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Information from a preceding lipid study contributed to the pathobiological assessment of laryngeal squamous cell carcinoma (LSCC). Lipid-driven signaling pathways are responsible for laryngeal carcinogenesis and immunodeficiency. The construction of fatty acid (FA) profiles for LSCC allowed the identification of FA role players. The integration of lipid and clinicomolecular information encountered in the literature, in turn, allowed the identification of biological prognostic markers to distinguish between early (less aggressive) and advanced (more aggressive) LSCCs. High arachidonic acid (AA) and cyclooxygenase (COX-2) activities are criteria for less aggressive growth, whilst low AA and COX-2 activities occur during more aggressive growth. Excessive tobacco use and environmental smoke or human papillomavirus (HPV) infection and alcohol abuse can, respectively, elicit cumulative oxidative stress and an oxidative burst or interfere with signaling pathways during essential fatty acid (EFA) metabolism, all factors and events which may cause LSCC. Research revealed that enhanced COX-2 activity and Bcl-2 expression prevent apoptosis and, hence, LSCCs become resistant to radiotherapy. It was also observed that recurrent laryngeal cancers become more aggressive after radiotherapy failure. It is predicted that manipulation of AA activity and consequently a cascade of downstream factors that include COX-2 and Bcl-2 expression responsible for LSCC may have therapeutic potential to improve radiotherapy outcome during early LSCC. Adjuvant FA therapy to improve early LSCC management by counteracting radiotherapy failure and unwanted complications for further management is proposed. FA therapeutic strategies before and during radiotherapeutic courses need to be evaluated.

In the third part of this study a basic lipid model (regarding phospholipids, triglycerides, cholesterol esters and free fatty acids) for keloids (n=20), compared with normal skin of keloid prone and non-keloid prone patients (n=20 of each), was constructed according to standard methods, to serve as a sound foundation for essential fatty acid supplementation strategies in the prevention and treatment of keloid formations. Essential fatty acid deficiency (EFAD) of the omega-6 series (linoleic acid (LA), g-linolenic acid (GLA), and dihomo-g-linolenic acid (DGLA)) and the omega-3 series (a-linolenic acid (ALA) and eicosapentaenoic acid (EPA)), but enhanced arachidonic acid (AA) levels, were prevalent in keloid formations. Enhanced AA, but a deficiency of AA precursors (LA, GLA and DGLA) and inflammatory competitors (DGLA and EPA), are inevitably responsible for the overproduction of pro-inflammatory metabolites (prostaglandin E(2)(PGE(2))) participating in the pathogenesis of inflammation. Of particular interest was the extremely high free oleic acid (OA) levels present, apart from the high free AA levels, in the keloid formations. OA stimulates PKC activity which, in turn, activates PLA(2)activity for the release or further release of AA from membrane pools. Interactions between EFAs, eicosanoids, cytokines, growth factors and free radicals can modulate the immune response and the immune system in undoubtedly involved in keloid formation. The histopathology of keloids can be adequately explained by: persistence of inflammatory- and cytokine-mediated reactions in the keloid/dermal interface and peripheral areas, where fibroblast proliferation and continuous depletion of membrane linoleic acid occur; microvascular regeneration and circulation of sufficient EFAs in the interface and peripheral areas, where maintenance of metabolic active fibroblasts for collagen production occur; microvessel occlusion and hypoxia in the central areas, where deprivation of EFAs and oxygen with consequent fibroblast apoptosis occur, while excessive collagen remain. All these factors contribute to different fibroblast populations present in: the keloid / dermal interface and peripheral areas where increases in fibroblast proliferation and endogenous TGF-b occur, and these metabolic active fibroblast populations are responsible for enhanced collagen production: the central areas where fibroblast populations under hypoxic conditions occur, and these fibroblasts are responsible for excessive collagen production. It was concluded that: fibroblast membrane EFAD of AA precursors and inflammatory competitors, but prevailing enhanced AA levels, can contribute to a chain of reactions eventually responsible for keloid formations., (Copyright 2000 Harcourt Publishers Ltd.)

In the second part of this study, emphasis is placed on nutritional intakes (fatty acids and micronutrients) and fatty acid intake and metabolism in the blood, respectively, according to a combined 24 h recall and standardized food frequency questionnaire analyses of keloid prone patients (n=10), compared with normal black South Africans (n=80), and total phospholipid blood (plasma and red blood cell ) analyses of keloid patients (n=20), compared with normal individuals (n=20). Lipid extraction and fractionation by standard procedures, total phospholipid (TPL) separation with thin layer chromatography, and fatty acid methyl ester analyses with gas liquid chromatography techniques were used. Since nutrition may play a role in several disease disorders, the purpose of this study was to confirm or refute a role for essential fatty acids (EFAs) in the hypothesis of keloid formations stated in part 1 of this study. (1)According to the Canadian recommendation (1991), we observed that in keloid patients linoleic acid (LA) and arachidonic acid (AA) dietary intakes, as EFAs of the omega-6-series, are higher than the recommended 7-11 g/d. However, the a-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) dietary intakes, as EFAs of the omega-3 series, are lower than the recommendation of 1.1-1.5 g/d. This was also the case in the control group, where a higher dietary intake of the omega-6 fatty acids and a slightly lower dietary intake of the omega-3 fatty acids occurred. Thus, we confirm a high dietary intake of LA (as a product of organ meats, diary products and many vegetable oils) and AA (as a product of meats and egg yolks), as well as lower dietary intakes of ALA (as a product of grains, green leafy vegetables, soy oil, rapeseed oil and linseed), and EPA and DHA (as products of marine oils). Lower micronutrient intakes than the recommended dietary allowances were observed in the keloid group that may influence EFA metabolism and/or collagen synthesis. Of cardinal importance may be the lower intake of calcium in the keloid patients that may contribute to abnormal cell signal transduction in fibroblasts and consequent collagen overproduction, and the lower copper intake that may influence the immune system, or perhaps even the high magnesium intake that stimulates metabolic activity. Micronutrient deficiencies also occurred in the diets of the normal black South Africans that served as a control group. In the case of plasma TPLs, deficiency of the omega-3 EFA series (ALA, EPA and DHA) occurred, and this is in accordance with the apparent lower omega-3 EFA intake in the diets of these patients. In the case of the red blood cell TPLs, as a true and reliable source of dietary fatty acid intake and metabolism, sufficient EFAs of the omega-6 series (LA and AA) and the omega-3 series (ALA, EPA and DHA) occurred. For this study group a relative deficiency of nutritional omega-3 EFA intake apparently did occur, but was probably compensated for by blood fatty acid metabolism., (Copyright 2000 Harcourt Publishers Ltd.)

In the first part of this study a general overview on the hypertrophic scar and keloid phenomena regarding history, epidemiology, histopathology and aetiology, in general, together with an essential fatty acid approach as basis for hypotheses of keloid formation and prevention are given. Upon reviewing the literature in planning a strategy for prevention and treatment of keloids, one encounters an overwhelming amount of hypotheses on this topic. Based on a preliminary study on total fatty acid compositions in keloids, compared with normal skin of keloid prone and non-keloid prone patients, there can be argued as follows: an essential fatty acid deficiency of precursors and inflammatory competitors for arachidonic acid may be a factor in the multifactorial aetiology of keloid formations, and apart from a local essential fatty acid deficiency in the wound area, nutrition may also be a contributing factor in rural black South Africans. To confirm or refute the stated hypotheses of the role of essential fatty acids in keloid formation and prevention (outlined in this part of the study), dietary questionnaires and blood (plasma and red blood cell) phospholipid analyses for general information and true fatty acid intake and metabolism, respectively, in the diets of these patients (outlined in part II of this study), as well as a lipid model for keloid formations regarding phospholipids, triglycerides, cholesterol esters and free fatty acids (outlined in part III of this study), are given. The purpose of this comprehensive fatty acid study was an attempt to assess the enigma surrounding keloids and to end the nightmare of the plastic and reconstructive surgeon, since these dermal tumours are notoriously recurrent., (Copyright 2000 Harcourt Publishers Ltd.)

The purpose of the third part of this study is to construct a basic lipid model (this includes information regarding total and free saturated, monounsaturated and polyunsaturated fatty acid contents, as well as total and free fatty acid saturation and double bond indexes, and comparisons of total and free n-3, n-6, n-7 and n-9 fatty acids in normal epithelial tissue, and intraepithelial and infiltrating lesions of the cervix) which, together with the individual total and free fatty acid profiles given in parts I and II of this study, should provide an understanding of the turnover of total and free acids, especially essential fatty acids, during cervical carcinogenesis. Such information can serve as a sound basis for further studies in an attempt to access this disease process. We observed an increase in monounsaturated fatty acid values in cancer tissue compared with normal tissue and a decrease of saturated fatty acid values in cancer tissue compared with normal tissue. Based on our observations, we speculate that because of the depletion of polyunsaturated fatty acids, monounsaturated fatty acid are synthesized to compensate for this loss; a possible source for the monounsaturated fatty acids are the saturated fatty acids via elongation and/or desaturation. Of particular interest is the n-3 fatty acid docosahexaenoic acid, the most unsaturated lipid in the biological systems, detected in very small amounts only in cancer cells of the cervix.

In the first part of this study, the possible role of essential total fatty acids and their metabolites during cervical carcinogenesis was investigated. Since membrane lipids play a key role in cell proliferation and differentiation, disturbances in the fatty acid compositions of cell membranes and the modulation of membrane fatty acid compositions received attention in several in vitro studies. There are, however, no reported studies where the actual total and free (unesterified) fatty acid compositions have been determined during the different stages of cervical carcinogenesis. In part I of this ex vivo study, the total fatty acid compositions of normal tissue, intraepithelial and infiltrating lesions of the cervix were compared. The fatty acid profiles that were determined make it possible to speculate about the metabolic pathways followed during cervical carcinogenesis. Lipids were extracted from biopsies of normal tissue (n=36), cervical intraepithelial lesions (n=47) and infiltrating lesions (n=47). Samples, from which the total fatty acid compositions were determined, were saponified, methylated and analysed by gas liquid chromatography (GLC). Essential fatty acid deficiency (EFAD) in the intraepithelial lesions, compared with normal tissue (linoleic acid, P< 0.01), and infiltrating lesions, compared with intraepithelial lesions (linoleic acid and arachidonic acid, P< 0.01) were observed. High levels of oleic acid were also observed when infiltrating lesions were compared with normal tissue (P< 0.01). This EFAD in cancer cells may result in many defective cell mechanisms. Although there are many risk factors for cervical cancer, the human papilloma virus has emerged over the past decade as the leading candidate to be an aetiological factor. There is ample evidence that human viral infections are associated with reduced levels of linoleic acid and thus participate in the depletion of essential fatty acids in cancer cells.

In the second part of this study, the emphasis is on the free fatty acids during cervical carginogenesis, since they may reflect active cell metabolism during this disease process. Lipids were extracted from biopsies of normal epithelial tissue (N) (n=36), cervical intraepithelial lesions (CIL) (n=47), and infiltrating lesions (Ca) (n=47) of the cervix. Samples, from which the free fatty acid compositions were determined, were saponified, methylated and analysed by GLC. In accordance with results obtained on total fatty acid compositions, essential fatty acid deficiency (EFAD) in the intraepithelial lesions, compared with normal tissue (linoleic acid, P< 0.01), and infiltrating lesions compared with intraepithelial lesions (linoleic acid and arachidonic acid, P< 0.01) were observed. High levels of oleic acid were also observed when infiltrating lesions were compared with normal tissue (P < 0.01). As previously mentioned by us in part I of this study, with regard to possible disturbances in metabolic pathways based on the total fatty acid profiles during stages of cervical cancer, EFAD is prevalent during cervical carcinogenesis. This EFAD in cancer cells may result in many defective cell mechanisms, since fatty acids are associated with biochemical events such as lipid peroxidation, signal transduction and immune responses. The high level of oleic acid in cancer cells is known to activate PKC and thus contribute to the continous growth stimulus thought to exist in malignant cells. From a therapeutic viewpoint, substantial changes in the fatty acid composition of the membranes can be produced in cancer cells by selective fatty acid supplementation strategies. At present, modifications of the fatty acid compositions of cell membranes represent an experimental model that has promoted increased understanding of lipid transportation, membrane remodelling, and the relationship between membrane lipids and membrane function. By addressing factors responsible for insufficient essential fatty acid levels, carginogenesis may be prevented or treated. The clinical feasibility of using modification of fatty acids in tumours or cancer by diet or perfusion as an adjunct to standard therapies should be tested.