Biomedical subjects

S Ishikura

Publications and source records attributed to S Ishikura.

At least 19 recordsLinked to original sources

PubMed2001

Identity of dimeric dihydrodiol dehydrogenase as NADP(+)-dependent D-xylose dehydrogenase in pig liver.

Dimeric dihydrodiol dehydrogenases (DDs, EC 1.3.1.20), which oxidize trans-dihydrodiols of aromatic hydrocarbons to the corresponding catechols, have been molecularly cloned from human intestine, monkey kidney, pig liver, dog liver, and rabbit lens. A comparison of the sequences with the DNA sequences in databases suggested that dimeric DDs constitute a novel protein family with 20 gene products. In addition, it was found that dimeric DD oxidizes several pentoses and hexoses, and the specificity resembles that of NADP(+)-dependent D-xylose dehydrogenase (EC 1.1.1.179) of pig liver. The inhibition of D-xylose dehydrogenase activity in the extracts of monkey kidney, dog liver and pig liver, its co-purification with dimeric DD activity from pig liver, and kinetic analysis of the D-xylose reduction by pig dimeric DD indicated that the two enzymes are the same protein.

Alcohol Oxidoreductases↗

PubMed2001

Molecular cloning, expression and tissue distribution of hamster diacetyl reductase. Identity with L-xylulose reductase.

Using rapid amplification of cDNA ends PCR, a cDNA species for diacetyl reductase (EC 1.1.1.5) was isolated from hamster liver. The encoded protein consisted of 244 amino acids, and showed high sequence identity to mouse lung carbonyl reductase and hamster sperm P26h protein, which belong to the short-chain dehydrogenase/reductase family. The enzyme efficiently reduced L-xylulose as well as diacetyl, and slowly oxidized xylitol. The K(m) values for L-xylulose and xylitol were similar to those reported for L-xylulose reductase (EC 1.1.1.10) of guinea pig liver. The identity of diacetyl reductase with L-xylulose reductase was demonstrated by co-purification of the two enzyme activities from hamster liver and their proportional distribution in other tissues.

Acetoin Dehydrogenase↗

PubMed2001

Enzymatic characteristics and subcellular distribution of a short-chain dehydrogenase/reductase family protein, P26h, in hamster testis and epididymis.

A hamster sperm 26 kDa protein (P26h) is strikingly homologous with mouse lung carbonyl reductase (MLCR) and is highly expressed in the testis, but its physiological functions in the testis are unknown. We show that recombinant P26h resembles NADP(H)-dependent MLCR in the tetrameric structure, broad substrate specificity, inhibitor sensitivity, and activation by arachidonic acid, but differs in a preference for NAD(H) and high efficiency for the oxidoreduction between 5alpha-androstane-3alpha,17beta-diol (k(cat)/K(M) = 243 s(-1) mM(-1)) and 5alpha-dihydrotestosterone (k(cat)/K(M) = 377 s(-1) mM(-1)). The replacement of Ser38-Leu39-Ile40 in P26h with the corresponding sequence (Thr38-Arg39-Thr40) of MLCR led to a switch in favor of NADP(H) specificity, suggesting the key role of the residues in the coenzyme specificity. While the P26h mRNA was detected only in the testis of the mature hamster tissues, its enzyme activity was found mainly in the mitochondrial fraction of the testis and in the nuclear fraction of the epididymis on subcellular fractionation, in which a mitochondrial enzyme, isocitrate dehydrogenase, exhibited a similar distribution pattern. The enzyme activity of P26h in the two tissue subcellular fractions was effectively solubilized by mixing with 1% Triton X-100 and 0.2 M KCl, and enhanced more than 10-fold. The enzymes purified from the two tissue fractions exhibited almost the same structural and catalytic properties as those of the recombinant P26h. These results suggest that P26h mainly exists as a tetrameric dehydrogenase in mitochondria of testicular cells and plays a role in controlling the intracellular concentration of a potent androgen, 5alpha-dihydrotestosterone, during spermatogenesis, in which it may be incorporated in mitochondrial sheaths of spermatozoa.

Alcohol Oxidoreductases↗

PubMed2001

Combination radiotherapy for hepatocellular carcinoma with intraductal tumor thrombus: a case report.

We report the successful treatment of hepatocellular carcinoma (HCC) associated with an intraductal tumor thrombus in a 67-year-old male. Abdominal ultrasonography (US) and computed tomography (CT) revealed intrahepatic biliary dilatation in the left hepatic lobe and an intraductal tumor thrombus. The main tumor lesion was not clearly visualized on abdominal US, dynamic CT, and hepatic angiography. We biopsied the intraductal tumor thrombus under US guidance. Histologically the biopsy specimen was a poorly differentiated HCC We thus diagnosed HCC with intraductal tumor thrombus. The total serum bilirubin level gradually rose to 3.1 mg/dl. This tumor was inoperable because of severe hepatic dysfunction. We chose to treat the patient with radiotherapy aimed only at the intraductal tumor thrombus because the main tumor was unclear. A percutaneous transhepatic biliary drainage (PTBD) tube was inserted into the common bile duct beyond the tumor thrombus and the tube was dilated. Once total serum bilirubin had reached the normal range, a combination of external beam radiation therapy (EBRT) plus an intraluminal brachytherapy, 192Ir boost was administered. The intraductal tumor thrombus was found to have vanished and the PTBD tube was removed. After this treatment, transcatheter hepatic arterial embolization was performed at the point of tumor appearance. This patient had a relatively long survival, approximately 30 months, with no clinical evidence of recurrent disease and biliary drainage was not necessary.

Aged↗

PubMed2001

Characterization of a major form of human isatin reductase and the reduced metabolite.

Isatin, an endogenous indole, has been shown to inhibit monoamine oxidase, and exhibit various pharmacological actions. However, the metabolism of isatin in humans remains unknown. We have found high isatin reductase activity in the 105,000 g supernatants of human liver and kidney homogenates, and have purified and characterized a major form of the enzyme in the two tissues. The hepatic and renal enzymes showed the same properties, including an M(r) of 31 kDa, substrate specificity for carbonyl compounds and inhibitor sensitivity, which were also identical to those of recombinant human carbonyl reductase. The identity of the isatin reductase with carbonyl reductase was immunologically demonstrated with an antibody against the recombinant carbonyl reductase. About 90% of the soluble isatin reductase activity in the liver and kidney was immunoprecipitated by the antibody. The Km (10 microm) and k(cat)/K(m) (1.7 s(-1) x microm(-1)) values for isatin at pH 7.0 were comparable to those for phenanthrenequinone, the best xenobiotic substrate of carbonyl reductase. The reduced product of isatin was chemically identified with 3-hydroxy-2-oxoindole, which is also excreted in human urine. The inhibitory potency of the reduced product for monoamine oxidase A and B was significantly lower than that of isatin. The results indicate that the novel metabolic pathway of isatin in humans is mediated mainly by carbonyl reductase, which may play a critical role in controlling the biological activity of isatin.

Alcohol Oxidoreductases↗

PubMed2001

Influence of postsurgical residual tumor volume on local control in radiotherapy for maxillary sinus cancer.

BACKGROUND: The aim was to study the influence of postsurgical gross residual tumor volume on local control of maxillary sinus cancer treated with radiotherapy combined with debulking surgery. METHODS: Forty-three patients who underwent combined surgery and radiotherapy (50-72 Gy, median 60 Gy) for squamous cell carcinoma of the maxillary sinus were reviewed. Gross residual tumor volume (GRTV) after surgery was measured on computed tomograms obtained during the radiotherapy planning. Patients were classified according to GRTV as follows: group AA, GRTV = 0 (microscopic residual, n = 2); group A, GRTV < 10 cm3 (n = 24); group B, 10-40 cm3 (n = 9); and group C, > or = 40 cm3 (n = 8). The relationship between local control and GRTV was analyzed using univariate and multivariate analysis. RESULTS: The 2-year local control rate for all patients was 62%. The differences in local control rates between groups AA, A and B were not significant (P > 0.05), but the rate was significantly lower in group C than in the other groups (69% at 2 years vs 31% at 1 year, P < 0.001). Multivariate analysis showed that GRTV (P = 0.002) and histological differentiation (poorly differentiated histology was favorable, P = 0.035) were independent prognostic factors and that intra-arterial chemotherapy and administered total dose were not. Local control in groups A and B significantly depended on the total dose of radiotherapy, with 2-year control rates of patients receiving 50 Gy (n = 6) and > or = 60 Gy (n = 27) of 17% vs 79%, respectively (P < 0.001). CONCLUSIONS: Our data suggest that adequate, not complete, debulking associated with a total radiotherapy dose of > or = 60 Gy can provide satisfactory local control for patients with squamous cell carcinoma of the maxillary sinus.

Carcinoma, Squamous Cell↗

PubMed2000

Kinetic alteration of a human dihydrodiol/3alpha-hydroxysteroid dehydrogenase isoenzyme, AKR1C4, by replacement of histidine-216 with tyrosine or phenylalanine.

Human dihydrodiol dehydrogenase with 3alpha-hydroxysteroid dehydrogenase activity exists in four forms (AKR1C1-1C4) that belong to the aldo-keto reductase (AKR) family. Recent crystallographic studies on the other proteins in this family have indicated a role for a tyrosine residue (corresponding to position 216 in these isoenzymes) in stacking the nicotinamide ring of the coenzyme. This tyrosine residue is conserved in most AKR family members including AKR1C1-1C3, but is replaced with histidine in AKR1C4 and phenylalanine in some AKR members. In the present study we prepared mutant enzymes of AKR1C4 in which His-216 was replaced with tyrosine or phenylalanine. The two mutations decreased 3-fold the K(m) for NADP(+) and differently influenced the K(m) and k(cat) for substrates depending on their structures. The kinetic constants for bile acids with a 12alpha-hydroxy group were decreased 1.5-7-fold and those for the other substrates were increased 1.3-9-fold. The mutation also yielded different changes in sensitivity to competitive inhibitors such as hexoestrol analogues, 17beta-oestradiol, phenolphthalein and flufenamic acid and 3,5,3', 5'-tetraiodothyropropionic acid analogues. Furthermore, the mutation decreased the stimulatory effects of the enzyme activity by sulphobromophthalein, clofibric acid and thyroxine, which increased the K(m) for the coenzyme and substrate of the mutant enzymes more highly than those of the wild-type enzyme. These results indicate the importance of this histidine residue in creating the cavity of the substrate-binding site of AKR1C4 through the orientation of the nicotinamide ring of the coenzyme, as well as its involvement in the conformational change by binding non-essential activators.

3-Hydroxysteroid Dehydrogenases↗

PubMed2000

Roles of His-79 and Tyr-180 of D-xylose/dihydrodiol dehydrogenase in catalytic function.

Mammalian dimeric dihydrodiol dehydrogenase is identical with d-xylose dehydrogenase and belongs to a protein family with prokaryotic proteins including glucose-fructose oxidoreductase. Of the conserved residues in this family, either His-79 or Tyr-180 of d-xylose/dihydrodiol dehydrogenase has been proposed to be involved in the catalytic function. Site-directed mutagenesis was used to examine the roles of the two residues of the monkey enzyme. A mutant, Y180F, was almost inactive, but, similarly to the wild-type enzyme, exhibited high affinity for NADP(H) and fluorescence energy transfer upon binding of NADPH. The H79Q mutation had kinetically largest effects on K(d) (>7-fold increase) and K(m) (>25-fold increase) for NADP(H), and eliminated the fluorescence energy transfer. Interestingly, the dehydrogenase activity of this mutant was potently inhibited with a 190-fold increase in the K(m) for NADP(+) by high ionic strength, which activated the activity of the wild-type enzyme. These results suggest a critical role of Tyr-180 in the catalytic function of this class of enzymes, in addition to functions of His-79 in the coenzyme binding and chemical steps of the reaction.

Animals↗

PubMed2000

A case of inoperable esophageal carcinoma with hepatic and nodal metastases which showed a long-term survival after chemoradiotherapy including nedaplatin.

We report a case of metastatic esophageal carcinoma successfully treated with chemoradiotherapy. A 61-year-old man, diagnosed as suffering from advanced esophageal carcinoma with liver and lymph node metastases, was treated with a combination of nedaplatin (90 mg/m2/day, 1 h drip infusion, day 1), 5-fluorouracil (800 mg/m2/day, continuous infusion, days 1-5), and radiotherapy (2 Gy/day, days 1-5, 8-12 and 15-19). The cycle was repeated twice every 5 weeks from July 2, 1997. He achieved a complete response 1 month after finishing two courses of chemoradiotherapy followed by an additional three courses of chemotherapy without radiation. Seven months after the completion of radiotherapy, pericardial effusion with negative cytology was recognized. The effusion was treated by pericardiocentesis and drainage for several days. After drainage, the effusion could be easily managed with diuretics. This patient is still alive with no evidence of disease more than 2.5 years after the initiation of the treatment.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2000

Structure-specific effects of thyroxine analogs on human liver 3 alpha-hydroxysteroid dehydrogenase.

The NADP(H)-linked oxidoreductase activity of a major isozyme of human liver 3 alpha-hydroxysteroid dehydrogenase was activated 5-, 4-, and 2-fold by D-thyroxine (T(4)), L-T(4) and DL-3,3', 5'-triiodothyronine (reverse T(3)), respectively. Kinetic analysis of the activation indicated that D-T(4), L-T(4), and reverse T(3) are non-essential activators, showing binding constants of 1.5, 1.1, and 3.6 microM, respectively. Comparison of the effects of the T(4) analogs on the activities of the mutant enzymes suggests that the binding site is composed of at least Lys-270, Arg-276, and the C-terminal loop of the enzyme. L-T(3), DL-thyronine, and D-tyrosine had no effect on the enzyme, but 3,5,3',5'-tetra- and 3,5, 3'-tri-iodo thyropropionic acids were potent competitive inhibitors with K(i) values of 42 and 60 nM, respectively, with respect to the substrate. The inhibition constant was lowered upon the activation of the enzyme by D-T(4), and the inhibition by the deamino derivatives of T(4) and T(3) disappeared upon modification of the C-terminal loop of the enzyme, but not upon replacement of Lys-270 or Arg-276 with Met. These results indicate that, depending on their structures, the T(4) analogs bind differently to two distinct sites at the active center of the enzyme to produce stimulatory and inhibitory effects.

3-Hydroxysteroid Dehydrogenases↗

PubMed2000

Results of breast-conserving therapy for early stage breast cancer: Kyoto University experiences.

This study evaluated the results of breast-conserving therapy (BCT). Nine hundred six patients who underwent BCT at our hospital between November 1987 and February 1998 were analyzed. The mean age was 48 years. According to the Union Internationale Contre le Cancer 1997 classification system, stages 0, I, IIA, IIB, IIIA, and IIIB were 37, 400, 344, 117, 7, and 1, respectively. Radiation therapy consisted of 50 Gy to the ipsilateral whole breast. Boost irradiation of 10 Gy was administered to 186 of 231 patients with close or positive margins. Nearly all patients received adjuvant chemohormonal therapy with tamoxifen and 5-fluorouracil or its derivatives for 2 years. The minimum and median follow-up periods were 18 and 52 months, respectively. The 5-year overall survival, cause-specific survival, local recurrence-free survival, and disease-free survival rates were 97.3%, 98.4%, 98.1%, and 91.5%, respectively. Local recurrence in preserved breast occurred in 20 patients 7 to 86 months after surgery. Multivariate analysis revealed that the most predictive factor for disease-free survival rates and distant failures was the number of pathologically positive lymph nodes (p < 0.0001), and that the factor for local failure was marginal status (p = 0.005). This study demonstrated that BCT was suitable for the treatment of early-stage breast cancer with its reasonable survival rates and acceptable toxicity.

Breast Neoplasms↗

PubMed2000

[Radiation therapy for malignant lymphoma].

For the treatment of malignant lymphoma(ML), it is important to recognize its clinical features. Recently, the role of radiation therapy(RT) has been reconsidered in the treatment of ML because of the effectiveness of combined modality treatment (CMT) for early-stage aggressive non-Hodgkin's lymphoma(NHL). Recent data suggest that adjuvant radiotherapy to the bulky site in advanced-stage aggressive NHL may significantly improve the relapse-free survival and overall survival. On the other hand, in the treatment of early-stage Hodgkin's disease(HD), meta-analysis data showed no apparent survival benefit from CMT or extended RT compared with RT alone. So in the initial treatment of early-stage HD, RT alone with adequate field should be recommended. Low-grade mucosa-associated lymphoid tissue(MALT) lymphoma is considered to be an additional indication for the use of RT because it is very sensitive to radiation and potentially curable with RT.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1999

Concurrent chemoradiotherapy for esophageal carcinoma patients with malignant fistulae.

BACKGROUND: It remains controversial whether chemotherapy and/or radiotherapy are/is contraindicated for esophageal carcinoma patients with malignant fistulae. In some case reports, closure of fistulae by chemotherapy or radiotherapy has been reported. The current study investigated chemoradiotherapy for these patients using various primary treatments to manage the pulmonary complications. The aim of this study was to evaluate the efficacy and feasibility of chemoradiotherapy for patients with locally advanced esophageal carcinoma with malignant fistulae. METHODS: Patients with endoscopically or radiologically confirmed fistulae were treated with concomitant chemoradiotherapy. Closure of fistulae was assessed by esophagography or endoscopy. Oral food intake also was assessed before and after treatment. RESULTS: Of 202 esophageal carcinoma patients treated at National Cancer Center Hospital East between July 1992 and May 1998, 24 patients (11.9%) developed malignant fistulae. Twelve patients developed fistulae before treatment and the remaining patients developed fistulae during treatment. Closure of the fistulae after chemoradiotherapy was observed in 17 of these patients (70.8%), and 16 of these 17 patients (94.1%) had oral alimentation restored after successful treatment. The median survival time from the diagnosis of the fistula for all patients with fistulae was 198 days; in the patients whose fistulae were present before chemoradiotherapy, the median survival time was 238 days. CONCLUSIONS: These results suggest that the presence of malignant fistulae does not contraindicate chemoradiotherapy. Once the inflammation due to the fistula has been controlled, chemoradiotherapy should be utilized because it may provide the best chance for survival and palliation of severe dysphagia.

Adult↗

PubMed1999

Cloning and sequencing of the cDNA species for mammalian dimeric dihydrodiol dehydrogenases.

Cynomolgus and Japanese monkey kidneys, dog and pig livers and rabbit lens contain dimeric dihydrodiol dehydrogenase (EC 1.3.1.20) associated with high carbonyl reductase activity. Here we have isolated cDNA species for the dimeric enzymes by reverse transcriptase-PCR from human intestine in addition to the above five animal tissues. The amino acid sequences deduced from the monkey, pig and dog cDNA species perfectly matched the partial sequences of peptides digested from the respective enzymes of these animal tissues, and active recombinant proteins were expressed in a bacterial system from the monkey and human cDNA species. Northern blot analysis revealed the existence of a single 1.3 kb mRNA species for the enzyme in these animal tissues. The human enzyme shared 94%, 85%, 84% and 82% amino acid identity with the enzymes of the two monkey strains (their sequences were identical), the dog, the pig and the rabbit respectively. The sequences of the primate enzymes consisted of 335 amino acid residues and lacked one amino acid compared with the other animal enzymes. In contrast with previous reports that other types of dihydrodiol dehydrogenase, carbonyl reductases and enzymes with either activity belong to the aldo-keto reductase family or the short-chain dehydrogenase/reductase family, dimeric dihydrodiol dehydrogenase showed no sequence similarity with the members of the two protein families. The dimeric enzyme aligned with low degrees of identity (14-25%) with several prokaryotic proteins, in which 47 residues are strictly or highly conserved. Thus dimeric dihydrodiol dehydrogenase has a primary structure distinct from the previously known mammalian enzymes and is suggested to constitute a novel protein family with the prokaryotic proteins.

Alcohol Oxidoreductases↗

PubMed1999

Local-regional control by conventional radiotherapy according to tumor volume in patients with squamous cell carcinoma of the pharyngolarynx.

BACKGROUND: To estimate the effect of tumor volume on local-regional control of pharyngolaryngeal cancer by radiotherapy (RT). METHODS: Definitive RT for 48 patients with squamous cell carcinoma of the lateral wall of the oropharynx, pyriform sinus and supraglottic larynx was reviewed. Tumor volume was estimated from computed tomography and it was expressed as the diameter of a sphere the volume of which is equal to the primary tumor (Td) and sum of the volumes of metastatic adenopathies (Nd). All patients received > or =60 Gy (median 66 Gy) to the gross tumor by conventional fractionation with or without chemotherapy. RESULTS: A median period of follow-up for survivors was 32.7 months (range, 12.4-68.6). The 2 year local control rate for T1/2 (n = 30) and T3/4 (n = 18) patients was 72 and 65%, respectively (P= 0.966), however, the rates for Td < 4 cm tumors (n = 37) and Td > or = 4 cm tumors (n = 11) were significantly different (80% vs 27%, P < 0.001). The 2 year regional control rates for Nd < 3 cm lesions (n = 29) and Nd > or = 3 cm (n = 19) lesions were 85 and 42%, respectively (P < 0.001). The 2 year ultimate regional control rates for N2/3 disease with Nd < 4 cm (n = 11) and Nd > or = 4 cm (n = 11) were 100 and 42%, respectively (P = 0.004). CONCLUSIONS: Conventional radiotherapy may allow organ preservation and ultimate local control in patients with Td < 4 cm and Nd < 4 cm disease, but larger volume tumors should be considered candidates for the most intensive chemoradiotherapy.

Adult↗

PubMed1999

Analysis of 57 nonagenarian cancer patients treated by radical radiotherapy: a survey of eight institutions.

BACKGROUND: As the human society grows more aged, it is considered important to elucidate factors essential in applying radical radiotherapy (RT) to the elderly, with ages as high as 90 years and greater. METHODS: A retrospective survey was conducted for patients 90 years of age or older who received radiotherapy with radical intent in eight leading institutions in Japan from 1990 through 1995. RESULTS: Fifty-seven nonagenarian patients were studied. Their ages ranged up to 98 (median 91) and there was a strong female preponderance (M/F: 16/41). The distribution by site was as follows: head and neck, 16; skin and adnexae, 11; uterine cervix, 7; esophagus, 6. The prevailing histopathological diagnosis was squamous cell carcinoma (34), followed by adenocarcinomas (8). The highest age at RT was 98 years [female, skin cancer, died of senility 2.5 years after treatment, with no evidence of disease (NED)] and the longest survivor is 102 years old (female, glottic cancer T2, age at RT 93, alive NED for 8 years, uses wheel-chair). The rate of completion of treatment was 75% (43/57), if the treatment field was limited to the gross primary tumor volume only and if the cumulative dose was above 80% of the tolerable adult dose. Familial escort was necessary for most of the patients in completing the day-to-day RT. CONCLUSION: Radiotherapy is feasible with radical intent even in the elderly, if the treatment field is limited to the gross primary tumor volume only, if the cumulative dose is above 80% of the tolerable adult dose and if familial support is adequate.

Aged↗

PubMed1999

Preliminary results of pelvic autonomic nerve-preserving surgery combined with intraoperative and postoperative radiation therapy for patients with low rectal cancer.

BACKGROUND: In Japan, lateral lymphadenectomy was widely performed for patients with stage II-III rectal tumors because it was thought to contribute to good local control, but the pelvic autonomic nerves were thus sacrificed. Although autonomic nerve-sparing surgery with lateral lymph node dissection has been tried from around 1987, the type of nerve sparing varied and the indications were not established. To examine the possibility of expanding the indications for total pelvic autonomic nerve preservation for patients with low rectal cancer, we conducted a pilot study. METHODS: Between 1993 and 1997, a total of 50 patients with low rectal cancer underwent pelvic autonomic nerve preservation with lateral lymphadenectomy of both sides and intraoperative radiation therapy followed by postoperative radiation therapy. RESULTS: The median follow-up period for surviving patients was 41 months. The 3-year local control rates for all patients, with stage I-II and stage III tumors were 88% (95% confidence interval, 78-97%), 97% (90-100%) and 73% (52-94%), respectively. The site of local recurrences was not near or within the preserved plexus. CONCLUSIONS: The preliminary results showed good local control rate for patients with stage I-II tumors. For patients with stage III tumors, the local control rate was unsatisfactory, but nerve sparing was not the cause of local recurrence. Further investigation of function-preserving surgery without decreasing curability is needed.

Adult↗

PubMed1999

Definitive chemoradiotherapy for T4 and/or M1 lymph node squamous cell carcinoma of the esophagus.

PURPOSE: To investigate the efficacy and feasibility of concurrent chemoradiotherapy for locally advanced carcinoma of the esophagus. PATIENTS AND METHODS: Fifty-four patients with clinically T4 and/or M1 lymph node (LYM) squamous cell carcinoma of the esophagus were enrolled. Patients received protracted infusion of fluorouracil 400 mg/m(2)/24 hours on days 1 to 5 and 8 to 12, 2-hour infusion of cisplatin 40 mg/m(2) on days 1 and 8, and concurrent radiation therapy at a dose of 30 Gy in 15 fractions over 3 weeks. Filgrastim was prophylactically administered to 35 patients. This schedule was repeated twice every 5 weeks, for a total radiation dose of 60 Gy, followed by two courses of fluorouracil (800 mg/m(2)/24 hours for 5 days) and cisplatin (80 mg/m(2) on day 1). RESULTS: There were 21 patients with T4M0 disease, one with T2M1 LYM, 17 with T3M1 LYM, and 15 withT4M1 LYM. Forty-nine patients (91%) completed at least the chemoradiotherapy segment. The 18 patients (33%) who achieved a complete response included nine (25%) of the 36 with T4 disease and nine (50%) of the 18 with non-T4 disease. Major toxicities were leukocytopenia and esophagitis; there were four (7%) treatment-related deaths. Prophylactic filgrastim reduced the incidence of grade 3 or worse leukopenia without improving dose-intensity or response. With a median follow-up duration of 43 months, median survival time was 9 months. The 3-year survival rate was 23%. CONCLUSION: Despite its significant toxicity, this combined modality seemed to have curative potential even in cases of locally advanced carcinoma of the esophagus.

Adult↗