemoradiation consisting of efficacious chemotherapy and a radiation dose of about 60 Gy is important to improve local control and survival of recurrent cases of head and neck carcinomas.

At diagnosis of head and neck cancer, over half of all patients show advanced stages. Cure rates for patients with advanced head and neck carcinomas remain low. Because of the poor outcome of unresectable patients with head and neck cancer after radiation therapy alone, concomitant chemoradiotherapy has been used for these advanced cases in order to improve locoregional and systemic tumor control. On the other hand, a recent treatment modality for resectable head and neck cancer has a new goal to preserve organ functions, i.e., speech, swallowing and appearance, which are affected by surgical resection. For both of these reasons, various concomitant administrations of chemotherapy and radiotherapy have been applied for advanced tumors. In this paper, the clinical results of the past and present reports are reviewed and summarized in terms of chemoradiotherapy using single and combination chemotherapeutic drug therapy. In conclusion, some aggressive concurrent chemoradiotherapy trials suggest an improved locoregional control rate, prolonged disease-free interval and a better overall survival rate.

We examined the postoperative swallowing function of 12 tongue and oral floor cancer patients reconstructed with a recto-abdominal myocutaneous free flap after glossectomy. On the basis of the resection site, the present cases were classified into either anterior type or lateral type. Subjective evaluation of postoperative swallowing function was obtained from self-reports from patients. The movement of the reconstructed tissue was evaluated videofluorographically during swallowing, by tracking the movement of two small pellets temporarily attached to the anterior and central portions of the reconstructed tongue. The trajectory of the two pellets and the selected point of the hyoid bone were recorded together with the distance between the plate and the tongue dorsum, and between the posterior pharyngeal wall and the tongue base. Using a personal computer, a quantitative study of the video images was performed. The results were summarized as follows. 1) The movement pattern of the reconstructed tissue was generally saccadic rather than smooth. It was suggested that the swallowing pattern of the patients was different to that of normal controls. 2) Postoperative swallowing function was poorer in cases of the anterior type when compared to the lateral type. 3) In general, cases which showed relatively wide movement range appeared to achieve subjectively satisfactory swallowing function.

The decline of immunity has been reported in head and neck carcinomas in the advanced stage. On the basis of this finding in head and neck carcinomas, additional immunotherapy in curative treatment, i.e., surgical therapy and/or radiation therapy, has been applied for patients with advanced tumors to improve their poor prognosis. Until now, only a few controlled randomized studies have evaluated the clinical efficacy of non-specific immunotherapy, i.e., Ubenimex and OK-432. Each result using these drugs showed that the survival rate in those receiving non-specific immunotherapy was higher than in the control. Cytokines, e.g., IFN-alpha, gamma, TNF-alpha, had immunologically modulating actions on the immunological conditions of patients and on the tumor cells, whereas immunotherapy using these cytokines has not shown a good clinical response, as with clinical administration of IL-2 alone. Furthermore, the clinical results of combined therapy of IL-2 and adoptive immunotherapy for head and neck carcinomas have not been satisfactory. In future, to improve the prognosis in patients with these carcinomas, it is indispensable to develop a new immunotherapy including transfer of cytokine-transfected cells having tumor-immunization ability and capable of inducing cytolytic effector cells in the peritumoral site, and specific antibody therapy against tumor cells.

Standard treatment for head and neck carcinomas consists of surgery, and/or radiotherapy. However, standard treatment alone is less successful for advanced head and neck carcinomas. With the development of cisplatin (CDDP), the efficacy of chemotherapy including CDDP has markedly increased in head and neck carcinomas. Accordingly, neo-adjuvant chemotherapy has been applied for advanced carcinomas. The purpose of neo-adjuvant chemotherapy for head and neck carcinomas is to improve the curability by means of this chemotherapy strategy followed by standard treatment, to eradicate micro-metastatic lesions, and, more recently, organ preservation without compromising overall survival. The previous studies have demonstrated that this chemotherapy is efficacious for patients with complete response (CR), especially pathological CR, after chemotherapy in terms of preserving primary organ and overall survival. Therefore, the development of intensive chemotherapy regimen showing a high CR rate is necessary. Furthermore, the control of the secondary malignancies frequently occurring in patients with head and neck cancer, and the management of complications caused by aging and/or heavy drinking, are also indispensable to improve survival in advanced head and neck cancer patients.