Monoclonal antibodies to Kaiso: a novel transcription factor and p120ctn-binding protein.

The POZ-zinc finger protein Kaiso belongs to a rapidly growing superfamily of BTB/POZ zinc finger transcription factors implicated in embryonic development and cancer. Kaiso interacts with the catenin p120(ctn), but the significance of the interaction remains unknown. Although p120(ctn) is normally found in association with E-cadherin at cell-cell junctions, it can translocate to the nucleus under certain circumstances. Thus, the p120(ctn)-Kaiso interaction may regulate transcriptional events, as has been described previously for the classical catenin, beta-catenin and the LEF1/TCF transcription factor. To facilitate further study of Kaiso and to determine the physiological relevance of its interaction with p120(ctn), we have generated and characterized a panel of five Kaiso-specific monoclonal antibodies (MAbs) that function in immunoblotting, immunoprecipitation, and immunofluorescence analyses.

Successful treatment of severe hemorrhagic cystitis with cystectomy following matched donor allogeneic hematopoietic cell transplantation.

We report a case of severe hemorrhagic cystitis complicating high-dose cyclophosphamide (CY), total body irradiation and allogeneic hematopoietic stem cell transplantation (HSCT). Supportive care with i.v. hydration, platelet transfusions, continuous bladder irrigation and aluminum irrigation of the bladder was ineffective and the patient developed multiple complications from hemorrhagic cystitis. His condition became critical with persistent bleeding, pulmonary edema and acute renal failure. These problems resolved following successful simple cystectomy and ileal conduit. The patient did not develop any acute or chronic complications following surgery. He is alive with a good quality of life and in third remission after receiving salvage chemotherapy 14 months after his transplantation.

Infusion of dendritic cells pulsed with HLA-A2-specific prostate-specific membrane antigen peptides: a phase II prostate cancer vaccine trial involving patients with hormone-refractory metastatic disease.

BACKGROUND: A phase II trial was conducted to assess the efficacy of infusions of dendritic cells (DC) and two HLA-A2-specific PSMA peptides (PSM-P1 and -P2). This report describes thirty three subjects with hormone-refractory metastatic prostate cancer without prior vaccine therapy history who were evaluated and reported as a group. METHODS: All subjects received six infusions of DC pulsed with PSM-P1 and -P2 at six week intervals. Clinical monitoring was conducted pre-, during, and post- phase II study. Data collected include: complete blood count, bone and total alkaline phosphatase, prostate markers, physical examination, performance status, bone scan, ProstaScint scan, chest x-ray, as well as assays to monitor cellular immune responses. RESULTS: Six partial and two complete responders were identified in the phase II study based on NPCP criteria, plus 50% reduction of prostate-specific antigen (PSA), or resolution in previously measurable lesions on ProstaScint scan. CONCLUSIONS: Over 30% of study participants in this group showed a positive response at the conclusion of the trial. This study suggested that DC-based cancer vaccines may provide an alternative therapy for prostate cancer patients whose disease no longer responds to hormone therapy.

Evaluation of phase I/II clinical trials in prostate cancer with dendritic cells and PSMA peptides.

BACKGROUND: A phase I trial involving patients with advanced prostate cancer was conducted to assess the safe administration of dendritic cells (DC) and HLA-A0201-specific prostate-specific membrane antigen (PSMA) peptides (PSM-P1 or -P2). Thirty-three of the phase I participants were subsequently enrolled in a phase II trial, which involved six infusions of DC pulsed with PSM-P1 and -P2 peptides. METHODS: Clinical monitoring was conducted up to 770 days from the start of the phase I study. Data collected included: complete blood count, bone and total alkaline phosphatase, prostate markers, physical examination, performance status, bone scan, ProstaScint scan, and chest X-ray, as well as assays to monitor cellular immune responses. RESULTS: Nine partial responders were identified in the phase II study based on National Prostate Cancer Project (NPCP) criteria, plus 50% reduction of prostate-specific antigen. Four of the partial responders were also responders in the phase I study, with an average response duration of 225 days. Their combined average total response period was over 370 days. Five other responders were nonresponders in the phase I study. Their average partial response period was 196 days. CONCLUSIONS: The responses observed in the phase I and II clinical trials were significant and of long duration. The partial-responder group included patients who continued to respond from phase I, as well as those who started to respond during the phase II trial.

Follow-up evaluation of prostate cancer patients infused with autologous dendritic cells pulsed with PSMA peptides.

BACKGROUND: We recently conducted a phase I clinical trial administering autologous dendritic cells pulsed with prostate-specific membrane antigen (PSMA) peptides to advanced prostate cancer patients. Participants were divided into 5 groups receiving 4 or 5 infusions of peptides alone (PSM-P1 or -P2; groups 1 and 2, respectively), autologous DC (group 3), or DC pulsed with PSM-P1 or -P2 (groups 4 and 5, respectively). Seven partial responders were observed. Follow-up evaluation of these responders is presented in this report. METHODS: Clinical monitoring for hematological studies and prostate markers was conducted up to 370 days from the start of the phase I study. Data collected include: lymphocyte, hematocrit, alkaline phosphatase, prostate-specific antigen (PSA), free PSA, and PSMA levels. RESULTS: Groups 4 and 5 (patients infused with DC pulsed with PSM-P1 or -P2) represented 5/7 responders. The length of response was between 100 days (1 patient) to 200 days or above (6 patients). Four patients still remained responsive at the end of the period of observation. CONCLUSIONS: The responses observed in this phase I clinical trial are significant and of long duration. Most of the responders were in treatment groups infused with DC pulsed with PSM-P1 or -P2, suggesting the requirement of both components for effective immunotherapy.

Intrathecal methadone and morphine for postoperative analgesia: a comparison of the efficacy, duration, and side effects.

A double-blind study of patients selected at random compared the analgesic and adverse effects of intrathecal methadone (1 mg) with those of intrathecal morphine (0.5 and 1 mg). The study was conducted on 30 patients who underwent major orthopedic or urologic surgery. The intrathecal opioid was administered at the end of surgery, and assessments began 1 h thereafter and continued for 20 h. Pain measurements, supplementary analgesia requirements, and adverse effects were recorded. Intrathecal morphine (0.5 and 1 mg) provided effective and prolonged analgesia. Methadone, however, was unable to ensure the same degree of analgesia; consequently, the median pain scores were consistently higher following methadone than morphine (0.5 and 1 mg) (P less than 0.05). The time to the onset of discomfort severe enough to require supplemental morphine was longer after intrathecal morphine than that following methadone (24 and 29 h with morphine 0.5 and 1 mg; 6.5 h with methadone; P less than 0.05). Respiratory depression (increases PaCO2) was not associated with methadone and morphine 0.5 mg but was common following morphine 1 mg (P less than 0.05). Facial pruritus was unique to intrathecal morphine. Urinary retention requiring bladder catheterization was more frequent following morphine than methadone, although this was not statistically significant. Nausea and vomiting were common to all groups. Intrathecal morphine (0.5 and 1 mg) provides superior postoperative analgesia to 1 mg methadone. Various explanations for the observed differences between the drugs are discussed, including the possibility that the dose of methadone used in the subarachnoid space was inadequate and that a larger dose might have produced an effect equal to that of morphine.

Transitional cell carcinoma of the urinary bladder: histologic clearance with combined 5-FU chemotherapy and radiation therapy. Preliminary results of a bladder-preservation study.

Fourteen patients with transitional cell carcinoma of the urinary bladder were treated with 4,000 cGy of pelvic irradiation concurrent with two 96-hour infusions of 5-fluorouracil (5-FU). Three weeks after completion of this regimen, patients underwent repeat cystoscopy and deep-muscle biopsy at the site of their original neoplasms. Eight of 14 (57%) had no tumor left in the biopsy specimen, and they received an additional course of chemotherapy and radiation therapy to a total dose of 4,400 cGy to the pelvis and 6,000 cGy to the bladder. Five of the 14 had residual tumor in the biopsy specimen (one did not undergo biopsy) and went on to planned cystectomy. Two of the five had no tumor in the cystectomy specimen. Overall, ten of the 14 patients (71%) have been downstaged to a condition of P0 (no tumor) following 4,000 cGy and two courses of 5-FU. Of eight patients with retained bladders, seven remain well at a median follow-up of 7 months. At a range of follow-up of 3-21 months and a median of 7 months, 13 of 14 patients remain tumor-free. This regimen results in a greater percentage of downstaging than conventional irradiation alone, and may allow bladder preservation for those with radiation therapy- and chemotherapy-responsive tumors.