AZD3514, an oral selective androgen receptor down-regulator in patients with castration-resistant prostate cancer - results of two parallel first-in-human phase I studies.

BACKGROUND: AZD3514 is a first-in-class, orally bio-available, androgen-dependent and -independent androgen receptor inhibitor and selective androgen-receptor down-regulator (SARD). METHODS: In study 1 and 2, castration-resistant prostate cancer (CRPC) patients (pts) were initially recruited into a once daily (QD) oral schedule (A). In study 1, pharmacokinetic assessments led to twice daily (BID) dosing (schedule B) to increase exposure. Study 2 explored a once daily schedule. RESULTS: In study 1, 49 pts were treated with escalating doses of AZD3514 (A 35 pts, B 14 pts). Starting doses were 100 mg (A) and 1000 mg (B). The AZD3514 formulation was switched from capsules to tablets at 1000 mg QD. 2000 mg BID was considered non-tolerable due to grade (G) 2 toxicities (nausea [N], vomiting [V]). No adverse events (AEs) met the dose-limiting toxicity (DLT) definition. Thirteen pts received AZD3514 in study 2, with starting doses of 250 mg QD. The most frequent drug-related AEs were N: G1/2 in 55/70 pts (79 %); G3 in 1 pt (1.4 %); & V: G1/2 in 34/70 pts (49 %) & G3 in 1 pt (1.4 %). PSA declines (≥50 %) were documented in 9/70 patients (13 %). Objective soft tissue responses per RECIST1.1 were observed in 4/24 (17 %) pts in study 1. CONCLUSION: AZD3514 has moderate anti-tumour activity in pts with advanced CRPC but with significant levels of nausea and vomiting. However, anti-tumour activity as judged by significant PSA declines, objective responses and durable disease stabilisations, provides the rationale for future development of SARD compounds.

Randomised phase III study of neoadjuvant chemotherapy with methotrexate, doxorubicin, vinblastine and cisplatin followed by radical cystectomy compared with radical cystectomy alone for muscle-invasive bladder cancer: Japan Clinical Oncology Group Study JCOG0209.

BACKGROUND: This study aimed to determine the clinical benefit of neoadjuvant methotrexate, doxorubicin, vinblastine, and cisplatin (MVAC) in patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy. PATIENTS AND METHODS: Patients with MIBC (T2-4aN0M0) were randomised to receive two cycles of neoadjuvant MVAC followed by radical cystectomy (NAC arm) or radical cystectomy alone (RC arm). The primary end point was overall survival (OS). Secondary end points were progression-free survival, surgery-related complications, adverse events during chemotherapy, proportion with no residual tumour in the cystectomy specimens, and quality of life. To detect an improvement in 5-year OS from 45% in the RC arm to 57% in the NAC arm with 80% power, 176 events were required per arm. RESULTS: Patients (N = 130) were randomly assigned to the RC arm (N = 66) and the NAC arm (N = 64). The patient registration was terminated before reaching the initially planned number of patients because of slow accrual. At the second interim analysis just after the early stoppage of patient accrual, the Data and Safety Monitoring Committee recommended early publication of the results because the trial did not have enough power to draw a confirmatory conclusion. OS of the NAC arm was better than that of the RC arm, although the difference was not statistically significant [hazard ratio 0.65, multiplicity adjusted 99.99% confidence interval 0.19-2.18, one-sided P = 0.07]. In the NAC arm and the RC arm, 34% and 9% of the patients had pT0, respectively (P < 0.01). In subgroup analyses, OS in almost all subgroups was in favour of NAC. CONCLUSIONS: This trial showed a significantly increased pT0 proportion and favourable OS of patients who received neoadjuvant MVAC. NAC with MVAC can still be considered promising as a standard treatment. UMIN CLINICAL TRIALS REGISTRY IDENTIFIER: C000000093.

[The role of tumor markers in the treatment of germ cell tumor].

Alfa fetoprotein (AFP), human chorionic gonadotropin (HCG), beta HCG and lactate dehydrogenase (LDH) are powerful markers of germ cell tumors. The role of tumor markers is very important in the diagnosis, treatment and follow-up of germ cell tumors, respectively. We can often deduce the histological typing of germ cell tumors by tumor marker elevation before surgery. Tumor markers also frequently provide clues as to outcome in individual cases before treatment. The half-life of tumor markers during chemotherapy indicate the effect of the treatment. The optimal regimen of chemotherapy should therefore be selected based on the half-life of tumor markers. Normalized tumor markers designate the phase of discussion on surgical indications. Determination of tumor markers is important in following patients after treatment of germ cell tumors. The elevation of serum tumor markers denotes recurrence and is often the first sign of treatment failure.

Allelic loss on chromosome 9 in bladder cancer tissues and urine samples detected by blunt-end single-strand DNA conformation polymorphism.

Allelic loss on chromosome 9 is the most frequent and earliest genetic event in bladder carcinogenesis, and its detection in urine samples would be useful for detecting bladder cancer. A highly sensitive method to detect loss of heterozygosity (LOH) at 5 polymorphic loci on chromosome 9p and 9q was developed by the use of blunt-end single-strand DNA conformation polymorphism (blunt-end SSCP) analysis. Tumor tissues, urine samples and peripheral blood lymphocytes from 34 patients with transitional cell carcinoma of the bladder were analyzed. LOHs on 9p and/or 9q were found in 24 (71%) of 34 tumor samples and 23 (70%) of 33 urine samples, while no allelic loss was detected in 20 urine samples from benign urothelial diseases. The frequency of allelic loss in tumor tissues was 67%, 71% and 80% in the pTa, pT1 and > or = pT2 stages and 50%, 80% and 79% in G1, G2 and G3 tumors, respectively. In comparison with a urine cytological examination, LOH on chromosome 9 was detected in 70% of urine samples diagnosed as transitional cell carcinoma, 67% of those as atypia and 70% of those as no malignant cells. Thus, detection of LOH on chromosome 9 from urine samples by blunt-end SSCP is a more sensitive diagnostic modality than cytologic examination for detecting bladder cancer. It would be useful for postoperative management of bladder cancer, particularly when the allelic loss is revealed in the tumor tissues obtained at first surgery.

[Significance of transrectal ultrasound and sextant systematic core biopsy for performing radical prostatectomy].

BACKGROUND: To estimate the usefulness of sextant systematic core biopsy or transrectal ultrasonography (TURS) for performing radical prostatectomy. METHODS: The findings of sextant biopsy and TRUS were compared with 52 step-sectioned specimens obtained from radical prostatectomy. RESULTS: In 34 cases with no influence of hormonal therapy at the time of TRUS and biopsy, sextant systematic core biopsy provided tumor distribution rather precisely. In 33% of the cases who had received hormonal therapy, tumor cells were not detected by this sextant biopsy series. In these cases, majority of residual cancer existed in transition zone, paraurethral or fibromuscular stroma. Six cases showed small adenocarcinoma in only one biopsy tip obtained from sextant biopsy, while 4 cases were revealed well differentiated adenocarcinoma (Gleason score less than 4) by these core biopsies. Comparing with tumor mapping, Gleason score, PSA level and pT stage of the radical prostatectomy specimens, these tumors presented as, not clinically insignificant, but clinically significant prostate cancer. Playing special attention to distraction of normal ultrasound zonal configuration, TRUS detected neurovascular invasion with 94.7% sensitivity, 78.3% positive predictive value and 90. 9% negative predictive value, while seminal vesicle invasion with 75% sensitivity, 50% positive predictive value, 90.9% negative value. CONCLUSION: Sextant biopsy tended to underestimate the tumors located in the transition zone, paraurethral and fibromuscular lesion. Additional or direct biopsies in transition zone are indispensable for accurate diagnosis. Findings of TRUS and distribution of positive core biopsy from sextant biopsy enable to extract stage C prostate cancer providing negative surgical margin.

[Prognosis after radical surgery in prostatic cancer patients with lymph nodes metastases].

We investigated prognosis of clinically localized prostatic adenocarcinoma patients who revealed to have had lymph nodes metastases by undergoing radical surgery. Eighty six patients were operated during the last 15 years under the clinical diagnosis of A2, 9 patients, B1, 15 B2, 13 and C, 49, respectively. Total prostatectomy was done to 51, total cystoprostatectomy to 33 and total pelvic excentration to 2 patients. Of these patients, 22.2% with stage A2, 20.2% with B1, 7.7% with B2 and 43.8% with C had positive nodes and the rate of positive nodes in stage C was significantly higher than that in other stages (p < 0.01). Regarding histological differentiation, 15.4% of well, 23.7% of moderate and 51.6% of poor by differentiated had positive nodes and the rate of positive nodes in poor by differentiated was significantly higher (p < 0.01). In 2 of 21 cases whose lymph nodes were dissected to the level of the aortic bifurcation, positive nodes were detected only in the external and common iliac areas. These two cases were missed, i.e., "false negative" if limited nodes dissection was performed. All patients with positive nodes were treated with hormonal therapy. The 5-year cancer specific survival rate of patients with positive (n = 27) and negative (n = 59) nodes were 66.4% and 92.4%, respectively. The prognosis of patients with positive nodes were significantly worse than that of patients with negative nodes (p < 0.001). Among 27 patients with positive nodes, significant prognostic factor was not number or extent of positive nodes, but histological differentiation.(ABSTRACT TRUNCATED AT 250 WORDS)

[Effect of combination chemotherapy for elderly patients with malignant lymphoma].

The remedial effect in elderly patients with malignant lymphoma in two groups treated with combination chemotherapy, one including doxorubicin (ADM) (A group) and the other excluding ADM (V group) were compared. Forty patients aged 65 years or more with malignant lymphoma were entered from January 1982 to December 1991. The A group was made up of 10 patients and the V group of 18 patients. As to pathological classification, two of the A group had low grade malignancy lymphoma, four had intermediate grade and three had high grade. Four of the V group had low grade, eight had intermediate grade and five had high grade. In terms of clinical stage, three of the A group were in stage II, 3 in stage III and 4 in stage IV. Two of the V group were in stage II, 7 in stage III and 9 in stage IV. The effective rate for the A group was 90% and the V group was 61%. The survival rate over five years in the A group was 37.5% and 21.8% in the V group. There were no adverse effects on the cardiovascular system in the A group. No significant differences of effects were shown in this study, however, the A group showed a higher tendency in terms of the CR rate and the survival rate. Cases of early death during chemotherapy were few and the quality of life of the patients was raised by discharge in the A group. Combination chemotherapy including ADM appears to be satisfactory in aged patients with malignant lymphoma.

[Optimal way of administration of granulocyte colony stimulating factor in the treatment of urological cancer].

Granulocyte-Colony Stimulating Factor (G-CSF) was administered to patients with bladder cancer, ureteral cancer and testicular cancer following chemotherapy. Chemotherapy included 23 courses of M-VAC (Methotrexate, Vinblastine, Adriamycin, Cisplatin) therapy to patients with bladder cancer or ureteral cancer and 10 courses of EP (Etoposide, Cisplatin) therapy to patients with testicular cancer. During M-VAC chemotherapy, about a half of the patients experienced leukopenia below 3000/mm3 until the 11th day. Leukopenia failed to improve promptly when G-CSF was started after leukocytes decreased below 3000/mm3. On the other hand, 5-days of prophylactic administrations of G-CSF from the 9th day of M-VAC therapy were able to increase leukocytes promptly. In EP chemotherapy against testicular tumor, G-CSF was started on the 9th day and continued for 5 days. Leukocytes increased immediately and the average duration of leukopenia below 3000/mm3 was only 1.2 day. These results indicate that a short term of prophylactic administration of G-CSF following these chemotherapies is able to accelerate a recovery from leukopenia and decrease a risk of bacterial infection. G-CSF is proposed to be enrolled in the treatment of urological cancer for the improvement of safety and the outcome of therapy.

[Fertility after treatment for testicular tumor].

Thirty-four patients with stage 1 or stage 2A testicular tumor all survived 5 years after the treatment, whereas eighteen patients with stage 2B or 3 testicular tumor, including only nonseminomatous tumor, had a 5-year survival rate of less than 50%. Spermatogenesis returned to normal in 3 patients surviving 22 months after chemotherapy. Five patients who had undergone retroperitoneal lymph node dissection with division of the inferior mesenteric artery developed impaired ejaculation, whereas 3 patients who had undergone the operation without division of the inferior mesenteric artery had normal ejaculation. In 17 patients with right testicular tumor metastases were found in the para-aortic, paracaval and interaortocaval lymph nodes. On the other hand, in 4 patients with left testicular tumor metastases were limited to the para-aortic nodes. These results indicate that impaired spermatogenesis by conventional chemotherapy is reversible in patients with stage 1 or 2 testicular tumor, and patients with stage 1 tumor or stage 2 tumor with localized para-aortic metastases, not involving the inferior mesenteric artery, should undergo retroperitoneal lymph node dissection without division of the inferior mesenteric artery to preserve postoperative fertility.

Macrophage colony-stimulating factor (M-CSF) enhances complement component C3 production by human monocytes/macrophages.

The third complement component, C3, is an important factor in the host defense mechanism in which monocytes/macrophages participate as the primary phagocytes. Monocytes/macrophages are the principal extrahepatic producers of C3, and this C3 production is thought to be regulated by several cytokines. In the present study, we demonstrated that human macrophage colony-stimulating factor (M-CSF) enhanced C3 production by human peripheral monocytes in serum-free culture. Analytical immunoblot and ELISA showed that the presence of M-CSF increased the production of intracellular pro-C3 and extracellular C3 for 24 h in a dose-dependent manner. To confirm the rapid effect of M-CSF on C3 production, we performed metabolic labeling of C3 with [35S]methionine. The production of [35S]C3 for the first 6 h in the presence of M-CSF was also increased as compared to that in the absence of M-CSF. In addition to the previously reported effects of M-CSF on monocytes/macrophages, such as the enhancement of C3 receptor expression and C3 receptor-mediated phagocytosis, we consider that the effects of M-CSF demonstrated in this study are of importance in the local immune system organization of C3 and monocytes/macrophages.

[Multiple myeloma with a mass formation in a pacemaker pocket].

A 74-year-old female was diagnosed as having multiple myeloma in August 1989 and was treated with combined vincristine, melphalan and prednisolone. Subsequently, she was followed followed up in the outpatient clinic using interferon-alpha. On August 6, 1990, she had a transvenous demand pacemaker inserted because of severe atrioventricular block. The pulse generator was placed in a subcutaneous pocket in the left pectoral area. On February 3, 1991, she developed a mass overlying the pulse generator. This tumor was diagnosed as plasmacytoma by histological examinations. A myelogram showed 5.1% plasma cells with 5.5 x 10(4) nucleated cells/microliter. The amounts of serum protein and IgA M protein were 6.8 g/dl and 1.8 g/dl, respectively. The tumor responded to combined chemotherapy, but reenlarged to the initial size 3-4 weeks later. On August 6, 1991, this tumor, including the pulse generator was removed. By October 1991, the patient had systemic subcutaneous tumors and a right maxillary tumor suggesting the aggressive phase. On December 19, 1991, she died due to cardiac failure. In this paper the discussion focussed on the etiopathogenesis of plasmacytoma arising in the region of pulse generator pockets.

Trisomy 4 in a case of acute lymphocytic leukemia (L1).

Trisomy 4 has been identified previously as a chromosome abnormality associated with acute nonlymphocytic leukemia (ANLL) with myelomonocytic lineage and in myelodysplastic syndromes (MDS). We report a case of acute lymphocytic leukemia (ALL) (French-American-British, FAB L1) in a 42-year-old Japanese man, with trisomy 4 as the sole chromosomal anomaly. Immunophenotypically, the leukemic blasts demonstrated reactivity with CD2, CD5, and CD7 and indicated on early stage of T cell.