A phase I/II study of cancer peptide vaccine S-288310 in patients with advanced urothelial carcinoma of the bladder.

Background: S-288310, a cancer peptide vaccine composed of two HLA-A*24:02-restricted peptides derived from two oncoantigens, DEP domain-containing 1 (DEPDC1) and M-phase phosphoprotein 1 (MPHOSPH1), was investigated in urothelial carcinoma (UC) of the bladder. Patients and methods: Thirty eight HLA-A*24:02-positive patients with progressive UC were enrolled in this study. In the phase I part of the study, three patients each were treated with S-288310 at 1 mg or 2 mg/peptide subcutaneously once a week to evaluate safety and tolerability. In the phase II, 32 patients were randomized to receive either 1 mg or 2 mg to evaluate the difference in cytotoxic T lymphocytes (CTL) induction and safety. Results: S-288310 was safe and well tolerated in the phase I. Of 27 patients evaluable for immune responses in the phase II, there was no difference in CTL induction rate between the 1 mg (100%) and 2 mg (80.0%) groups. Of 32 patients receiving S-288310 in the phase II, the most frequent drug-related AE was the injection site reaction that was observed in 29 patients (90.6%), but none of the patients discontinued administration due to these reactions and no dose relationship in the frequency and severity was observed. The objective response rate of the 32 patients was 6.3% and the disease control rate was 56.3%. The median overall survival (OS) rates for patients vaccinated with S-288310 after one regimen of chemotherapy, 2 regimens, or 3 or more were 14.4, 9.1 and 3.7 months, respectively, and 32.2% of patients post first-line treatment were alive at 2 years. OS of patients who showed CTL induction to both peptides was longer than that of those with CTL induction to no or one peptide. Conclusion: S-288310 was well-tolerated and effectively induced peptide-specific CTLs, which were correlated with longer survival for patients with UC of the bladder. Trial registration ID: JapicCTI-090980.

Last resort for renal transplant recipients, 'restored kidneys' from living donors/patients.

Because of the grave shortage of deceased kidney allografts in Japan, we have embarked on a new source of organs, 'Restored kidneys' from living patients. From January 1991 through September 2006, 42 kidneys (eight benign pathology, eight small renal cancers, eight ureteral cancers, six aneurysms, eight severe nephrotic syndrome from four patients and four ureteral stenosis) were obtained from 38 patients/donors after extensive discussion of treatment modalities and risks. All patients/donors agreed to undergo total nephrectomy. The lesions were removed/repaired ex vivo on the back table, then transplanted. All recipients were notified of all possible risks including donor disease recurrence. One, 5 and 10-year patient survival rates of restored transplant patients were 92.9%, 79.3% and 63.8%, respectively. One, 5 and 10-year graft survival rates of restored kidney transplant patients were 78.6%, 51.8% and 42.7%, respectively. There were no recurrences of small renal cell carcinomas. There was one recurrence of ureteral cancer in the transplanted kidney 15 months after operation. In countries where deceased donors are scarce, such as Japan, the restored kidneys can be a last resort for renal allografts.

Transplantation of Restored Kidneys From Unrelated Donors After Resection of Renal Cell Carcinoma: Results From 10 Patients.

PURPOSE: To relieve the chronic shortage of donor kidneys, we conducted a prospective kidney transplantation trial using kidneys removed from 10 unrelated patients (51 to 79 years of age) who had undergone nephrectomy for small renal cell carcinoma (1.5 to 3.9 cm) of low-to-moderate complexity based on RENAL (radius, exophytic/endophytic properties, nearness of tumor to the collecting system or sinus in millimeters, anterior/posterior location relative to polar lines) nephrometry (objective description helpful for operative indication and planning). METHODS: Donors were selected from among 15 patients who opted to undergo nephrectomy for small renal cell carcinoma. A total of 76 dialysis patients 34 to 85 years of age who agreed to undergo restored kidney transplantation were recruited as transplant candidates. RESULTS: In stage 1 (5 cases), high-risk patients were selected without human leukocyte antigen testing, and accelerated acute rejection occurred in 4 of 5 recipients. This trial was subsequently extended with human leukocyte antigen testing, and an additional 5 patients were enrolled in stage 2. Eight recipients, including 4 recipients with a history of renal transplantation, experienced rejection; 1 patient resumed dialysis 35 months after transplantation. The most recent serum creatinine levels ranged from 1.10 to 3.19 mg/dL in the 9 recipients with functioning grafts and from 0.84 to 4.68 mg/dL in the 10 donors. No tumor recurrence was noted at 32 to 58 months after surgery in either the recipients or the donors. CONCLUSIONS: Restored kidney transplantation using kidneys with a small renal tumor seems suitable for carefully selected high-risk recipients and, in particular, elderly kidneys can also function well. Avoiding cancer transmission, fair recipient selection, close follow-up, and a well-organized tracking system warrant further study.

A new adrenal computer imaging technique using dual-radioisotopes.

Computer processed adrenal imaging using dual-radioisotopes, 6 beta-iodomethyl-19-nor-cholest-5(10)-en-3 beta-ol-131I and 99mTc-phytate was performed in 12 patients with primary aldosteronism and 4 with Cushing's syndrome due to adrenocortical tumor. Adreno-photoscanning and hepato-photoscanning were performed in the same position 2-4 days following intravenous administration of radiocholesterol. The scintigraphic information was stored on cassettes and scan subtraction and a digital-computer method for data smoothing were performed on an oscilloscope. The tumor site could be determined in all cases until day 4 by this computer processed image.

[Intraarterial DDP and angiotensin II infusion chemotherapy].

Twenty-four patients, each with advanced bladder cancer (BC) or brain tumor (BT), were treated by intraarterial infusion of angiotensin II in combination with DDP as the main drug together with other anticancer drugs. As for the frequency of treatment by the intraarterial therapy, only one course was given in 15 cases, two courses in 9 (BC), one course in 21 cases, and two courses in 3 (BT). CR was obtained in ten of 24 evaluable patients with BC and PR in eleven. Of 20 evaluable patients with BT, 3CRs and 7PRs were attained. The selective enhancement of tumoral blood flow induced by regionally infused angiotensin II was observed using continuous intraarterial infusion of krypton-81 m.

[Intracarotid arterial infusion with CDDP in combination with angiotensin II].

Intracarotid CDDP infusion in combination with angiotensin II was performed in two patients with metastatic brain tumor, lung carcinoma (LC) and ovarian carcinoma (OC). The patient with OC received 40 mg/m2 CDDP while the other patient with LC was administered intra-arterially with 50 mg/m2 CDDP, 30 mg/m2 ADM and 2.5 mg/m2 MMC. 50% or greater reduction in the size of metastatic lesions was observed in both patients in whom no neurological toxicities developed. Intra-arterial infusion of CDDP either alone or in combination with ADM or MMC seems to present an aggressive approach in dealing with other metastatic neoplasms without increasing toxicity, especially if intra-arterial angiotensin II is infused concomitantly.

[Intra-arterial infusion chemotherapy in combination with angiotensin II in advanced bladder cancer].

Intra-arterial infusion chemotherapy in combination with angiotensin II was performed in 5 patients with advanced bladder cancer (all T3M0). The infusion catheter was inserted from a femoral artery into the internal iliac artery. The basic dosage was 70 mg/m2 of Cis-diammine-dichloroplatinum (CDDP) and 40 mg/m2 of Adriamycin (ADM) or 4'-0-tetrahydropyranyl-ADM (THP) in combination with 20-40 micrograms angiotensin II over a total duration of 20 minutes for both sides. Of the 5 patients, 3 CR and 2 PR were obtained by only one or two courses of intra-arterial infusion chemotherapy. Histological examination showed no viable cells in the three CR cases. Intra-arterial infusion chemotherapy in combination with angiotensin II may thus be clinically useful for advanced bladder cancer.

[A clinicopathological study of 218 patients with bladder carcinoma treated by radical cystectomy].

Between 1986 and 1995, 218 patients with primary carcinoma of the bladder were treated with radical cystectomy at our hospitals. Clinicopathological specimens and the relative value of prognostic factors were analyzed with both the univariate and multivariate method. Univariate analysis indicated that age, sex, pathological tumor stage, grade, vessel involvement, tumor infiltrating type and positive nodes were predictive of poor cancer-specific survival. Multivariate analysis demonstrated that female patients were predictive of poor cancer-specific survival. As for the risk ratio, the prognostic factors in lymphatics involvement and tumor infiltrating type were 2.77 and 2.47, respectively.

Intra-arterial infusion chemotherapy in combination with angiotensin II for advanced bladder cancer.

A combination of 50 to 80 mg. per m.2 cis-platinum and 30 to 50 mg. per m.2 doxorubicin or 30 to 50 mg. per m.2 tetrahydropyranyl-doxorubicin instead of doxorubicin was infused into the bilateral internal iliac artery for the treatment of 20 patients with T3 or T4 advanced bladder cancer. Angiotensin II was administered together with these chemotherapeutic agents by means of an infusion pump at a rate of 1.5 to 2.0 micrograms. per minute for 20 minutes for both sides. Among the 20 patients complete (9) and partial (8) responses were obtained after only 1 or 2 courses of this intra-arterial treatment. Histological examination showed severe tumor destruction with no viable cells in 6 and no tumor in 4 of the 15 evaluable cases. Selective enhancement of regional blood flow in the tumor region after intra-arterial infusion of angiotensin II was observed by continuous target arterial 81mkrypton infusion. Intra-arterial chemotherapy with combined angiotensin II may be clinically useful for treatment of primary or metastatic bladder carcinoma.

Phyllodes tumor of the prostate: a case report.

A case of prostatic phyllodes tumor which developed in a 78-yr-old man is reported. Histologically, the tumor comprised myxomatous and cellular portions with a proliferation of atypical stromal cells. Multinucleated giant cells were occasionally present, but mitoses were rare. Fibroblastic differentiation of the tumor cells was confirmed by numerous rough endoplasmic reticulums and free ribosomes, and by immunoreactivity for vimentin. Approximately one-third of the tumor cells showed estrogen-receptor immunoreactivity at their nuclei. The patient is well, with no evidence of tumor recurrence, five years after the resection. The tumor was diagnosed as being a benign prostatic phyllodes tumor showing fibroblastic differentiation, and of an estrogen-dependent nature.

[R 1881 binding receptor and DHT concentrations in prostatic cytosol].

R 1881 binding receptor and DHT concentrations in human prostatic cytosol were assayed in surgically removed prostatic tissues of benign prostatic hyperplasia (BPH) and of the normal prostate. The normal prostates were obtained from totally cystectomized male patients with bladder cancer. Cytosols were incubated with 0.25--8.0 nM (6 points) of 3H-R 1881 in the presence or absence of excess radioinert R 1881 at 4 degrees C for 20 hours, thereafter treated with 0.5% dextran coated charcoal. Specific bindings were analysed in the form of scatchard plot analysis. Cytosol DHT levels were determined by radioimmunoassay reported previously. Steroid specificity studies revealed that R 1881 binding receptor was inhibited not only by androgens but also by progesterone, however, an addition of 1000 fold excess triamcinolone acetonide (TCA) reduced the inhibition by progesterone. As R 1881-receptor complex was eluted at the void volume of sephacryl S-200 chromatography, the receptor was considered to be 8-9S protein. Cytosol DHT levels were 35.5 +/- 13.6 pg/mg cytosol protein in BPH and 18.9 +/- 7.1 pg/mg protein in the normal prostates, showing a significantly higher value in the former (p less than 0.01). Kd and NBS of R 1881 receptor in BPH were 0.73 +/- 0.21 nM and 30.1 +/- 9.0 fmol/mg cytosol protein and those in normal prostate were 0.68 +/- 0.28 nM, 10.2 +/- 4.2 fmol/mg protein, respectively. NBS were also higher in BPH compared to the normal prostate (p less than 0.001). Moreover, DHT levels (y) and NBS (x) showed a significant correlation (y = 0.631 X + 15.764, r = 0.506).(ABSTRACT TRUNCATED AT 250 WORDS)

[Endogenous androgen levels of human prostatic tissues].

Endogenous androgen levels of prostatic tissues in patients with benign prostatic hypertrophy (BPH) and untreated prostatic cancer (PC) were determined by radioimmunoassay using sephadex LH-20 column chromatography. By this assay procedure, it was possible to measure tissue androgen levels with only 30 approximately 40 mg weight of tissues. In BPH (n=20) the concentrations of steroids (mean +/- standard deviation, ng/g. tissue weight) were 5 alpha-androstane 3 alpha, 17 beta diol (A-diol), 2.31 +/- 1.29; dihydrotestosterone (DHT), 4.97 +/- 2.17; testosterone (T), 0.62 +/- 0.33. In PC (n=17) the concentrations were 5.51 +/- 3.23; 3.94 +/- 3.16; and 0.93 +/- 0.38; respectively. The concentrations of DHT were raised and the levels of A-diol were reduced significantly (P less than 0.01) in BPH compared with PC. Tissue DHT levels of PC were variable, but they could be classified in to two groups. One was below 2 ng levels (n=8) similar to those of non-androgen target tissues and the other was over 2 ng (n=19). The relationships between histological differentiation and tissue DHT levels in prostatic cancer were examined. In poorly differentiated cancer (n=4), DHT levels were low in all cases, furthermore even in well differentiated ones there were 4 cases with levels below 2 ng. Thus, the measurement of endogenous DHT levels of prostatic tissues was considered to be valuable for the judgment of androgen dependency in prostatic cancer.

[Plasma 11-deoxycortisol response to single dose metyrapone in prostatic cancer patients (author's transl)].

A radioimmunoassay procedure for plasma 11-deoxycortisol (S) was developed using an antiserum prepared by immunizing rabbits with S-21-hemisuccinate bovine serum albumin and S-3-oxime-bovine serum albumin. Thereafter plasma S, cortisol (F) and adrenocorticotropic hormone (ACTH) responses to metyrapone were investigated in 13 normal adult males and 39 patients with prostatic cancer. The results were as follows: 1) The antiserum against S-3-oxime-bovine serum albumin had less cross reactivity (less than 10%) with other steroids than that against S-21-hemisuccinate bovine serum albumin and obtained a good standard curve. The intra-assay variance and interassay variance of this method using the former antiserum (N = 10) were 12.4% asd 14.9% respectively, and the blank value was 3.7 +/- 1.6 pg. 2) Basal levels of S. F and ACTH in plasma from 13 normal adult males, ranged 21 approximately 80 years, old, were 98.4 +/- 15.7 ng/dl (mean value +/- S.E.), 12.7 +/- 0.78 micrograms/dl and 30.6 +/- 3.02 pg/ml respectively. Those level increased to 7060 +/- 598 ng/dl, 24.3 +/- 1.69 micrograms/dl and 24.3 +/- 1.6 pg/ml at 9 a.m. following oral administration of metyrapone (30 mg/kg b.w.) at midnight. 3) Both basal levels and responses of plasma S and F to metyrapone increased remarkably, while those of ACTH were within the normal range in prostatic cancer patients during the estrogen therapy. It was considered that protein-bound S and F increased following elevation of corticosteroid binding globulin but returned to the normal range about 2 weeks after discontinuation of the therapy. 4) In case treated wih estrogens, plasma, S, F and AC normal range in prostatic cancer patients during the estrogen therapy. It was considered that protein-bound S and F increased following elevation of corticosteroid binding globulin but returned to the normal range about 2 weeks after discontinuation of the therapy. 4) In case treated wih estrogens, plasma, S, F and AC normal range in prostatic cancer patients during the estrogen therapy. It was considered that protein-bound S and F increased following elevation of corticosteroid binding globulin but returned to the normal range about 2 weeks after discontinuation of the therapy. 4) In case treated wih estrogens, plasma, S, F and ACTH responses to metyrapone were unchanged compared to normal adult males 2 approximately 4 weeks after discontinuation of the therapy, and this data suggested that estrogens had no inhibitory effect on the pituitary-adrenal axis. However, in cases treated with progestational agents over a long-term period, plasma S and ACTH responses to metyrapone decreased slightly but returned to the normal range 2 approximately 4 weeks after discontinuation of the therapy. This suggested that the inhibitory effect of these agents on the pituitary-adrenal axis was mild and reversible.