Melanoma lymphoscintigraphy and lymphatic mapping.

Lymphoscintigraphy in melanoma has proven to be a reliable method to identify regional lymph nodes at risk for metastases. The first lymph node to drain a cutaneous lesion, the sentinel lymph node (SLN), is predictive of the metastatic status of the regional lymph node group. Lymphatic mapping allows for the identification of the SLN and for selective lymph node sampling. Selective lymph node sampling is less invasive and because only a small quantity of high-risk tissue is submitted for pathological examination, it allows for a more complete and comprehensive pathological examination, which identifies melanoma with up to 100 times the sensitivity of conventional examinations.

Supramalleolar osteotomy for the treatment of symptomatic tibial malunion.

Supramalleolar osteotomy was performed on eight patients who were symptomatic from a malunion of the distal two-thirds of the tibia. The patient's subjective reports of pain, limp, appearance, instability, and limitation of activity were evaluated pre- and postoperatively. Objective measurements of range of motion, angular deformity, and radiographic signs of ankle arthritis were also evaluated. All of the patients had varus malunion with a mean angulation of 15 degrees. Three of these patients also had sagittal malalignment. Supramalleolar dome or wedge osteotomies were performed to correct the coronal and sagittal plane deformities. Either internal (three patients) or external (five patients) fixation devices were applied to maintain correction. All osteotomies healed. The final mean angulation was 0 degrees in the coronal plane and 8 degrees of recurvatum. Complications included pin tract infections, wound breakdown, failure to completely correct the deformities, and loss of reduction. Seven of the patients reported symptomatic improvement after the procedure. The one patient who had a loss of reduction became more symptomatic.

High-performance liquid chromatographic assay for etoposide in human plasma.

A sensitive, selective reversed phase-high performance liquid chromatographic (HPLC) assay that uses UV detection has been developed for etoposide (4'-demethylepipodophyllotoxin 9-[4,6-O-(R)-ethylidene-beta-D-glucopyranoside) 1. Parent drug is separated from its known metabolites, the cis-picrolactone 2, the hydroxy derivative 3, and the aglycone 4. After the addition of the internal standard (teniposide, 5) to 0.5 mL of plasma, 3 mL of chloroform is added and the sample is centrifuged. The lower organic layer is removed, evaporated in a stream of nitrogen, and reconstituted with 500 microL of mobile phase prior to injection. A phenyl mu Bondapak column (30 cm X 4 mm) and a mobile phase, consisting of 10 microM ammonium acetate (pH 5.5) in methanol:water:acetonitrile (50:45:5), were used to separate the compounds. The flow rate was 2 mL/min. Detection was achieved with a UV monitor set at 230 nm. The aglycone 4, etoposide (1), cis-picrolactone 2, and teniposide (5) had retention times of 3, 4, 4.8, and 9 min, respectively. The extraction efficiency of etoposide ranged from 88 to 94% with a coefficient of variation of 12% at 0.8 micrograms/mL and 4% at 28 micrograms/mL. This assay has an intraday and interday coefficient of variation of 6%, quantitates etoposide at concentrations as low as 0.4 micrograms/mL, and separates etoposide from its known metabolites. The procedure described represents an alternative to a previously published assay that also separated etoposide from its metabolites, but used electrochemical detection.

Electrocardiographic monitoring of patients receiving phase I cancer chemotherapy.

Previous reports have characterized the various non-drug-induced cardiac disorders in cancer patients as well as the cardiotoxicity of commonly used anticancer agents. This study was conducted to determine the non-drug-related incidence of arrhythmias in patients receiving phase I antineoplastics. Twenty-four-hour Holter monitors were placed on 36 consecutive patients about to receive phase I agents. A 1-4-hour baseline was obtained before treatment was begun. Sixty-four percent of the patients observed had a wide variety of ventricular and supraventricular dysrhythmias which did not increase during or after chemotherapy. Eighty-four percent of these arrhythmias were not detected during routine monitoring consisting of baseline 12-lead ECGs and 1-minute rhythm strips prior to, during, and after treatment, but were detected with the Holter monitor. Thirty-six percent of the dysrhythmias detected by the Holter monitor were considered potentially treatable arrhythmias requiring further evaluation and possible therapeutic intervention. During the early development of phase I agents, careful evaluation should be exercised so as not to confuse pre-existing, undiagnosed arrhythmias with drug-induced changes. To more accurately determine the true arrhythmogenic potential of phase I agents, Holter monitoring should be considered as a standard part of patient assessment prior to entry of a patient in phase I trials.

Pharmacokinetic study of fludarabine phosphate (NSC 312887).

Characterization of the pharmacokinetics of 2-FLAA has been completed in seven patients receiving 18 or 25 mg/m2 daily X 5 of 2-FLAMP over 30 min. Assuming 2-FLAMP was instantaneously converted to 2-FLAA, the plasma levels of 2-FLAA declined in a biexponential fashion. Computer fitting of the plasma concentration-time curves yielded an average distribution half-life (t1/2 alpha) of 0.60 h and a terminal half-life (t1/2 beta) of 9.3 h. The estimated plasma clearance was 9.07 +/- 3.77 l/h per m2 and the steady state volume of distribution, 96.2 +/- 26.0 l/m2. There was a significant inverse correlation between the area under the curve (AUC) and absolute granulocyte count (r = -0.94, P less than 0.02). A relationship between creatinine clearance and total body clearance was noted, but was not statistically significant (r = 0.828; P less than 0.1). Approximately 24% +/- 3% of 2-FLAA was excreted renally over the 5-day course of drug administration.

Phase I evaluation and pharmacokinetics of tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC 286193).

Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, TCAR, Riboxamide, NSC 286193) is a novel C-nucleoside with antitumor activity against several murine tumor models, including Lewis lung carcinoma. The mechanism whereby this compound exerts its antineoplastic effects is most likely related to a state of guanine nucleotide depletion whereby the anabolite, thiazole-4-carboxamide adenine dinucleotide, potently inhibits inosine-5'-monophosphate dehydrogenase. This Phase I study was designed to determine the maximally tolerated dose of Tiazofurin administered on a 5-day, every-28-day schedule. Tiazofurin levels were measured using a high-pressure liquid chromatography assay, and pharmacokinetic studies were performed in patients treated at each dose level. Nineteen patients received a total of 24 courses of the drug in doses ranging from 550 to 2200 mg/sq m. The dose-limiting toxicities were pleuropericarditis and a general illness best described as a "viral-like" syndrome (manifested by severe malaise, headaches, myalgias, fever, nausea, vomiting, and diarrhea). Other toxicity included myelosuppression, hyperuricemia, elevated serum creatine phosphokinase and serum glutamic oxaloacetic transaminase, conjunctivitis, mucositis, and desquamation of the palms of the hands. Plasma clearance of Tiazofurin followed a biexponential pattern with a harmonic mean terminal half-life of 7.6 h. The mean volume of distribution at steady state was 30 liters/sq m, and the mean plasma clearance was 3 liters/h/sq m. The total cumulative urinary excretion ranged from 15 to 49%. The maximally tolerated dose of Tiazofurin on a 5-day schedule was 1650 mg/sq m. The recommended dose for Phase II evaluations is 1100 mg/sq m for 5 days. However, exploration of other schedules which might allow administration of more Tiazofurin combined with biochemical studies including thiazole-4-carboxamide adenine dinucleotide measurements would be desirable.

Pharmacokinetics of high dose melphalan.

A pharmacokinetic study of high dose intravenous melphalan, 180 mg/m2, was performed in eight patients. Plasma levels of melphalan declined in a biexponential fashion with a mean terminal half-life (t 1/2 beta) of 61 min (range 40.3-132.8 min). Estimated peak concentrations ranged from 5.45 to 16.57 mcg/ml. The average volume of distribution at steady state (Vdss) and clearance were 0.479 +/- 0.164 l/kg and 6.73 +/- 1.60 ml/min/kg, respectively. These kinetic parameters are similar to those reported from studies using lower doses of melphalan.