Pharmacokinetic and tolerability profile of once-daily zibotentan (ZD4054) in Japanese and Caucasian patients with hormone-resistant prostate cancer.

OBJECTIVE: To investigate potential differences in zibotentan pharmacokinetics between Japanese and Caucasian patients with hormone-resistant prostate cancer (HRPC) following single and multiple dosing. METHODS: In the Japanese study, 18 patients received a single dose of zibotentan 5, 10 or 15 mg followed by 72 h washout before 26 days' once-daily dosing. In the Caucasian study, 21 patients received a single dose of zibotentan 5, 10 or 15 mg followed by 72 h washout before 12 days' once-daily dosing. RESULTS: Pharmacokinetic parameters were similar between populations. Absorption of zibotentan was rapid with maximum plasma concentrations typically achieved within 3 h of dosing. Mean clearance, 17.9 and 18.7 ml/min in Japanese and Caucasian patients, respectively (range 7.0 - 36.3 ml/min in Japanese patients and 7.8 - 29.5 ml/min in Caucasian patients) and volume of distribution, 14.0 and 15.6 l for Japanese and Caucasian patients, respectively (range 7.9 - 29.1 l in Japanese patients and 9.6 - 23.8 l in Caucasian patients) were relatively low, and t1/2 was approximately 12 h (range 5.7 - 18.8 h in Japanese patients and 5.0 - 22.9 h in Caucasian patients) following single dosing. Little accumulation was observed following daily dosing and multiple-dose pharmacokinetics were predictable. Exposure levels achieved in some Japanese patients receiving zibotentan 15 mg were higher than those observed in Caucasian patients, however, this may be due to differences in body weight, as exposure levels were similar when data were normalized for body weight. Zibotentan was well tolerated in both populations. CONCLUSIONS: There are no clinically relevant differences in the disposition and pharmacokinetics of zibotentan between Japanese and Caucasian patients with HRPC.

Forced expression of murine IL-17E induces growth retardation, jaundice, a Th2-biased response, and multiorgan inflammation in mice.

IL-17 is a proinflammatory cytokine, and its in vivo expression induces neutrophilia in mice. IL-17E is a recently described member of an emerging family of IL-17-related cytokines. IL-17E has been shown to bind IL-17Rh1, a protein distantly related to the IL-17R, suggesting that IL-17E probably possesses unique biological functions. In this study, we have identified the murine ortholog of IL-17E and developed transgenic mice to characterize its actions in vivo. Biological consequences of overexpression of murine (m)IL-17E, both unique to IL-17E and similar to IL-17, were revealed. Exposure to mIL-17E resulted in a Th2-biased response, characterized by eosinophilia, increased serum IgE and IgG1, and a Th2 cytokine profile including elevated serum levels of IL-13 and IL-5 and elevated gene expression of IL-4, IL-5, IL-10, and IL-13 was observed in many tissues. Increased gene expression of IFN-gamma in several tissues and elevated serum TNF-alpha were also noted. In addition, IL-17E induces G-CSF production in vitro and mIL-17E-transgenic mice had increased serum G-CSF and exhibit neutrophilia, a property shared by IL-17. Moreover, exposure to mIL-17E elicited pathological changes in multiple tissues, particularly liver, heart, and lungs, characterized by mixed inflammatory cell infiltration, epithelial hyperplasia, and hypertrophy. Taken together, these findings suggest that IL-17E is a unique pleiotropic cytokine and may be an important mediator of inflammatory and immune responses.

IL-17s adopt a cystine knot fold: structure and activity of a novel cytokine, IL-17F, and implications for receptor binding.

The proinflammatory cytokine interleukin 17 (IL-17) is the founding member of a family of secreted proteins that elicit potent cellular responses. We report a novel human IL-17 homolog, IL-17F, and show that it is expressed by activated T cells, can stimulate production of other cytokines such as IL-6, IL-8 and granulocyte colony-stimulating factor, and can regulate cartilage matrix turnover. Unexpectedly, the crystal structure of IL-17F reveals that IL-17 family members adopt a monomer fold typical of cystine knot growth factors, despite lacking the disulfide responsible for defining the canonical "knot" structure. IL-17F dimerizes in a parallel manner like neurotrophins, and features an unusually large cavity on its surface. Remarkably, this cavity is located in precisely the same position where nerve growth factor binds its high affinity receptor, TrkA, suggesting further parallels between IL-17s and neurotrophins with respect to receptor recognition.

beta-estradiol 3-benzoate affects spermatogenesis in the adult mouse.

beta-estradiol 3-benzoate (E(2)B) (10, 16, 20, 40, 80 and 160 microg/kg body weight) was administered daily to experimental groups of adult mice for the following periods; 2, 3 days, 1, 2, 4, and 8 weeks. Morphological changes in the testes were observed by both light and electron microscopy. Exfoliation of the germ cells was observed in the lumen of the seminiferous tubule. The spermatogenic cycle, especially stage XII, was disordered. Spermatids older than step 6 were severely affected. Detected abnormalities in the spermatids were deformation of the nucleus and acrosome. Partial deletion in the Sertoli-spermatid ectoplasmic specialization was also observed. Germ cells younger than step 7 spermatids were not affected morphologically. These abnormalities were not detected in the mice treated with the chemical at less than 16 microg/kg body weight. It is concluded that the chemical seems to affect round spermatids metabolically, but the morphological effect can be detected only from the spermatids older than step 6. The effects of the chemical on adult mice were reversible.

The impact of a 4 cm. cutoff point for stratification of T1N0M0 renal cell carcinoma after radical nephrectomy.

PURPOSE: The 1997 TNM classification defines T1 tumors as those smaller than 7 cm. Recently, a cutoff point of 4 cm. has been proposed to create a subclass of T1 tumors. We evaluated the validity of this cutoff point by assessing the pathological findings and prognoses of patients with T1N0M0 renal cell carcinoma following radical nephrectomy. MATERIALS AND METHODS: We reviewed the hospital charts of 333 patients with T1N0M0 tumors, followed as long as 282 months (median 63) after radical nephrectomy. The validity of tumor size cutoff point for predicting survival outcome was tested in relation to other prognostic factors, including patient age, tumor position, nuclear grade, tumor histopathology and degree of microscopic venous invasion. RESULTS: During followup 32 patients (9.6%) had tumor recurrence and 21 (6.3%) died of renal cell carcinoma. A 5 cm. cutoff point maximized the differences in cancer specific survival rates and a 4 cm. cutoff point maximized the differences in disease-free survival rates. Tumor size was directly related to microscopic venous invasion and nuclear grade, which are significant prognostic factors, and a 4 cm. cutoff point enhanced these relationships. CONCLUSIONS: Tumor size is an important prognostic factor for patients with T1N0M0 renal cell carcinoma. A cutoff point of 4 cm. is practical for dividing the T1N0M0 classification into T1a and T1b subclasses.

IL-17E, a novel proinflammatory ligand for the IL-17 receptor homolog IL-17Rh1.

We report identification of interleukin (IL)-17E, a novel member of the IL-17 family of cytokines. IL-17E is a ligand for the recently identified protein termed EVI27/IL-17BR, which we term IL-17 receptor homolog 1 (IL-17Rh1) in light of the multiple reported ligand-receptor relationships. Murine EVI27 was identified through its location at a common site of retroviral integration in BXH2 murine myeloid leukemias. IL-17Rh1 shows highest level expression in kidney with moderate expression in multiple other organs, whereas IL-17E mRNA was detected at very low levels in several peripheral tissues. IL-17E induces activation of NF-kappaB and stimulates production of the proinflammatory chemokine IL-8.

Acinar cells of the pancreas are a target of interleukin-22.

Interleukin-22 (IL-22) (also reported as IL-10-related T cell-derived inducible factor, IL-TIF) is a recently identified cytokine found to signal through a receptor comprising the class II cytokine receptor family members IL-10Rbeta/CRF2-4 and IL-22R. Previous work has established that IL-10Rbeta, also a component of the IL10R complex, exhibits a broad distribution of mRNA expression. Here, we observe that IL-22R exhibits a restricted expression pattern, with highest levels of mRNA expression in pancreas and detectable expression in multiple other tissues, particularly liver, small intestine, colon, and kidney. We find that isolated primary pancreatic acinar cells and the acinar cell line 266-6 respond to IL-22 with activation of Stat3 and changes in gene transcription. IL-22 mediates robust induction of mRNA for pancreatitis-associated protein (PAP1)/Reg2 and osteopontin (OPN). PAP1 is a secreted protein related to the Reg family of trophic factors and was initially characterized as a protein elevated in pancreatitis. In vivo injection of IL-22 resulted in rapid induction of PAP1 in pancreas, a response not observed in mice deficient in IL-10Rbeta. These results support the conclusion that IL-10Rbeta is a required common component of both the IL-10 and IL-22 receptors and suggest that IL-22 may play a role in the immune response in pancreas.

[Case report of a long-term home parenteral nutrition patient].

We experienced a patient who received long-term home parenteral nutrition. A 55-year-old woman underwent left adrenalectomy in June, 1992. The histopathological diagnosis was aldosteronism. Abdominal pain and ileus appeared in July, 1993, and an adhesiotomy was conducted. Due to poor appetite and weight loss, fluid was sometimes injected peripherally. After abdominal pain in November, 1996 and April, 1997, the ileus reappeared in July, 1997. A Groshong catheter with a port was then inserted through the subclavian vein to the superior vena cava/right atrial junction. Using this catheter, home parenteral nutrition started. Some time later oral nutrition became possible, but now high calorie parenteral nutrition is continued. The only complications were pain and red skin at the port. A Groshong catheter with port is thus useful for home parenteral nutrition.

[Histopathological effect of neoadjuvant chemohormonal therapy for prostatic cancer].

To improve the therapeutic results in prostatic cancer, radical prostatectomy or total cystoprostatectomy were performed with chemohormonal therapy before operation. Radical prostatectomies were conducted in eight patients with localized prostatic cancer and total cystoprostatectomies in ten patients with severe cystic infiltration. The administration schedule of chemohormonal therapy was as follows: prior to operation, 30-60 mg/sqm/day of etoposide was administered for 7 days every 3 weeks, 250-500 mg/day of diethylbestrol diphosphate for 30 days, and 3.6 mg of LH-RH agonist was also administered. Sixteen of the subjects survived, and were socially rehabilitated (14 cases of NED, 1 case of NC and 1 case of PD) and 2 of the subjects died of cancer. Histopathological findings showed 9 cases of poorly differentiated adenocarcinoma, 4 cases of well differentiated adenocarcinoma and 5 cases of moderately differentiated adenocarcinoma. Histopathological effect of neoadjuvant chemohormonal therapy in surgical specimen showed that 2 of the subjects had grade 0a effect, grade 0b in 7 cases, grade 1 in 5 cases and grade 2 in 4 cases.

[Continuous subcutaneous injection therapy with interferon-alpha for renal cell carcinoma patients with bone metastasis].

Thirteen patients with renal cell carcinoma who had proven bony metastases were treated with multimodal treatment including surgery, radiotherapy and immunotherapy in the form of subcutaneous continuous injection of by natural type interferon-alpha (INF). The mode of administration of IFN was as follows: IFN, 2,5000 x 10(4) unit dissolved in 60 ml saline, was continuously injected (0.5 ml/hr) via a subcutaneous route as one course of the treatment and was given two courses in two weeks preoperatively. Postoperatively, IFN was given every week and the number of courses totally amounted to 15. In some cases IFN was given thereafter either every week or every other week. In four patients whose serum concentration of IFN was measured during and after administration of continuous IFN, the concentration of IFN rose after injection and showed 40.5 IU/ml in average 24 hours later. The concentration was kept measurable in six to eight days long and the maximum concentration was 167 IU/ml. In IFN-treated patients nine survived including two CRs, two NCs, five PDs and four deaths. The five year survival rate was 53%. Continuous subcutaneous injection of IFN in combination with surgery and/or radiotherapy is effective in the treatment of bony metastasis from renal cell carcinoma.

[Surgical neoadjuvant chemo-hormonal therapy for advanced prostatic carcinoma].

To improve the therapeutic results as well as the patient's quality of life (QOL) in advanced prostatic carcinoma, total cystprostatectomy or pelvic exenteration was performed in combination with chemo-hormonal therapy before and after operation on twelve patients with stage D2 prostatic carcinoma who had infiltration in the periprostatic organs including urinary bladder and large intestine and showed strong bladder irritation, gross hematuria and ileus symptoms. Eight patients with severe cystic infiltration underwent total cystprostatectomy, urinary division and lymph node dissection, and four with ileus symptoms had pelvic exenteration, urinary division, proctostomy and lymph node dissection. As a rule of dosing schedule for chemo-hormonal therapy, 30-60mg/sq m of etoposide was continuously administered for 5 days before operation in addition to 250-500 mg of diethylbestrol diphosphate given for 30 days after operation. Furthermore, 2-3 courses of 30-60 mg/sq m of etoposide was administered for successive days, at 3-week intervals and then 30-60 mg/sq m of etoposide at 6-to-8-week intervals for 2 years together with 75-100 mg of chrolmadinone acetate as maintenance treatment. Nine of the 12 patients survived, including 4 patients with complete response, 3 patients with partial response and 2 patients with no change. These findings, suggested that the combination of surgical treatment and chemo-hormonal therapy is of use not only for providing an effective therapeutic means but also for improving the QOL in patients with advanced prostatic carcinoma.

[Verrucous carcinoma of the penis: a case report and MRI findings].

A 54-year-old male visited our cancer center with the chief complaint of penile tumor in May, 1992. Magnetic resonance imaging (MRI) demonstrated a penile tumor and showed that this tumor invaded the submucosa but neither corpora cavernosa nor corpus spongiosum. Partial penectomy was performed in June, 1992. Histopathological examination of the resected tumor showed verrucous carcinoma. MRI was useful to investigate the degree of invasion of the penile tumor.

An autopsy case of purulent mycobacterial meningitis in AIDS.

The patient was a 46-year-old male hemophiliac who died of acute mycobacterial meningitis associated with AIDS (acquired immune deficiency syndrome). Autopsy revealed severe basal meningitis which was characterized by an infiltration of numerous polymorphonuclear leukocytes. Severe mural inflammation of the subarachnoid arteries was noted, and innumerable acid-fast bacilli were demonstrated. Epithelioid cell granulomas were not found in the meningeal lesion. The lungs, liver, spleen, and bone marrow contained many epithelioid cell granulomas with caseous necrosis. Massive proliferation of swollen histiocytes could not be identified in any organ. The absence of epithelioid cell granulomas in the meningeal lesion indicate a severe impairment of cell-mediated immunity in the patient; this anergic type of lesion is one of the characteristics of tuberculosis occurring in association with terminal AIDS.

[A case of cytomegalovirus infection that caused gastrointestinal perforation after surgery for cancer of the bladder].

A 78-year-old man visited our department for macroscopic hematuria in June, 1989. On the basis of the diagnosis of tumor of the bladder and right afunctional kidney, total right nephro-uretero-cystectomy and skin grafting of the left ureter were performed on August 2. The patient continued to have fever of unknown origin postoperatively. Repeat laparotomy, which was performed for rectal fistula on August 25, revealed that the abdominal wall, colon, small intestine and mesenterium adhered to one another, producing a mass and that two sites in the rectum were perforated. A part of the small intestine was excised, the perforated sites were sutured, and an artificial anus was created at the transverse colon. Since the patient had intermittent fever and continued to complain of abdominal pain after creation of the artificial anus, nosotropic therapy was continued. However, the patient died from cardiac insufficiency on October 10. Erosion and ulcer were histologically observed over a wide range in the excised small intestine. In addition there was a defect in one area of the small intestine, penetrating the tunca muscularis propria, in which many cytomegalovirus (CMV) inclusion bodies were observed. CMV inclusion bodies were also detected in the bladder with re-examination of specimens from the excised bladder. From these findings, it appears that endogenetic CMV may have been reactivated in the present case.

[Clinical study of bilateral metachronous testicular tumors with different histological findings].

Seventy-seven patients with primary malignant testicular tumors were treated in our hospital. Twenty-five of them were given antineoplastic agents containing cis diamine dichloro platinum (CDDP). In three long-term survivors, new malignant testicular tumors developed meta-chronously and had different histological findings from those of the initial tumors. Case 1. A 28-year-old patient with a yolk sac tumor of the left testicle, stage IIO, developed metastasis to the supraclavicular lymph nodes five years after radiation. Chemotherapy containing of VP-16 (837 mg), CDDP (1050 mg), vincristine (32 mg), bleomycin (480 mg), and actinomycin-D (16 mg) achieved complete remission. Four years 11 months later a seminoma of the contralateral testicle, stage I, was disclosed and he died of cancer 11 years and four months after the onset of the initial disease. Case 2. A 30-year-old patient with testicular teratoma, stage IIIA, on the right side gained complete remission after a CDDP containing chemotherapy. One year and four months after the beginning of the CDDP use (1,300 mg totally as CDDP) a seminoma on the contralateral side, stage I, was detected. He died of cancer eight years and two months after his initial tumor was detected. Case 3. A 37-year-old patient with combined tumor of seminoma and yolk sac tumor of the right testicle, stage IIIO, was free from disease for six years and five months under chemotherapy. At this point a seminoma, stage I, of the contralateral testicle was newly found and treated by radiation.(ABSTRACT TRUNCATED AT 250 WORDS)

[Surgical treatment of renal cell carcinoma with bone metastasis].

Eighty-six patients with renal cell carcinoma underwent radical nephrectomy in Chiba Cancer Center Hospital. Fifteen of the 86 patients developed bone metastases. Seven of the 15 patients with bone metastases had received chemotherapy and radiotherapy. Six of the 15 patients underwent surgical treatment and two received radiotherapy alone. Of the six patients treated surgically for bone metastases, two patients were treated with wide resection and the remaining four patients underwent excision of the metastatic lesions in combination with radiotherapy, chemotherapy or immunotherapy. One of the two patients who underwent wide resection of a pelvic bone lesion is alive without evidence of disease for 6 years and 4 months. Another patient who underwent wide resection of femoral bone lesion survived for 14 years and 2 months but died of recurrent cancer. Pathologic findings of renal cell carcinoma in the long-time survivors showed adenocarcinoma of alveolar type of clear cell subtype and in grade 1. Wide resection of bone metastases of renal cell carcinoma can significantly prolong the survival time and improve the quality of life of the patients.

[Results of the treatment of carcinoma of the renal pelvis and ureter].

Twenty-one patients with renal pelvic carcinoma and eighteen patients with ureteral carcinoma were treated with surgical therapy. In 14 of the 39 patients, we performed nephroureterectomy with a bladder cuff (NUpB), nephroureterectomy with total cystectomy (NUtB) in 12, nephrectomy with partial ureteric resection (NpU) in 8 and others in 5. Following surgery, 8 had recurrences and metastasis and 21 died with carcinoma and 10 survived without evidence of disease. The 5-year survival rate of the patients with renal pelvis carcinoma is 33.5% and 52.0% in ureteral carcinoma.

[A multimodal treatment of prostatic carcinoma and the 5-year survival rate].

One hundred and twenty-nine patients with prostatic carcinoma were treated in our hospital. They were between 49 and 88 (average, 70.3) years old and histological diagnosis was adenocarcinoma in all 129 patients; 42 had well differentiated, 55 moderately differentiated, 31 had poorly differentiated carcinomas, and one undeterminated type. Twenty two patients had stage A carcinoma, 18 stage B, 14 stage C and 75 stage D. As the therapeutic principle no castration was done, radiation therapy was delivered to cases with carcinoma more advanced than stage B in combination with estrogen or alone, and antimetabolites were given to some patients. Cryosurgical procedure to prostate was adjunctively used in patients with dysuria. Since 1986, total prostatectomy was carried out in patients with stage B disease and younger than 60 years old, and total combined resection of the urinary bladder and prostate was performed in patients with more advanced than stage C disease. Etoposide was given to patients with recurrent or metastatic lesions. Twenty-two of the 124 patients who did not receive castration surgery were categorized in stage A, 17 in stage B, 14 in stage C, and 71 in stage D. The 5-year survival rate in each stage group was 100%. 56.2%, 70.0%, and 28.8%, respectively, and the statistical difference between stage A and B, and between stage C and D was respectively significant. The relative 5-year survival rate among the total patient group, 71 patients in stage D, 40 patients in stage D treated with hormone therapy, and 15 patients in stage D treated with radiation therapy was 44.5, 28.7, 18.4 and 36.1%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)