Phase I/II study of docetaxel and S-1 in patients with advanced gastric cancer.

The aims of this phase I/II study of docetaxel and S-1 were to determine the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and recommended dose (RD) in the phase I part and to explore the tumour response, survival and safety in the phase II part. Patients with histologically- or cytologically confirmed unresectable or recurrent gastric cancer were eligible. Treatment consisted of intravenous docetaxel on day 1 (starting dose 50 mg m(-2)) and oral S-1 at a fixed dose of 40 mg m(-2) twice daily on days 1-14, every 4 weeks up to six cycles. Nine patients took part in the phase I portion of the study. The MTD of docetaxel was determined to be 50 mg m(-2), with the DLTs of grade 3 infection associated with grade 3 neutropenia and grade 4 neutropenia during S-1 administration. The RD of docetaxel was 40 mg m(-2) in combination with S-1 40 mg m(-2) b.i.d. The efficacy and safety of this regimen was therefore assessed in 46 patients with at least one measurable lesion. The overall response rate and estimated median overall survival were 46% (95% CI, 31-61%) and 14.0 months (8.3-17.3 months), respectively. The most common grade 3/4 toxicity was neutropenia (67% of patients), which was predictable and manageable. This regimen showed promising activity with moderate toxicities in advanced gastric cancer.

Remarkable antiagglomeration effect of a yeast biosurfactant, diacylmannosylerythritol, on ice-water slurry for cold thermal storage.

Antiagglomeration effects of different surfactants on ice slurry formation were examined to improve the efficiency of an ice-water slurry system to be used for cold thermal storage. Among the chemical surfactants tested, a nonionic surfactant, poly(oxyethylene) sorbitan dioleate, was found to show a greater antiagglomeration effect on the slurry than anionic, cationic, or amphoteric surfactants. More interestingly, diacylmannosylerythritol, a glycolipid biosurfactant produced by a yeast strain of Candida antarctica, exhibited a remarkable effect on the slurry, attaining a high ice packing factor (35%) for 8 h at a biosurfactant concentration of 10 mg/L. These nonionic glycolipid surfactants are likely to effectively adsorb on the ice surface in a highly regulated manner to suppress the agglomeration or growth of the ice particles. This is the first report on the utilization of biosurfactant for thermal energy storage, which may significantly expand the commercial applications of the highly environmentally friendly slurry system.

Analysis of gene expression profiles associated with cisplatin resistance in human ovarian cancer cell lines and tissues using cDNA microarray.

Gene expression profiles were analyzed by using cDNA microarray for a cisplatin-sensitive cell line (KF), and three- and thirty-fold cisplatin-resistant ovarian cancer cell lines (KFr and KFrP200) both showing no p53 mutation within exon 5, 6, 7, 8 and no pglycoprotein overexpression. Expression of GST-pi mRNA increased as the level of resistance to cisplatin became high. Microarray analysis revealed that DNA repair associated genes, i.e., XRCC5, XRCC6, ERCC5, hMLH1 were over-expressed in three-fold cisplatin-resistant cell line, KFr as compared to cisplatin-sensitive parental cell line, KF. Apoptosis inhibitors, i.e., IGFR type I and II were over-expressed, and apoptosis inducer, i.e., caspase 3 and BAK were underexpressed in highly cisplatin-resistant cell line, KFrP200 as compared to KFr. As for clinical cases, cDNA microarray was used to compare gene expression profiles directly between two groups, i.e., the chemotherapy (CAP) sensitive group (n = 2) and the resistant group (n = 2). Six genes such as beta tubulin, high-mobility group (nonhistone chromosomal) protein 1, connective tissue growth factor, insulin-like growth factor binding protein 2, alpha tubulin, and RAS-related gene were overexpressed in CAP therapy resistance group, whereas seven genes such as CD9 antigen, alpha-2-macroglobulin, caveolin 2, interleukin 1 receptor antagonist, Rho GTPase activating protein 1, reticulon 3, cyclin-dependent kinase 10, keratin 7 were underexpressed in CAP therapy resistance group. By increasing clinical case number and gene number of microarray to be used in the analysis of expression profile of gene cluster affecting anticancer drug resistance and sensitivity of the ovarian cancer, it would be possible to apply microarray analysis to personalization of chemotherapy such as selection of effective chemotherapy protocol and prediction of therapeutic effect in the near future.

Genetic aberrations detected by comparative genomic hybridization in ovarian clear cell adenocarcinomas.

Genetic abnormalities were detected by comparative genomic hybridization (CGH) in 12 ovarian clear cell adenocarcinomas. DNA sequence copy number abnormalities (CNAs) occurring in more than 20% of the cancers included increased copy numbers of 8q11-q13, 8q21-q22, 8q23, 8q24-qter, 17q25-qter, 20q13-qter and 21q22-qter and reduced copy numbers of 19p. Increases in copy numbers of 8q11-q13, 8q21-q22, 8q23 and 8q24-qter occurred more frequently in disease-free patients than in recurrent/non-surviving patients (p < 0.05). However, increases in copy numbers of 17q25-qter and 20q13-qter occurred more frequently in recurrent/non-surviving patients than in disease-free patients (p < 0.05). Furthermore, increases in copy numbers of 17q25-qter and 20q13-qter occurred together (p < 0.05). Additionally, there were negative correlations between increases in copy numbers of 8q21-q22 and 17q25-qter, and between 8q21-q22 and 20q13-qter (p < 0.05). It appears that ovarian clear cell adenocarcinomas can be classified into two subtypes, one being cancer with an increase in copy numbers of 8q and the other being cancer with increases in copy numbers of 17q25-qter and 20q13-qter.

[Medical therapy in ulcerative colitis].

Salazosulfapyridine(SASP) and 5-aminosalicyclic acid(5-ASA) are useful in the therapy of mildly to moderately active ulcerative colitis. 5-ASA lacks sulfa moiety of SASP and is associated with a decreased incidence of side effects. In patients with moderate or severe ulcerative colitis, glucocorticoids which may be given in conjunction with SASP or 5-ASA are beneficial in producing remission. Proctitis or left-sided colitis is effectively treated with glucocorticoid enemas. If symptoms are refractory to outpatient management, the patient should be hospitalized and given initial therapy with glucocorticoids. Total colectomy(ileo-anal anastomosis; IAA et al) must be considered for acutely ill patients not responding to intensive medical therapy. Early surgical consultation is necessary in severely ill patients.

Application of PDT for Uterine Cervical Cancer.

We have been performing PDT using Excimer Dye Laser (EDL) or YAG-OPO laser, a type of low power laser, both of which have a considerably higher degree of tissue penetration even when compared to PDT using Argon Dye Laser (ADL).PDT is a relatively simple procedure without any bleeding and does not require anesthesia since it causes no pain. PDT is performed 48 h after intravenous injection of 1.5-2.0 mg/kg of PHE (Photofrin((R))). Precise spot irradiation is possible using a colposcope with an optical laser path. We also use a cervical probe which enables photoirradiation of the entire cervical canal.We have performed PDT on 131 cases (95 CIS, 31 dysplasia, 1 vulval dysplasia (VIN), 3 squamous cell carcinoma, microinvasion, and 1 CIS + endocervical adenocarcinoma, microinvasion). Of these cases, 127 became CR (96.9%). The first CR case was 10 years ago and no recurrence has been observed yet.PDT is extremely effective to preserve fertility. Except for sensitive reactions to sunlight, there are no noticeable side effects or difficulties related to pregnancy or delivery. We expect that in the near future PDT will be performed using diode lasers and without hospitalization due to new photosensitizers which have shorter retention times.

[Cancer-associated gene abnormalities and chemosensitivity].

One of the most important clinical issues in cancer chemotherapy is the presence of intrinsic resistance or the appearance of acquired resistance against chemotherapy. As for intrinsic resistance, we had to perform direct chemo-sensitivity testing, or had to rely on the knowledge empirically acquired from randomized clinical trials. However, molecular or genetic markers associated with chemo-sensitivity have been reported recently. For example, inactivation of p53 or GML gene has been reported to be associated with chemo-resistance. Overexpression of topo-isomerase I has been reported to be associated with chemo-sensitivity to Topo I inhibitor. Overexpression of Thymidine Phosphorylase has been found to be associated with chemo-sensitivity to prodrug of 5-FU. By checking the status of such chemo-sensitivity markers prior to chemotherapy, it would be possible to predict the chemotherapeutic effect and even the necessity of the chemotherapy in the near future. In this article, we review the chemo-sensitivity markers reported so far, and methodology contributing to the discovery of new chemo-sensitivity markers. As a clinical study, 11 cases of ovarian cancer with high sensitivity to cisplatin-based chemotherapy and 29 cases of ovarian cancer with chemoresistance were analyzed by Comparative Genomic Hybridization (CGH). Copy number decrease in Xp, and copy number increase in 19q were observed in 13, 12 out of 29 resistant cases (45, 41%) and zero, 1 out of 11 sensitive cases (0, 9%), suggesting that -Xp and +19q were likely to be a genetic event associated with intrinsic drug-resistance (p = 0.006, 0.05, respectively). This effort should contribute to the discovery of new chemo-sensitivity and resistance markers.

Clinical importance of late potential in patients with angina pectoris.

Angina pectoris, especially vasospastic angina, is associated with lethal ventricular tachycardia. The clinical importance of late potential in angina pectoris was assessed in 171 patients with angina-like pain. Patients were categorized into three groups based on coronary angiography. Patients in the exertional angina pectoris (AP) group exhibited at least 75% organic stenosis of a major coronary artery after intracoronary injection of a nitrate drug (82 patients). Patients in the chest pain syndrome (CPS) group had no significant organic stenosis of the coronary artery and the acetylcholine-loading test produced negative results (39 patients). Patients in the vasospastic angina (VSA) group had a positive acetylcholine-loading test (50 patients). When the filtered QRS duration was prolonged to above 130 msec and/or the root-mean-square voltage in the last 40 msec was below 15 microV in VCM-3000, the late potential was judged to be positive. The incidence of late potential was higher in the AP group (23.2%) and the VSA group (38.0%) than in the CPS group (7.7%) (p < 0.05, p < 0.01). Comparison of late potential incidence between patients with coronary vasospasm below 90% (group 1) and patients with above 90% (group 2) induced by the acetyl-choline-loading test in the VSA group showed more late potential in group 2 than in group 1 (84.2% vs 15.8%). Late potential was present in 19 (23.2%) patients in the AP group, but only 2 (10.5%) had under 90% degrees of coronary stenosis and the other 17 (89.5%) had greater than 90% degrees of stenosis. Thus, late potential was mainly observed in patients with severe organic stenosis. These results suggest that the origin of late potential is associated with inhomogeneous electrical excitation induced by frequent angina attack and the duration of total or near total occlusion. Strict clinical management is required for patients with VSA or AP associated with late potential.

[CGH (comparative genomic hybridization)].

Comparative Genomic Hybridization (CGH) is a powerful new method which allows genome-wide mapping of regions with DNA sequence copy number changes (both increases and decreases) in a single experiment without previous knowledge of the locations of the regions of abnormality. CGH is based on in situ hybridization of differentially labeled total genomic tumor DNA and normal DNA to normal human metaphase chromosomes. After hybridization copy number variations among the sequences in the tumor DNA are detected by measuring the tumor/normal fluorescence intensity ratio for each locus in the target chromosomes. Many previously unknown chromosomal regions with relative copy number changes have been detected in various tumors by CGH. Some changes have been identified as genetic markers associated with biological and clinico-pathological characteristics (i.e., histopathological grade, and clinical outcome). We review the published CGH articles and discuss briefly on current progress in CGH analysis to ovarian and uterine cervical cancer in our laboratory.

[Photodynamic therapy (PDT) for early cervical cancer].

The incidence of carcinoma in situ (CIS) and dysplasia of the uterine cervix has been increasing among young women in recent years. Most of these patients want to preserve their fertility. Also, to accommodate high-risk patients with complications, elderly patients, and those who refuse surgery, we perform PDT as a method to preserve fertility. The technique required for PDT is relatively simple, and can be performed without anesthesia, since it causes no pain or bleeding. PDT, with the use of Excimer Dye Laser (EDL), a type of low pulse laser, has a considerably higher degree of tissue penetration, even compared to PDT using Argon Dye Laser (ADL). Also, PDT using EDL can manage glandular involvement of CIN, and its special feature of selective destruction of malignant cells with almost no effect on normal tissues is noteworthy. Beginning in 1995, PDT using YAG-OPO Laser with a variable laser wavelength has been performed. PDT is performed 48 hours after intravenous injection of 1.5 mg/kg to 2 mg/kg photosensitizer Porfimer sodium (PHE) when the difference in density of PHE becomes greatest between malignant cells and normal tissue. The most advanced features of our method compared to conventional radiation which uses cut fiber are: First, by using colposcope with an optical path for the laser, it is possible to show a 10 mm circular spot at the focus of observation. With this method, cervical lesions can be observed and checked while receiving stable and precise photoradiation by using colposcope through direct observation. Second, for cervical canal treatment, by using a cervical probe to administer photoradiation in the forward direction in the cervical canal and to the side walls, 70% of the laser light is scattered to the side walls, so that all of the cervical canal can be radiated. Also, the cervical canal probe used to administer photoradiation, by inserting 2 cm to 3 cm depending on the conditions of the cervical canal and withdrawing the probe 1 mm, can be performed precisely and promptly by using the cervical probe manipulator feature of the colposcope. At the present time, studies using the PDT method have been conducted on 56 patients (39 CIS and 17 dysplasia patients). Out of these 56 patients, there were 54 CR (96.4%), only one NC, and one PR with very limited remnants but most of the lesions had disappeared. The NC was highly suspected to be invasive carcinoma and the PR was CIS. In the CIS case, some remnant was evident at the end of the cervical canal, and PDT was administered again. After this treatment, it became CR. This was 10 months ago, and no abnormal condition has been reported since. The first CR case was reported 6 years ago among the 56 cases studied, and no recurrence has been observed to date. Five patients became pregnant after the treatment. Four had normal deliveries and one had a cesarean section. PDT's side effect is similar to symptoms of sunburn such as minor skin irritation due to sensitive reaction to sunlight. Normally, it can be relieved by applying carmine lotion, and even cases that required treatment were cured completely within a few days after applying steroid ointment. Before hospitalization, if the patient gets a sunburn from being outside, the sensitive reaction to laser light is almost nonexistent. Thus, we advise patients to get some exposure to the sun before being hospitalized. Also, in cases where strict shading time is observed, side effects are not apparent at all, and no abnormal findings are recognized in the blood and urine due to using PHE. With almost no side effects, bleeding or pain, and with certain improvements in administration methods, a better choice of photosensitizer which would shorten the shading time, PDT is considered to be the best therapy for treating CIS and dysplasia while preserving fertility.

[Outpatient ESWL in 500 kidneys].

Between March 1989 and January 1992, 600 cases (636 kidneys) with upper urinary tract stones were treated with ESWL, using a Lithostar. Of these, 78.6% were carried out in our outpatient service, and in the last two years approximately 90% of cases have been treated as outpatient. We evaluated first 500 kidneys, treated with ESWL as outpatient. There were 481 cases involving 500 kidneys (19 bilateral cases). The ages of the 367 men and 114 women ranged from 16 to 77 years. There were 227 kidney stones and 273 ureter stones. Most of the stones were less than 20 mm. The average number of sessions and shock waves for each patient were 1.4 times and 6,988 waves, respectively. While 74% of the patients could be treated in only one session, 9% of them needed 3 sessions or more. Auxiliary measures were needed in 23 cases (D-J stent insertion in 5 cases and ureteral catheterization in 18 cases) and 474 cases (94.8%) were treated by in-situ procedures. At 3 months after treatment, 470 cases were evaluated and the stone-free rates of kidney stones and ureter stones were 70.3% and 84.5%, respectively with an overall stone-free rate of 78.1%. With regard to complications, the rate of the clinic visit because of pain after treatment was observed in 4.6% and higher than 38 degrees C in 2.5%. However, no serious perioperative complications occurred. From these results, outpatient ESWL was considered to be safe and efficient without serious complications.(ABSTRACT TRUNCATED AT 250 WORDS)

The basic study on kappa-lambda imaging by delta-curve for the detection of a monoclonal B-cell population in the peripheral blood.

Recently, kappa-lambda analysis with the "D" value was developed by Ault to detect a minor population of malignant B cells in peripheral blood. This analysis is based on the Kolmogorov-Smirnov test, and the D value is calculated by a flowcytometer and a computer. We have recently devised a more sensitive parameter for the kappa-lambda analysis than the D value called the delta-curve (delta c); the delta c applies the same principle as that of the D value. Mixing experiments with kappa-type and lambda-type chronic lymphocytic leukemia cells revealed that the delta c could not only detect a minor population of malignant kappa-B cells, but also that of malignant lambda-B cells using more sensitivity than the D value. A total of 49 blood samples obtained from 27 patients with various B-cell malignancies were investigated. D values were abnormal in 37% of all samples, while abnormal patterns of the delta c were recognized in 71%. On the other hand, 59% of samples obtained from the patients with B-cell lymphoma in aleukemic phase showed abnormal delta c, whereas D values exceeded the upper limit of the normal value in only 15% of the samples. It was suggested that the delta c could detect 3% to 7% of malignant B cells that were mixed with a population of normal lymphocytes.

Hyperplasia of juxtaglomerular cells and renomedullary interstitial cells after renal arterial embolization in patients with renal cell carcinoma.

Renal tissue was obtained from 36 patients with renal cell carcinoma, some of whom received renal arterial embolization. The removed specimens was examined histopathologically and the concentration of some vasoactive substances in these patients was measured. Nephrectomy alone produced no discernible changes in blood pressure, vasoactive substances determined or histopathological findings of the kidney. Renal arterial embolization raised the blood pressure in association with the elevation of plasma renin activity (PRA) and urinary prostaglandin (PG) E2 excretion. A linear relationship was found to exist between PRA and mean blood pressure (r = 0.70, p less than 0.001). Hyperplasia of the juxtaglomerular (JG) apparatus, and high granularity of sudan black B granules in renomedullary interstitial cells were confirmed in removed kidneys of patients who had received embolization alone. Subsequently high renin production would be anticipated to influence overproduction of renal PG E2 in acute ischemic kidney in patients with renal cell carcinoma, and hypertension following renal arterial embolization appears to be caused by the hyperplasia of the JG apparatus.

[Renal cyst puncture under ultrasound guidance: complications of ethanol injection].

Under ultrasound guidance, we treated 25 cases of renal cyst with 99% ethanol instillation to prevent the recurrence of this disease from January 1985 to June 1987. Patients' age was from 17 to 85 years old with the average age of 63 years. Twelve cases were men, and 13 cases were women. Among the 25 cases, eleven were asymptomatic and 14 showed clinical features of lumbago, microhematuria, hypertension or proteinuria. The aspirated site was the right side in 9, left side in 14 and bilateral kidneys in 2 cases. Subsequently, cyst puncture was carried out 27 times. We encountered 12 complications following puncture. These complications were derived from the puncture itself or caused by the ethanol instillation. Flank pain caused by the injection of ethanol, nausea, causalgia or a feeling of drunkenness appeared immediately after the inoculation procedure. However, no serious complications such as pneumothorax, perirenal hematoma or infection were recognized. Some complications arose in 7 cases of 9 examples (77.8%) following more than 50 ml of ethanol injection, but the complications were observed in only 5 cases of 18 examples (22.8%) following less than 50 ml of administration. Based on these findings, ethanol injection in renal cysts appears to be useful for the treatment of this disease. In case of huge cysts when more than 50 ml of ethanol, is instilled the case should be followed up carefully after the instillation procedure.

[Three case reports of monorchism].

A 3-year-old boy, with left testicle absent, a 3-year-old boy with right testicle absent and a 5-year-old with left testicle absent visited our clinic. On operation the testes and the vas could not be found in the inguinal canal or in the retroperitoneal space in all 3 cases. These three cases are reported along with embryological studies.

Superoxide dismutase activity in renal cell carcinoma.

Both Cu-Zn- and Mn-superoxide dismutase (SOD) activities were determined in renal cell carcinoma and tumor-uninvolved renal tissues in 25 patients with renal cancer. These enzymatic activities were similar in tumor and tumor-uninvolved renal tissues. The age of the patients, grade or stage of tumors had no apparent effect on SOD activities. Renal arterial embolization caused a slight decrease (p less than 0.05) in Cu-Zn-SOD activity in tumor tissues, but none in other enzymes in the same tissues, while renal arterial embolization reduced each SOD activity in tumor-uninvolved renal tissues (p less than 0.01 - p less than 0.001). Therefore the development of renal cell carcinoma is probably not related to the abnormality of renal SOD, but renal ischemic changes appear to lower each SOD activity in normal renal tissues.

Therapeutic results of primary aldosteronism with special reference to renal or renovascular lesions.

A study was made of 9 patients with primary aldosteronism due to aldosterone-producing adenoma (APA) and 8 subjects with idiopathic adrenal hyperplasia (IHA) to clarify the pathogenesis of sustained hypertension after surgical or non-surgical treatment. Following each treatment, a complete improvement of hypertension was obtained in 12 patients (6 APA, 6 IHA), while 5 (3 APA, 2 IHA) showed still hypertensive status. Renal or renovascular lesions were prominent only in the hypertension-unchanged group. Under regular sodium diet, the ratio of urinary excretion of sodium to creatinine of this hypertensive group was significantly lower than that of the hypertension-improved group. However, the results of other renal function tests were similar in both groups. After respective treatments, suppressed plasma renin activity and elevated plasma aldosterone concentration were improved in all patients. In addition, patients of both groups showed normal response of the renin-aldosterone system following diuretic and dietary induced sodium and volume depletion. Based on these findings, renal or renovascular lesions appear to play an important role in the pathogenesis of maintenance of hypertension in this disorder after respective treatments.

Hyperbaric oxygenation for experimental bladder tumor. II. Hyperbaric oxygenation in combination with chemotherapy in N-butyl-N-(4-hydroxybutyl)nitrosamine-induced bladder tumors.

Two series of experiments were conducted to ascertain whether hyperbaric oxygenation (HBO) treatment with or without antineoplastic chemotherapy can really suppress tumor development in N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced bladder tumor in rats. HBO treatment of 2 ATA of air saturating with 30-35% of oxygen for 90 min daily plus 0.5 mg/100 g body weight of 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) administration for 5 times suppressed the neoplastic spread of the bladder for 9 weeks and reduced the bladder weight in BBN-treated rats. Similar effects were also obtained in ACNU-treated rats, but to a lesser extent. HBO treatment associated with or without doxorubicin failed to suppress tumor growth in BBN-treated animals. Based on these findings combined with the previous study (part I), HBO treatment associated with ACNU might be available for the treatment of some cases of bladder tumors.