Thyroid nodules in xeroderma pigmentosum patients: a feature of premature aging.

PURPOSE: Xeroderma pigmentosum (XP) is an autosomal recessive disease with defective DNA repair, a markedly increased risk of skin cancer, and premature aging. Reports from North Africa have described thyroid nodules in XP patients, but thyroid nodule prevalence has never been determined in XP patients enrolled in our natural history study at the National Institutes of Health (NIH). METHODS: We performed thyroid ultrasound examinations on all 29 XP patients examined from 2011 to 2019 and assessed nodule malignancy using the Thyroid Imaging Reporting and Data System. Thyroid nodule prevalence was also obtained from comparison cohorts. DNA sequencing was performed on thyroid tissue from XP patients who had surgery for thyroid cancer. RESULTS: Thyroid nodules were identified in 18/29 XP patients (62%). The median age of patients with thyroid nodules in our XP cohort (20 years) was younger than that of three comparison groups: 36 years (California study-208 subjects), 48 years (Korean study-24,757 subjects), and 52 years (NIH-682 research subjects). Multiple (2-4) thyroid nodules were found in 12/18 (67%) of the patients with nodules. Autopsy examination revealed follicular adenomas in 4/8 (50%) additional XP patients. DNA sequencing revealed rare mutations in two other XP patients with papillary thyroid cancer. CONCLUSIONS: XP patients have an increased incidence of thyroid nodules at an early age in comparison to the general population. These finding confirm another premature aging feature of XP.

Miliary fibromas in tuberous sclerosis complex.

BACKGROUND: Tuberous sclerosis complex (TSC) is a hamartoma syndrome characterized by multiple skin lesions, such as angiofibromas, shagreen patch and miliary fibromas (MiF). OBJECTIVE: To determine the clinical and histological features of MiF. METHODS: A retrospective analysis was conducted on 133 adults with TSC. Photography was used to characterize the appearance and location of MiF. Histological features in five skin samples from four individuals were evaluated by a board-certified dermatopathologist. RESULTS: MiF were observed in 19 of 133 (14%) individuals with TSC. MiF were 1- to 3-mm skin-coloured, sessile papules scattered on the back and rarely buttocks or thighs. Most were scattered in a bilaterally symmetric distribution, but others were asymmetric or associated with a shagreen patch. Histological features of MiF included expansion of the papillary and periadnexal dermis with variable hamartomatous abnormalities involving adjacent epithelial components. CONCLUSIONS: MiF are distinct from other cutaneous lesions in TSC such as shagreen patches and angiofibromas. Recognition of this entity is important in defining the spectrum of TSC disease and reassuring individuals with TSC that these lesions are benign.

Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology.

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N=78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5 × 10-8), we found suggestive evidence (P<5 × 10-6) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.

All-optically controllable random laser based on a dye-doped polymer-dispersed liquid crystal with nano-sized droplets.

This study elucidates for the first time an all-optically controllable random laser in a dye-doped polymer-dispersed liquid crystal (DDPDLC) with nano-sized LC droplets. Experimental results demonstrate that the lasing intensity of the random laser can be controlled to decrease by increasing irradiation time/intensity of one green beam, and increase by increasing the irradiation time of one red beam. The all-optical controllability of the random laser is attributed to the green (red)-beaminduced isothermal nematic-->isotropic (isotropic-->nematic) phase transition in LC droplets by trans-->cis (cis-->trans back) isomerization of azo dyes. This isomerization may decrease (increase) the difference between the refractive indices of the LC droplets and the polymer, thereby increasing (decreasing) the diffusion constant (or transport mean free path), subsequently decreasing the scattering strength and, thus, random lasing intensity.

Spatially band-tunable color-cone lasing emission in a dye-doped cholesteric liquid crystal with a photoisomerizable chiral dopant.

This study investigates a spatially band-tunable color-cone lasing emission (CCLE) based on a dye-doped cholesteric liquid crystal with a photoisomerizable chiral dopant (IBM). Experimental results show that the lasing band of the formed CCLE of the cell with a photoinduced pitch gradient can be spatially tuned among various color regions by adjusting the pumped position of the cell. The spatially band tunability of the laser results from the UV-irradiation-induced decrease of the helical twisting power of IBM via trans-->cis isomerization, accordingly shrinking the pitch of the cholesteric-liquid-crystal host. The total spatially tunable wavelength range for the laser exceeds 100 nm.

Band-tunable color cone lasing emission based on dye-doped cholesteric liquid crystals with various pitches and a pitch gradient.

This study elucidates, for the first time, a novel band-tunable color cone lasing emission (CCLE) based on dye-doped cholesteric liquid crystal (DDCLC) films with various pitches. For several CLC cells with different pitches it was shown experimentally that the lasing band on the CCLE can be tuned among various color regions measured within different angular ranges. Some important features of the tunable CCLE are also identified and discussed. A spatially band-tunable color cone laser, based on a single DDCLC with a gradient pitch, is developed as a real application.

Color cone lasing emission in a dye-doped cholesteric liquid crystal with a single pitch.

This work investigates a novel color cone lasing emission (CCLE) based on a one-dimensional photonic crystal-like dye-doped cholesteric liquid crystal (DDCLC) film with a single pitch. The lasing wavelength in the CCLE is distributed continuously at 676.7-595.6 nm, as measured at a continuously increasing oblique angle relative to the helical axis of 0-50 degrees . This work demonstrates that lasing wavelength coincides exactly with the wavelength at the long wavelength edge of the CLC reflection band at oblique angles of 0-50 degrees . Simulation results of dispersion relations at different oblique angles using Berreman's 4X4 matrix method agrees closely with experimental results. Some unique and important features of the CCLE are identified and discussed.

Manganese does not alter the severe neurotoxicity of MPTP.

We utilized a mice model of Parkinsonism: (1) to evaluate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity; and (2) to evaluate whether manganese (Mn) exposure can affect MPTP-induced neurotoxicity. A 2 x 3 experimental design (MPTP x+/- Mn) was as follows: SS, MPTP(-) x Mn(-); SLMn, MPTP(-) x low Mn(+); SHMn, MPTP(-) x high Mn(+); MpS, MPTP(+) x Mn(-); MpLMn, MPTP(+) x low Mn(+); MpHMn, MPTP(+) x high Mn(+). We administered MPTP (30 mg/kg per day) to male C57BL/6 mice intraperitoneally, once a day for 5 days. Subsequently, mice were treated with either 2 or 8 mg/kg of MnCl(2).4H(2)O intraperitoneally, once a day for 3 weeks. Blood and striatal Mn levels were elevated in the Mnexposed groups. The number of tyrosine hydroxylase (TH)-immunoreactive (ir) neurons in the substantia nigra pars compacta were decreased significantly in the MPTP-exposed groups. The densities of TH-ir axon terminals in caudate-putamen (CPU) were significantly decreased in the MPTP-treated groups. However, Mn treatment did not affect MPTP neurotoxicity. The densities of glial fibrillary acidic protein (GFAP)-ir astrocytes in the CPU or globus pallidus were significantly increased in the MPTP-treated groups. Concentrations of dopamine in the striatum were decreased significantly in the MPTP-exposed groups only, but Mn had no effect.

Patient compliance with oral chemotherapy as assessed by a novel electronic technique.

PURPOSE: Previous reports have suggested low rates of compliance with the oral component of cancer chemotherapy, which, if confirmed, would have serious implications on treatment. Because of the uncertainties in the methodology used in previous studies, we have assessed compliance with a novel technique. PATIENTS AND METHODS: An "intelligent" tablet bottle was used, which, unknown to the patient, electronically records the times of opening over a period of weeks. The records were scored for overall compliance (total number of bottle openings as a percentage of the prescribed number) and for daily and hourly irregularity indices. Twenty-one patients undergoing treatment for Hodgkin's or non-Hodgkin's lymphoma were monitored for a total of 65 treatment periods, each of up to 2 weeks (852 days in total). Eight measures of side effects and quality of life were self-assessed daily by the patients using a diary card. RESULTS: The overall compliance was 100.6% +/- 20.6% (mean +/- SD). Overall compliance was lower (mean reduction, 10%) in treatment periods with drugs prescribed to be taken three times a day. It was not possible to demonstrate convincingly any relationship between compliance and any of the following: drug type, monitoring period sequence, the diary card scores of side effects and quality of life, number of relapses, and time since initial diagnosis. CONCLUSION: These results are reassuring, but further work is in progress to measure compliance in other treatment regimens in which the side effects are more severe and the prognosis is worse.

Robotic surgery for thyroid disease.

While conventional open thyroidectomy techniques are the most widely performed thyroid operation, they produce an anterior neck scar that may be difficult to conceal. The endoscopic thyroidectomy was developed to decrease the cosmetic impact on the patient and has the advantage of reducing the incidence of anterior neck hypoesthesia and paresthesia. However, this procedure has some drawbacks, which motivated surgeons to develop a new operation method. Robotic thyroidectomy is a relatively new approach for treating differentiated thyroid cancer. Over the last few years, robotic thyroidectomies have become more common. Robotic thyroidectomies are a feasible, safe alternative for managing thyroid disease that has remarkable functional benefits beyond those of conventional open methods. The applications for robotic thyroidectomy have expanded to include increasingly advanced cases, which will consequently change the thyroid surgery paradigm in the future.

Delivery of plasmid DNA to articular chondrocytes via novel collagen-glycosaminoglycan matrices.

Our primary objective was to fabricate a porous gene-supplemented collagen-glycosaminoglycan (GSCG) matrix for sustained delivery (over a period of several weeks) of plasmid DNA to articular chondrocytes when implanted into cartilage lesions. The specific aims of this in vitro study were to determine the release kinetics profiles of plasmid DNA from the GSCG matrices, and to determine the ability of the released plasmid DNA to transfect adult canine articular chondrocytes. In particular, we evaluated the effects of two variables, cross-linking treatment and the pH at which the DNA was incorporated into the matrices, on the amount of the plasmid DNA that remained bound to the GSCG matrices after passive (nonenzymatic) leaching and on the expression of a reporter gene in articular chondrocytes grown in the GSCG matrices. Collagen-glycosaminoglycan matrices were synthesized without cross-linking, and by three cross-linking treatments: dehydrothermal (DHT) treatment, 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC) treatment, and exposure to ultraviolet (UV) radiation. The plasmid DNA was incorporated into the collagen-glycosaminoglycan matrices in solutions at pH 2.5 or 7.5. Transmission electron microscopy studies revealed plasmid DNA bound to the walls of the porous GSCG matrices. In general, the GSCG matrices fabricated at pH 2.5 retained a larger fraction of the initial DNA load after 28 days of incubation in Tris-EDTA buffer. The passive, solvent-mediated release of the plasmid DNA from the GSCG matrices showed a biphasic pattern consisting of a faster, early release rate over the initial 8 hr of leaching followed by a slower, late release rate that was relatively constant over the subsequent 28 days of leaching. Electrophoretic analyses revealed that the plasmid DNA released from the GSCG matrices fabricated at pH 2.5 had been linearized and/or degraded; whereas the plasmid DNA leached from the GSCG matrices prepared with a DNA solution at pH 7.5 was primarily supercoiled and linear. Plasmid DNA released from all GSCG matrix formulations was able to generate luciferase reporter gene expression in monolayer-cultured chondrocytes transfected with the aid of a commercial lipid reagent, and in chondrocytes cultured in the GSCG matrices without the aid of a supplemental transfection reagent. Luciferase expression in chondrocyte-seeded GSCG constructs was evident throughout the culture period (28 days), with the EDC and UV cross-linked matrices prepared at pH 7.5 providing the highest transgene expression levels. We conclude that released plasmid DNA continually transfected canine articular chondrocytes seeded into GSCG matrices in vitro for a 4-week period as evidenced by luciferase reporter gene expression. Thus, GSCG matrices can be fabricated to provide sustained release of plasmid DNA carrying a potential therapeutic gene.

Pallidal control of substantia nigra dopaminergic neuron firing pattern and its relation to extracellular neostriatal dopamine levels.

The firing patterns of dopaminergic neurons in vivo are strongly modulated by afferent input. The principal GABAergic inputs to the dopaminergic neurons of the substantia nigra originate from neurons of the neostriatum, globus pallidus and substantia nigra pars reticulata. It has previously been shown that the firing pattern of nigral dopaminergic neurons can be manipulated by pharmacologically induced excitation or inhibition of the globus pallidus with relatively little effect on firing rate. We used this technique to explore the relation between the firing pattern of dopaminergic neurons and extracellular dopamine levels in the neostriatum in vivo. Specifically, we tested whether an increase in burst firing in dopaminergic neurons produced by increased pallidal activity led to increased extracellular dopamine levels in the neostriatum. Single unit extracellular recording combined with simultaneous microdialysis was used to measure the firing rates and patterns of dopaminergic neurons and extracellular striatal dopamine levels, respectively, during bicuculline-induced excitation of the globus pallidus. Pallidal excitation resulted in a marked increase in burst firing in dopaminergic neurons along with only a slight increase in firing rate, but produced a significant elevation (approximately 45%) in neostriatal dopamine levels. These data suggest that afferent-induced burst firing in dopaminergic neurons leads to an increase in extracellular dopamine levels in the neostriatum when compared with less bursty patterns with similar overall firing rates.

Mechanisms involved in the antiplatelet activity of Staphylococcus aureus lipoteichoic acid in human platelets.

In this study, gram-positive Staphylococcus aureus lipoteichoic acid (LTA) dose-dependently (0.1-1.0 microg/ml) and time-dependently (10-60 min) inhibited platelet aggregation in human platelets stimulated by agonists. LTA also dose-dependently inhibited phosphoinositide breakdown and intracellular Ca+2 mobilization in human platelets stimulated by collagen. LTA (0.5 and 1.0 microg/ml) also significantly inhibited thromboxane A2 formation stimulated by collagen in human platelets. Moreover, LTA (0.1-1.0 microg/ml) dose-dependently decreased the fluorescence of platelet membranes tagged with diphenylhexatrience. Rapid phosphorylation of a platelet protein of Mr. 47,000 (P47), a marker of protein kinase C activation, was triggered by PDBu (30 nM). This phosphorylation was markedly inhibited by LTA (0.5 and 1.0 microg/ml) within a 10-min incubation period. These results indicate that the antiplatelet activity of LTA may be involved in the following pathways: LTA's effects may initially be due to induction of conformational changes in the platelet membrane, leading to a change in the activity of phospholipase C, and subsequent inhibition of phosphoinositide breakdown and thromboxane A2 formation, thereby leading to inhibition of both intracellular Ca+2 mobilization and phosphorylation of P47 protein. Therefore, LTA-mediated alteration of platelet function may contribute to bleeding diathesis in gram-positive septicemic and endotoxemic patients.

The beta 1-adrenoceptor antagonist, betaxolol, is not released from the heart of the anaesthetized dog during sympathetic nerve stimulation.

1. We investigated the hypothesis that the beta 1-adrenoceptor antagonist, betaxolol, can be accumulated by cardiac sympathetic nerve endings and then released together with noradrenaline during accelerans nerve stimulation. 2. Dogs were chronically treated with betaxolol (1 mg kg-1 daily, s.c.) for 7 days. Twenty four hours after the last dose, there was a significant retention of betaxolol in the heart of these dogs treated chronically with the beta 1-adrenoceptor antagonist. However, during in vivo accelerans nerve stimulation, the concentration of betaxolol in the coronary sinus was not modified, whereas the noradrenaline concentration increased significantly. 3. Chronic betaxolol treatment antagonized the tachycardia induced by electrical stimulation of the cardiac accelerator nerves or by intravenous isoprenaline. However, the tachycardia induced by nerve stimulation was not antagonized to a greater extent than that induced by isoprenaline. 4. These findings are discussed in relation to a similar in vivo study in dogs treated with propranolol, in which the drug was found to be released into the coronary circulation during stimulation of the accelerans nerve.

Protection by scoparone against the alterations of plasma lipoproteins, vascular morphology and vascular reactivity in hyperlipidaemic diabetic rabbit.

1. The in vivo pharmacological effects of scoparone (6,7-dimethoxycoumarin) in a hyperlipidaemic diabetic rabbit model were investigated. 2. Three groups of rabbits were studied: (1) normal, (2) hyperlipidaemic and diabetic-untreated and (3) hyperlipidaemic and diabetic-scoparone treated. The hyperlipidaemic diabetic rabbits were fed with 1% cholesterol and treated with alloxan, a diabetogenic agent. The plasma levels of total cholesterol, total triglyceride, very low-density lipoprotein (VLDL) cholesterol, low density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol were markedly increased as soon as the rabbit became diabetic at the second week. Scoparone-treatment (5 mg kg-1 day-1, s.c.) significantly reduced the plasma lipid and lipoprotein cholesterol levels of the hyperlipidaemic diabetic rabbit to 73.3% of total cholesterol, 48.3% of total triglyceride, 66.0% of VLDL cholesterol, 55.7% of LDL cholesterol and 79.5% of HDL cholesterol. 3. Six weeks after cholesterol-feeding, the aortic arch and thoracic aorta were dissected for morphological and functional studies. In vascular rings from the untreated hyperlipidaemic diabetic rabbit, there was intimal thickening with accumulation of fatty streaks, foam cells and migration of smooth muscle cells to the intima. In the rabbits treated with scoparone, there were fewer pathological morphology changes found in vascular segments than in the untreated hyperlipidaemic diabetic rabbits. 4. In the vascular reactivity experiments, the phenylephrine-induced contraction and nitroprusside induced dilatation did not differ significantly among the three rabbit groups, except that the contraction was enhanced in the thoracic aorta of hyperlipidaemic diabetic rabbits either untreated or treated withscoparone, as compared to the normal group, and the sensitivity to nitroprusside was increased in the thoracic aorta of the scoparone-treated group as compared to the untreated group.5. The endothelium-dependent dilatation induced by acetylcholine was significantly attenuated in both the aortic arch and thoracic aorta from the hyperlipidaemic diabetic rabbits as compared to the normal rabbits. This attenuation was partially prevented, when scoparone (5 mg kg-1) was administered daily.6. These results suggest that scoparone protects against some alterations of plasma lipoproteins,vascular morphology and vascular reactivity in the hyperlipidaemic diabetic rabbit. These protective effects of scoparone may be partly related to its free radical scavenging property.

The antiplatelet activity of PMC, a potent alpha-tocopherol analogue, is mediated through inhibition of cyclo-oxygenase.

PMC, a potent alpha-tocopherol derivative, dose-dependently (5-25 microM) inhibited the ATP-release reaction and platelet aggregation in washed human platelets stimulated by agonists (collagen and ADP). PMC also dose-dependently inhibited the intracellular Ca2+ mobilization, whereas it did not inhibit phosphoinositide breakdown in human platelets stimulated by collagen. PMC (10 and 25 microM) significantly inhibited collagen-stimulated thromboxane A2 (TxA2) formation in human platelets. On the other hand, PMC (25 and 100 microM) did not increase the formation of cyclic AMP or cyclic GMP in platelets. Moreover, PMC (25, 100, and 200 microM) did not affect the thromboxane synthetase activity of aspirin-treated platelet microsomes. PMC (10 and 25 microM) markedly inhibited the exogenous arachidonic acid (100 microM)-induced prostaglandin E2 (PGE2) formation in the presence of imidazole (600 microM) in washed human platelets, indicating that PMC inhibits cyclo-oxygenase activity. We conclude that PMC may exert its anti-platelet aggregation activity by inhibiting cyclooxygenase activity, which leads to reduced prostaglandin formation; this, in turn, is followed by a reduction of TxA2 formation, and finally inhibition of [Ca2+]i mobilization and ATP-release.

The effect of lithium salts on the urinary excretion of -oxoglutarate in man.

1. Lithium ions in therapeutic doses cause an increase in the renal excretion of alpha-oxoglutarate and glutaric acid.2. The excretion is probably due to reduced renal tubular reabsorption.3. Neither citrate, lactate nor pyruvate excretion rises.

Day-night rhythm of 5-methoxytryptamine biosynthesis in the pineal gland of the golden hamster (Mesocricetus auratus).

5-Methoxytryptamine is a potent agonist of presynaptic 5-hydroxytryptamine autoreceptors modulating serotonin release in the central nervous system. This methoxyindole can be synthesized in the pineal gland, but its presence in vivo is still controversial, probably because of rapid catabolism by monoamine oxidase. An improved high-pressure liquid chromatography method, with coulometric detection, has been developed for the simultaneous measurement of melatonin, 5-methoxytryptamine, 5-methoxytryptophol and 5-methoxyindolacetic acid. We have demonstrated a day-night rhythmicity in the amount of 5-methoxytryptamine in the pineal gland of golden hamsters (Mesocricetus auratus) maintained under a long photoperiod (14 h light: 10 h darkness) and pretreated with the monoamine oxidase inhibitor pargyline. Levels of 5-methoxytryptamine were highest at 16.30 h and lowest at 00.30 h. The rhythm for 5-methoxytryptamine appears to be the same as for serotonin (opposite in phase to that of melatonin). The identification of 5-methoxytryptamine has been confirmed by analysis with gas chromatography-mass spectrometry.

Piroxicam-beta-cyclodextrin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in rheumatic diseases and pain states.

Piroxicam-beta-cyclodextrin is a complex of the established nonsteroidal antiinflammatory drug (NSAID) piroxicam and an inert cyclic macromolecule, beta-cyclodextrin. In clinical trials in patients with rheumatic diseases or pain arising from other conditions, it was as effective an analgesic as standard piroxicam, and showed a faster onset of action on the first day of treatment. In short term pharmacodynamic studies in healthy volunteers, piroxicam-beta-cyclodextrin was equivalent to or tended to show less gastrointestinal mucosal toxicity than standard piroxicam, as assessed by endoscopy and faecal blood loss. However, no data are available on its comparative gastrointestinal mucosal effects from long term clinical trials using similar measures. Preliminary findings from a clinical study suggest piroxicam-beta-cyclodextrin caused fewer gastroduodenal lesions than tenoxicam. As with other NSAIDs, the majority of adverse events associated with piroxicam-beta-cyclodextrin in clinical trials were gastrointestinal in origin, with epigastric pain, heartburn and nausea the most common. Thus, piroxicam-beta-cyclodextrin is an effective agent in patients with rheumatic diseases or other pain states. When rapid analgesia is required in the initial treatment of acute pain, the faster onset of action of piroxicam-beta-cyclodextrin may be an advantage over the parent compound; however, this is unlikely to be important during long term therapy. The results of further long term trials are awaited before firm conclusions can be reached regarding the gastrointestinal tolerability of piroxicam-beta-cyclodextrin compared with that of standard piroxicam and other NSAIDs.

Altretamine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in cancer chemotherapy.

Altretamine (hexamethylmelamine) is a cytotoxic antineoplastic agent which appears to require metabolic activation. Metabolic intermediates may act as alkylating agents; however, altretamine is not directly cross-resistant with classical alkylating agents. Objective response rates to orally administered altretamine as salvage therapy in patients with advanced ovarian cancer were 0 to 33%, with disease stabilisation in a further 8 to 78% of patients. Response rates appear to be higher in patients who have responded to previous alkylating agent or cisplatin-based therapy. There is some evidence that addition of altretamine to platinum-based combination regimens used for induction therapy of advanced ovarian cancer may improve long term survival, particularly in patients with limited residual disease. Although altretamine displays some activity in small cell lung cancer, it is unlikely to have any clinical role in the management of non-ovarian cancer. Altretamine appears to be relatively well tolerated, with gastrointestinal, neurological and haematological toxicities being the main dose-limiting adverse effects. However, assessment of accurate incidence rates for these effects is complicated by the use of altretamine with cisplatin. On the basis of the emerging body of clinical evidence, altretamine appears to have a limited role in the treatment of persistent or recurrent advanced ovarian cancer, primarily in patients who are potentially platinum sensitive yet intolerant of platinum analogues. Additionally, altretamine may be added to platinum-based regimens for induction therapy of advanced ovarian cancer. At the doses currently recommended, altretamine offers a reasonably well tolerated regimen that can be administered orally and is suitable for use on an outpatient basis.