Successful desensitization with cetuximab after an infusion reaction to panitumumab in patients with metastatic colorectal cancer.

BACKGROUND: Cetuximab and panitumumab are chimeric and fully human monoclonal antibodies, respectively, against epidermal growth factor receptor used in the treatment of metastatic colorectal cancer (mCRC). Incidence of documented infusion reaction (IR) is more common with cetuximab (all grades [g]: 15-21%, g 3/4: 2-5%) than panitumumab (all g: 4%, g 3/4: 1%). Anecdotal reports suggest successful challenge with panitumumab following IR with cetuximab (Saif et al. in Cancer Chemother Pharmacol 63(6):1017-1022, 2009). However, safety of cetuximab after IR with panitumumab is not known. We report two patients successfully desensitized with cetuximab after IR with panitumumab. PATIENTS AND METHODS: A 42-year-old female with mCRC received panitumumab as a third-line agent. She developed severe chest tightness, pain, and shortness of breath (SOB), 5 min after first panitumumab infusion. A second 70-year-old male with mCRC developed severe facial flushing, back pain, SOB, tachycardia and hypotension, 5 min after second dose of panitumumab plus irinotecan as a second-line therapy. These two patients received desensitization protocol for cetuximab after a test dose of 20 mg IV over 10 min followed by a slow infusion 10% of original rate in 0-2 h, 25% of original rate in 2-2.5 h, 50% reduced rate in 2.5-3 h, and then 100% infusion rate after 3 h. Patients were observed 4 h after completion of infusion. RESULTS: First patient received a total of 12 cycles of cetuximab with stable disease, no recurrence of IR, and grade 1-2 acniform rash that first developed after third cycle. Second patient received a total of eight cycles uneventfully without IR. CONCLUSIONS: To our knowledge, this is the first report of two patients with documented IR with panitumumab being desensitized successfully with cetuximab. Though anecdotal reports suggest safety of panitumumab in patients following IR with cetuximab, panitumumab can also cause severe IR. Our experience suggests that in case of limited options, such patients can be successfully challenged with cetuximab in a hospital after appropriate desensitization and premedication. Further studies focusing on desensitization and identifying hypersensitivity profile of different anti-epidermal growth factor receptor antibodies are warranted.

Soils, agriculture, and society in precontact Hawai'i.

Before European contact, Hawai'i supported large human populations in complex societies that were based on multiple pathways of intensive agriculture. We show that soils within a long-abandoned 60-square-kilometer dryland agricultural complex are substantially richer in bases and phosphorus than are those just outside it, and that this enrichment predated the establishment of intensive agriculture. Climate and soil fertility combined to constrain large dryland agricultural systems and the societies they supported to well-defined portions of just the younger islands within the Hawaiian archipelago; societies on the older islands were based on irrigated wetland agriculture. Similar processes may have influenced the dynamics of agricultural intensification across the tropics.

Radiation dose implications of airborne contaminant deposition to humans.

In nuclear accident consequence assessment, dose contributions from radionuclide deposition on the human body have in the past generally been either ignored or estimated on the basis of rather simple models. Recent experimental work has improved the state of knowledge of relevant processes and parameter ranges. The results presented in this paper represent a first approach to a detailed assessment of doses from radiopollutant deposition on the human body, based on contaminant-specific data. Both the dose to skin from beta-emitters and the whole-body dose from gamma-emitters on body surfaces were found to give potentially significant contributions to dose. Further, skin penetration of some contaminants could lead to significant internal doses.

In vitro skin absorption and decontamination of sulphur mustard: comparison of human and pig-ear skin.

The aim of this study was to evaluate the use of an in vitro skin diffusion cell system as a model for assessing decontaminants against the chemical warfare agent sulphur mustard (SM). The in vitro absorption rates of SM through heat-separated human (157 +/- 66 microg cm(-2) h(-1)) and pig-ear (411 +/- 175 microg cm(-2) h(-1)) epidermal membranes were in agreement with previous in vivo studies that quoted skin absorption rates of 150 and 366 microg cm(-2) h(-1), respectively. Decontaminants (fuller's earth, Ambergard and BDH spillage granules) were ranked in order of effectiveness by measuring the skin absorption rates and the percentage of applied dose of SM that penetrated human and pig-ear epidermal membranes. The effectiveness of fuller's earth measured in this in vitro study using human epidermal membranes was in agreement with a previous in vivo human volunteer study. Similarly, the effectiveness of fuller's earth and Ambergard measured in vitro with pig-ear epidermal membranes was in agreement with a previous in vivo study conducted on rats. However, there was complete disparity in the ranking of decontaminants between human and pig-ear epidermal membranes measured in vitro. Thus, although pig-ear skin may be a relatively good model for predicting the human skin absorption of SM, it is a poor model for testing decontamination systems. The results of this study further validate the use of Franz-type glass diffusion cells containing human epidermal membranes as a model for predicting in vivo human skin absorption.

High-performance liquid chromatography method for the quantification of non-radiolabelled cinnamic compounds in analytes derived from human skin absorption and metabolism experiments.

An isocratic high-performance liquid chromatography method has been developed for the quantification of the skin sensitisers trans-cinnamaldehyde and trans-cinnamic alcohol, and their cinnamic metabolites. The relative standard deviations (RSDs) between the gradients of eight sets of standard curves were 2.8, 3.1 and 1.9% for cinnamic alcohol, cinnamaldehyde and cinnamic acid, respectively. Sample analytes were derived from two series of experiments: in vitro full-thickness human skin absorption and metabolism studies and metabolism studies using human skin homogenates, with non-radiolabelled cinnamic compounds. Skin absorption and metabolism experiments were performed in the absence and presence of the alcohol dehydrogenase inhibitor, pyrazole. Samples from full-thickness skin absorption studies were analysed without extraction; cinnamic compounds from within skin were extracted into methanolic solutions using newly developed methods. The intra-assay RSDs ranged from 0.17 to 2.52% for cinnamic alcohol, 0.24 to 9.14% for cinnamaldehyde and 0.26 to 6.43% for cinnamic acid. The inter-assay RSDs for cinnamic alcohol, cinnamaldehyde and cinnamic acid, respectively, as determined from n=20 HPLC runs, were 2.10, 4.16 and 2.26%.

Skin-sensitization structure-activity relationships for aldehydes.

A selection of 17 aldehydes (13 sensitizing and 4 non-sensitizing), all of which possessed a benzene ring, were evaluated using structure-activity relationships (SARs). The sensitizing compounds were classified as strong, moderate or weak skin sensitizers on the basis of in vivo data. The aldehydes were grouped into 4 distinct subcategories of functionally related aldehydes that were termed aryl-substituted aliphatic, aryl, aryl with special features (that can undergo metabolism) and alpha,beta-unsaturated aldehydes. It was observed that a structure-activity relationship could be derived for a subset of aldehydes that could react via the same chemical mechanism. This further supports the view that applying knowledge on reaction mechanisms to develop SAR models can provide a more accurate means of investigating and predicting the sensitization potential of structurally and functionally related chemicals.

Measurement of bioavailability: measurement of absorption through skin in vitro.

New therapeutic compounds intended for use on the skin or for delivery through application to the skin and agrochemicals, whose use may result in skin exposure, must be tested for bioavailability as the result of absorption. This unit contains a protocol for measuring skin absorption in vitro using the diffusion cell skin absorption method (SAM), which can be used to measure percutaneous absorption after topical application. Usually a radiolabeled compound is used, but if a suitable specific assay is available, nonradioactive compounds may be tested. The procedure is applicable to skin from a variety of species.

Human skin absorption and metabolism of the contact allergens, cinnamic aldehyde, and cinnamic alcohol.

trans-Cinnamaldehyde and trans-cinnamic alcohol have been commonly reported to cause allergic contact dermatitis (ACD) in humans. Cinnamaldehyde is a more potent skin sensitizer than cinnamic alcohol. It has been hypothesized that cinnamic alcohol is a "prohapten" that requires metabolic activation, presumably by oxidoreductase enzymes such as alcohol dehydrogenase (ADH) or cytochrome P450 2E1 (CYP2E1), to the protein-reactive cinnamaldehyde (a hapten). In this study, the in vitro percutaneous absorption and metabolism of cinnamaldehyde and cinnamic alcohol (78 micromol dose) has been examined using freshly excised, metabolically viable, full-thickness breast and abdomen skin from six female donors. Penetration rates and total cumulative recoveries of cinnamic compounds that were present in receptor fluid, extracted from within the skin, evaporated from the skin surface, or remained unabsorbed on the skin surface after 24 h were quantified by reversed-phase high-performance liquid chromatography. Biotransformation of cinnamaldehyde to both cinnamic alcohol and cinnamic acid was observed. Topically applied cinnamic alcohol was converted to cinnamaldehyde (found on the skin surface only) and cinnamic acid. To establish whether these biotransformations were enzymatic, experiments were performed in the absence and presence of varying concentrations (80-320 micromol) of the ADH/CYP2E1 inhibitors pyrazole or 4-methylpyrazole. The observation that pyrazole significantly reduced (p < 0.05) the total penetration of cinnamic metabolites into receptor fluid, following either cinnamaldehyde or cinnamic alcohol treatment, but did not significantly affect parent chemical penetration, suggests that we are measuring cutaneous metabolic products of ADH activity. The skin absorption and metabolism of cinnamaldehyde and cinnamic alcohol will play an important role in the manifestation of ACD following topical exposure to these compounds.

Metabolism of fluroxypyr, fluroxypyr methyl ester, and the herbicide fluroxypyr methylheptyl ester. I: during percutaneous absorption through fresh rat and human skin in vitro.

Percutaneous absorption of pesticides is a major determinant for risk assessment. Furthermore, cutaneous metabolism plays a role in penetration of certain chemicals. Therefore, the aim of these studies was to determine the transdermal metabolism of three related compounds [the herbicide, fluroxypyr methylheptyl ester (FPMH), fluroxypyr methyl ester (FPM), and fluroxypyr (FP)] during penetration through human and rat skin in vitro. The data presented in this article show that both FPM and FPMH were completely metabolized during their passage through human and rat skin in vitro. The only metabolite produced was that of the hydrolysis product, FP, with no parent ester penetrating through the skin. The extent of FP formation within the skin was directly correlated to the degree of stratum corneum reservoir formation. The larger the stratum corneum reservoir, the lower the levels of FP recovered from within the skin. This suggests that as the ester partitioned out of the SC it was immediately hydrolyzed to FP, which could then pass freely through the remainder of the epidermis and dermis. Similar metabolic profiles were observed for the transdermal metabolism of FPM and FPMH in previously frozen rat skin, indicating the robust nature of the esterase enzymes involved. In conclusion, systemic exposure after skin contact with FPM or FPMH is likely to be to the acid metabolite, FP, only and not to the parent ester. In addition, the rate and extent of percutaneous absorption will be a major determinant of cutaneous metabolism.

Metabolism of fluroxypyr, fluroxypyr methyl ester, and the herbicide fluroxypyr methylheptyl ester. II: in rat skin homogenates.

Fluroxypyr methyl ester (FPM) and the herbicide fluroxypyr methylheptyl ester (FPMH) are completely hydrolyzed during penetration through human and rat skin in vitro to the acid metabolite, fluroxypyr (FP) (). This article presents additional studies to determine the enzyme kinetics (K(m) and V(max)) of this ester hydrolysis, using crude rat whole-skin homogenate. Both FPM and FPMH were extensively metabolized in rat skin homogenates to the acid metabolite, FP. In no instance were any other metabolites detected. FPM was essentially hydrolyzed completely within 1 h. In FPMH incubations, there was still parent ester present after 24 h at all concentrations tested. The kinetics of hydrolysis of the two esters were different: V(max) was approximately 3-fold greater for FPM than FPMH (1400 and 490 micromol FP/min/g of tissue, respectively); however, K(m) values were very similar, 251 and 256 microM, respectively. Preliminary inhibitory studies suggest that FPM and FPMH are hydrolyzed by a carboxylesterase, because this reaction was inhibited by bis-p-nitrophenyl phosphate. Mercuric chloride (an inhibitor of A-esterase and arylesterase) and eserine (a cholinesterase inhibitor) had no inhibitory effect on the hydrolysis of FPM or FPMH. Taken together with the data presented by, it can be concluded that no parent ester will pass through the skin in vivo, only the metabolite, FP. Therefore, first pass metabolism will be complete before these compounds reach the systemic circulation.

Human skin absorption of Bis-2-(chloroethyl)sulphide (sulphur mustard) in vitro.

The purpose of this study was to measure the absorption and intra-epidermal fate of 35S-radiolabelled sulphur mustard (35SM) in human breast skin in vitro. Skin (full-thickness or heat-separated epidermis) was placed into static diffusion cells and was exposed to droplets of liquid 35SM or saturated 35SM vapour. Amounts of 35SM penetrating the skin were measured from which skin absorption rates were calculated. Unbound radiolabel was washed from the surface, extracted from the skin and analysed to determine the identity of the radiolabelled species in order to measure the extent of hydrolysis of sulphur mustard. Penetration rates of liquid 35SM measured in vitro (71-294 microg cm(-2) h(-1)) were in agreement with those measured previously in vivo using human volunteers (60-240 microg cm(-2) h(-1)). Rates of liquid 35SM skin absorption under occluded, infinite dose conditions were highest through heat-separated epidermal membranes (294+/-58 microg cm(-2) h(-1)) and lowest through full-thickness skin (71+/-14 microg cm(-2) h(-1)). Fluxes of saturated 35SM vapour (110+/-75 microg cm(-2) h(-1)) through heat-separated membranes were similar to those previously measured through human forearm skin in vivo (162 microg cm(-2) h(-1)). Although hydrolysis of 35SM did occur, both on the surface and within the skin, it accounted for only a small percentage of the total applied dose (<2.7+/-1.2%). The difference in total amount of liquid 35SM penetrated between occluded and unoccluded conditions in vitro (79+/-14%) was similar to that lost as vapour from unoccluded skin in vivo (80%). A substantial reservoir of 35SM (14-36% of the applied dose) was measured within heat-separated epidermal membranes for up to 24 h which may have significant implications for the management of personnel exposed to sulphur mustard.

Induction and localization of cutaneous interleukin-1 beta mRNA during contact sensitization.

Chemical allergens that induce contact sensitivity cause changes in levels of epidermal cytokines. In mice one of the earliest epidermal cytokines to be upregulated following sensitization is interleukin-1 beta (Iota L-1 beta). The present study investigated the kinetics and in situ localization of induced IL-1 beta expression in mouse skin following topical exposure to the contact allergen oxazolone. Mice were exposed topically to 1% oxazolone, with control mice exposed to vehicle (acetone:olive oil 4:1) alone, and at various times thereafter skin was excised for IL-1 beta mRNA and protein determination by in situ hybridization and enzyme-linked immunosorbant assay (ELISA), respectively. IL-1 beta mRNA was found to be expressed constitutively at low levels in skin from naïve (untreated) and vehicle-treated mice, with mRNA localized in some hair follicles and sebaceous glands; no IL-1 beta mRNA was detected in the epidermis of control animals. Following topical exposure of mice to oxazolone for 5-15 min, upregulation of IL-1 beta mRNA was observed in the epidermis, dermis, hair follicles, and sebaceous glands; at 90 min and beyond the pattern of IL-1 beta mRNA expression declined toward control. Analysis of whole skin homogenates by ELISA demonstrated cutaneous IL-1 beta protein to be present constitutively in both vehicle-treated and naïve mice. Following exposure to oxazolone, cutaneous IL-1 beta protein expression was elevated at 30 min, decreased at 1 h, and fell below the limit of detection of the assay at 2 h before returning to constitutive levels at 4 and 24 h. IL-1 beta protein levels in vehicle-treated mice, naïve mice, and mice treated with the respiratory allergen trimellitic anhydride were unchanged over this time period. The present study demonstrated that IL-1 beta mRNA expression was upregulated rapidly and transiently in well-defined regions of mouse epidermis and dermis during contact sensitization, and was succeeded by an elevation in IL-1 beta protein. This early highly localized upregulation of IL-1 beta lends further support to the hypothesis that this cytokine plays a key role in the initial stages of skin sensitization. Such information will enhance our understanding of the molecular processes involved in allergic contact dermatitis and may provide a mechanistic basis for designing refined animal and in vitro alternatives to existing models of skin sensitization.

Expression and localization of human alcohol and aldehyde dehydrogenase enzymes in skin.

Alcohol dehydrogenase (ADH; EC 1.1.1.1) and aldehyde dehydrogenase (ALDH; EC 1.2.1.3.) are important enzymes involved in the biotransformation of both alcohols and aldehydes. Today, six classes of ADH and twelve classes of ALDH have been defined in mammals. Here we report the detection and localisation of three classes of ADH and two classes of ALDH in human skin, using Western blot analysis and immunohistochemistry with class-specific antisera. Western blot analysis of human skin cytosol revealed that class I-III ADH and class 1 and class 3 ALDH enzymes are expressed, constitutively, in three different anatomical regions of human skin (foreskin, breast, abdomen). Densitometric analysis of the immunoreactive bands revealed differential constitutive expression of these enzymes in foreskin, breast, and abdomen skin. Immunohistochemistry showed the presence of class I ADH and class III ADH enzymes, predominantly in the epidermis with some localised expression in the dermal appendages of human skin. In comparison, staining for class II ADH was more faint in the epidermis with very little dermal expression. Class 1 ALDH and class 3 ALDH were predominantly localised to the epidermis with minimal, highly localised dermal appendageal expression. These cutaneous ADH and ALDH enzymes may play significant roles in the metabolism of endogenous or xenobiotic alcohols and aldehydes.

Production and in situ localization of cutaneous tumour necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) following skin sensitization.

The induction of contact sensitization and other cutaneous immune responses is dependent upon the activity of epidermal cytokines. One such, keratinocyte-derived tumour necrosis factor alpha (TNF-alpha), is thought to provide the stimulus for the migration of Langerhans cells from the epidermis and their accumulation as immunocompetent dendritic cells in draining lymph nodes. In these investigations we have examined the stimulation by allergen of cutaneous TNF-alpha production and the induced epidermal expression of mRNA for TNF-alpha. Topical exposure of mice to oxazolone, a skin-sensitizing chemical, resulted in cutaneous TNF-alpha protein production that was maximal 2-h following treatment and then declined markedly. The same treatment resulted in highly localized and transient expression of epidermal TNF-alpha mRNA as judged by in situ hybridization. Epidermal mRNA for TNF-alpha was apparent 10 min following exposure to oxazolone, but was no longer detectable at 20 min. A similar pattern of TNF-alpha mRNA expression in the epidermis was provoked by intradermal exposure to interleukin 1 beta, a cytokine shown previously to induce TNF-alpha. Such rigorous regulation of temporal and spatial expression was shown not to be a characteristic of all epidermal cytokines induced by chemical allergen. Exposure to oxazolone under the same conditions resulted in a more widespread and more persistent expression of epidermal mRNA for interleukin 6. These data demonstrate that during skin sensitization the induced expression of epidermal TNF-alpha is finely controlled in space and time. It is proposed that such regulation facilitates the initiation of cutaneous immune responses while preventing excessive inflammation that would result from more persistent TNF-alpha production.

Comparative in vitro skin absorption and metabolism of coumarin (1,2-benzopyrone) in human, rat, and mouse.

The in vitro percutaneous absorption and skin metabolism of coumarin (1,2-benzopyrone) was studied in metabolically viable human, rat (F344), and mouse (CD1 and DBA/2) skin. Following application of [14C]coumarin (3.7 microg/cm2; 0.02% in ethanol) to unoccluded skin in flow-through diffusion cells of a skin absorption model (SAM), the absorption through the skin into the receptor fluid at 72 hr was rapid and extensive in all species, reaching (mean +/- SD) 50.4 + 9.1% of the applied dose in human, 51.3 +/- 7.3% in rat, and 44.9 +/- 13.5% in mouse. When the skin was occluded immediately after exposure, the extent of absorption at 72 hr was enhanced in all species. At 72 hr, substantial amounts of [14C]coumarin were found in unoccluded mouse skin (31.7 +/- 13.6%), with less in human (10.2 +/- 6.5%) and rat (12.7 +/- 5.0%) tissue. When occluded, the skin residues at 72 hr were 10.4 +/- 11.7% (mouse), 8.5 +/- 3.9% (human), and 11.9 +/- 7.5% (rat). The absorption of coumarin through rat skin into the receptor fluid over 72 hr was linearly related to the applied dose (r2 = 0.998 unoccluded skin; r2 = 0.999 occluded skin) over the dose range 3.7 to 378.7 microg/cm2. The nature and extent of cutaneous metabolism was studied following (i) topical application for 24 hr to human, rat, and mouse skin in the SAM system; (ii) incubation at 37 degrees C for up to 6 hr with human, rat, and mouse whole skin homogenates; and (iii) incubation at 37 degrees C for up to 24 hr with freshly isolated and cultured human epidermal keratinocytes. HPLC and GCMS analyses of skin extracts and receptor fluid confirmed that, in all three species, only the parent compound, coumarin, was present at all times from 10 min to 24 hr. These data indicate that topically applied coumarin is rapidly and extensively absorbed through human, rat, and mouse skin, and that the compound remains metabolically unchanged during absorption. These observations may have implications for the safe and effective use of coumarin in consumer products which come into contact with the skin and as a topical therapeutic agent.

Cutaneous xenobiotic metabolism: glycine conjugation in human and rat keratinocytes.

Glycine conjugation is an important route of metabolism and detoxication of carboxylic acids in the liver. In this paper the in vitro cutaneous metabolism of [carboxyl-14C]benzoic acid to its glycine conjugate hippuric acid in rat and human skin is reported. Cutaneous glycine conjugation was studied in F344 rat and human epidermal keratinocytes using two systems: (1) freshly isolated keratinocytes in suspension and (2) primary keratinocyte cultures. For comparative purposes, studies were also carried out in freshly isolated and cultured F344 rat hepatocytes. After incubation of 5 x 10(6) cells with 1 microM benzoic acid at 37 degrees C for 8 hr, no glycine conjugation was observed in rat and human keratinocyte suspensions, with greater than 98% of the radioactivity recovered as the parent compound. In contrast, cultured keratinocytes exhibited glycine conjugation, with 10.9 +/- 1.0% (mean SEM, n = 3) and 2.1 +/- 0.6% (mean SEM, n = 3) conversion to hippuric acid at 8 hr in rat and human cells, respectively. Tissue-specific differences in metabolism were observed, with conjugation in hepatocytes significantly greater (P < 0.05) than in keratinocytes at all times up to 8 hr. After incubation of benzoic acid with cultured hepatocytes for 8 hr, more than 98% of the of the radioactivity was recovered as the glycine conjugate. These studies indicate that rat and human skin possesses low, but demonstrable, glycine-conjugating activity, and that keratinocytes in primary culture may provide a better system than freshly isolated cell suspensions for studying such activity.

Decontamination procedures after in vitro topical exposure of human and rat skin to 4,4'-methylenebis[2-chloroaniline] and 4,4'-methylenedianiline.

4,4'-Methylenebis[2-chloroaniline] (MbOCA) and 4,4'-methylenedianiline (MDA) are widely used industrial chemicals classified as suspect human carcinogens. There is considerable occupational skin exposure to these compounds, and consequently, it is important to establish an efficient washing procedure after skin contamination. Four washing solutions were studied (100% ethanol, 100% water, 1 and 10% (v/v) aqueous soap) using fresh human and male F344 rat skin in flow-through diffusion cells. All solutions were equally effective at removing MbOCA and MDA from the surface of human skin, with 21-47% of the applied dose removed at 72 hr. In contrast, with rat skin 100% water and 1% soap solution were significantly less (p < 0.05) effective than 10% soap solution and 100% ethanol at removing MbOCA and MDA. Washing the skin surface at 3 or 30 min significantly reduced (p < 0.05) the absorption of MbOCA and MDA into and through human and rat skin at 72 hr by two- to threefold, compared with control unwashed skin. Washing the skin after this critical time point did not significantly reduce the absorption. These studies suggest that MbOCA and MDA are rapidly absorbed from the skin surface into the skin. Therefore, in order to reduce systemic exposure, the skin must be washed within the first 30 min after contamination has occurred. For human skin, the choice of washing solution employed was not as critical as the time of washing. This is in contrast to the rat, where the higher concentration soap and ethanol solutions were more effective for skin decontamination.

Percutaneous absorption of benzyl acetate through rat skin in vitro. 3. A comparison with human skin.

The comparative absorption of the fragrance and industrial compound, benzyl acetate, has been studied in rat and human skin, using shaved, full-thickness dorsal skin of male Fischer 344 rats and full-thickness human skin obtained from patients undergoing surgical resection. Penetration of the compound through rat and human skin was evaluated in vitro in flow-through diffusion cells following topical application of neat [methylene-14C] benzyl acetate (33.1 mg/cm2) to the epidermal surface and occlusion with a teflon cap, 2.9 cm above the skin surface. The absorption of benzyl acetate across rat skin was rapid and extensive, reaching 34.3 +/- 3.9% of the applied dose (11.3 +/- 1.3 mg/cm2) (mean +/- SD, n = 12) at 24 hr and 55.8 +/- 5.0% of the applied dose (18.5 +/- 1.7 mg/cm2) at 72 hr. The penetration of benzyl acetate was significantly (P < 0.05) less rapid and extensive through human skin, reaching 5.5 +/- 0.1% of the applied dose (1.8 +/- 0.0 mg/cm2) (mean +/- SD, n = 12) at 24 hr and 17.8 +/- 3.3% of the applied dose (5.9 +/- 1.1 mg/cm2) at 72 hr. The rate of penetration of benzyl acetate was greater through rat skin than through human tissue at all time points studied up to 72 hr. The maximum rate of skin penetration was 0.6 +/- 0.1 mg/cm2/hr and 0.1 +/- 0.0 mg/cm2/hr through rat and human skin, respectively. These data indicate that systemic exposure to benzyl acetate may occur after skin contact in humans. They also support the evidence from the literature that human skin is generally less permeable to xenobiotics than rat skin.

Correlation between lipid-associated sialic acid and tumor burden in melanoma.

Recent studies have suggested that lipid-associated sialic acid (LSA) may be a useful tumor marker for monitoring patients with melanoma, but the relationship between LSA and tumor burden has not been previously studied. We therefore examined LSA levels in 240 patients of whom 169 had no clinical evidence of disease (NED) and 71 had metastatic disease. There was a statistically significant difference in LSA levels in patients with NED compared with metastatic disease as well as those with high tumor burden compared with low or intermediate tumor burden. There was no difference between the groups with low and intermediate tumor burden. An LSA level of 25 mg/dl provided a positive predictive value of 70% and a negative value of approximately 80%. Our data show that LSA levels correlate with tumor burden in patients with melanoma.