Pharmacokinetic profile of Mitoguazone (MGBG) in patients with AIDS related non-Hodgkin's lymphoma

Summary Mitoguazone is a unique chemotherapeutic agent whose activity is believed to result primarily from the competitive inhibition of S-adenosyl-methionine decarboxylase leading to a disruption in polyamine biosynthesis. Initial clinical trials demonstrated that the dose-limiting toxicities (mucositis and myelosuppression) of Mitoguazone were both dose and schedule dependent. Early pharmacokinetic studies of Mitoguazone in man revealed a prolonged half-life. Concurrent with a recent Phase II trial of Mitoguazone in patients with AIDS related non-Hodgkin's lymphoma, the single dose pharmacokinetics of Mitoguazone were characterized. Twelve patients received 600 mg/m² of intravenous Mitoguazone over 30 minutes on an intermittent every 2 week schedule. Blood, urine, cerebrospinal fluid (CSF), pleural fluid and tissue samples were collected and analyzed by HPLC. Mitoguazone was cleared from the plasma triexponentially with a harmonic mean terminal half-life of 175 hours and a mean residence time of 192 hours. Peak plasma levels occurred immediately post-infusion, ranged from 6.47 to 42.8 g/ml, and remained (for an extended period) well above the reported concentration for inhibition of polyamine biosynthesis. Plasma clearance averaged 4.73 l/hr/m² with a relatively large apparent volume of distribution at steady-state of 1012 l/m² indicating tissue sequestration. Renal excretion of unchanged Mitoguazone accounted for an average of 15.8% of the dose within 48 to 72 hours post-administration. Detectable levels of drug were present in random voided samples eight days post-dose. Mitoguazone levels in CSF ranged from 22 to 186 ng/ml post-dose with CSF/plasma ratios ranging from 0.6% to 7%. The pleural fluid/plasma ratio was approximately 1. Tissue levels of Mitoguazone were highest in the liver followed by lymph node, spleen and the brain.     

The Use of Transureteroureterostomy in the Management of Complex Ureteral Problems

Purpose

Transureteroureterostomy has primarily been performed for benign disease in children with reflux or undergoing undiversion, and in adults with lower ureteral injury. We report the use of transureteroureterostomy for other than these traditional indications, including malignant disease.

Materials and Methods

Transureteroureterostomy was performed in 6 patients at the time of tumor resection to bypass large ureteral defects and in 4 as a secondary operation, usually associated with a ureteral leak after previous surgery.

Results

Complications related to transureteroureterostomy included 1 ureteral stricture and 1 ureteral leak. Good renal function was maintained with a mean followup of 77.9 months.

Conclusions

Our experience suggests that transureteroureterostomy can be useful for urinary diversion when a segment of lower ureter is involved with malignant disease.     

Bladder calcifications after photodynamic therapy: Analysis of a rare complication

Objectives

We analyzed bladder calcifications occurring after photodynamic therapy administered for the treatment of superficial bladder cancer, a finding not previously reported after this treatment.

Methods

Bladder biopsies from 20 patients undergoing photodynamic therapy were evaluated. Bladder calcifications were identified in 2 patients and analyzed for composition.

Results

One patient had diffuse microcrystalline deposition in two biopsies composed of calcium oxalate monohydrate A. A second patient had a focal stone at a healing biopsy site composed of monoclinic calcium hydrogen phosphate dihydrate (brushite) (66%), calcium oxalate (25%), hydroxyapatite (6%), and protein (3%).

Conclusions

Rare calcium oxalate and brushite calcifications were identified after photodynamic therapy and presumed to occur because of tissue injury associated with treatment.     

Diagnosis of pericardial cyst in a young child by computed tomography of the thorax

Computed tomography can be very useful in the assessment of mediastinal masses in children. In this case, it provided for the specific diagnosis of a pericardial cyst in a young child, obviating the need for invasive evaluation or surgery.     

Human genetics and transplantation]

Transplantations represent an important element of treatment in end-stage chronic disease both inborn (mostly genetic) and acquired (degenerative, neoplastic). They are supposed to establish durable coexistence of cells with different genetic origin (in most cases). This union is contradictory to immunological properties of the tissues involved and can only succeed in case of sufficient histocompatibility to be identified by the diagnostic tests of immunogenetics. This review discusses the current approach used in choosing the most appropriate donor for an individual patient, and in monitoring the maintenance of "chimerism" established by the transplantation focussing on bone marrow transplantation. Initially a general outline of indications for organ transplantation is given with emphasis laid on genetic disorders as the outlook of conservative treatments in inborn diseases is generally very poor.     

Long-term observation of chronic subsutaneous administration of lisuride in the treatment of motor fluctuations in parkinson's disease

Summary Twenty-nine patients with advanced Parkinson's disease were treated with subcutaneous lisuride infusion in addition to a basic therapy consisting of levodopa + PDI in all, and deprenyl in some patients. At the time of the report, 13 patients are still receiving lisuride infusion after 5–36 months, while 16 have dropped out after 0.5–30 months one because of psychosis, three because of insufficient efficacy, three due to death unrelated to treatment, three because of difficulties in handling the pump as outpatients, and six for other reasons. Off-periods and parkinsonian disability in off and in on were reduced significantly. These improvements remained constant throughout the observation period. Once the optimal dose regimen is established, only minor adjustments of the doses of lisuride and levodopa are required in the individual case.     

Evaluation of the HCFA model for the analysis of mortality following hospitalization.

From 1987 through 1990, the Health Care Financing Administration (HCFA) evaluated variations in the mortality rates experienced by patients admitted to hospitals participating in the Medicare program. This study was conducted to evaluate the adequacy of the model used for that purpose. Detailed clinical data were gathered on 42,773 patients admitted to 84 statistically selected hospitals. The effect of risk adjustment using the HCFA model, which is based on claims data, was compared to a risk-adjustment model based on physiologic and clinical data. Models that include claims data were markedly superior to those containing only demographic characteristics in predicting the probability of patient death, and the addition of clinical data resulted in further improvement. The correlation of ranks of hospitals based on a model that uses only the claims data and on one that uses, in addition, clinical data, was .91. As a screen for the identification of "high (mortality) outlier" hospitals, the claims model had moderate sensitivity (81 percent) and specificity (79 percent), a high negative predictive value (90 percent), and a low positive predictive value (64 percent) when compared to the clinical model. The two mortality models gave similar results when used to determine which structural characteristics of hospitals were related to mortality rates: hospitals with a higher proportion of registered nurses or board-certified physician specialists, or with a greater level of access to high-technology equipment had lower risk-adjusted mortality rates. These data suggest that the current claims-based risk-adjustment procedure may satisfactorily be used to characterize variations in mortality rates associated with hospitalization. The procedure could also be used as a basis for further epidemiological analyses of factors that affect the probability of patient death. However, it does not positively identify outlier hospitals as providers of problematic care.     

The impact of the “cisplatin era” of treatment on survival in testicular cancer

Summary The records of all testicular cancer patients evaluated and treated at our medical center during two consecutive 9-year periods were reviewed and analyzed for prognostic factors, particularly the impact of cisplatin-based combination chemotherapy. The data base of 244 patients was divided into two eras: 1970–1978, defined as the pre-cisplatin era (n=101) and 1979–1987, the cisplatin era (n=143). Statistically improved survival (P=0.024) was noted for the 165 nonseminoma patients and for a grouping of 143 patients treated with combination chemotherapy (P=0.004) during the cisplatin era. Stratification by stage revealed that stage II patients had the most significant survival advantage (P=0.001) during the cisplatin era; cancer mortality improved from 48% to 9%. Cancer death rates for stage III patients decreased from 58% to 39% which is clinically but not statistically significant (P=0.497). Stage I patients and the seminoma population did well during both eras, and the impact of cisplatin could not be statistically confirmed in this study for these subgroups. Multivariate statistical analysis confirmed the importance of the era of treatment for the nonseminoma population.