The College of Nuclear Physicians of South Africa Practice Guidelines on Peptide Receptor Radionuclide Therapy in Neuroendocrine Tumours.

BACKGROUND: Peptide receptor radionuclide therapy (PRRT) for metastatic or inoperable neuroendocrine tumours (NETs) is a systemic therapy which targets somatostatin receptors overexpressed by differentiated NETs for endoradiotherapy. This guideline has been compiled by the College of Nuclear Physicians of the Colleges of Medicine of South Africa, with endorsement by the South African Society of Nuclear Medicine and the Association of Nuclear Physicians to guide Nuclear Medicine Physicians in its application during the management of these patients. RECOMMENDATIONS: Patients with well- to moderately-differentiated NETs should be comprehensively worked-up to determine their suitability for PRRT. Treatment should be administered by a Nuclear Medicine Physician in a licensed, appropriately equipped and fully staffed facility. Patient monitoring is mandatory during and after each therapy cycle to identify and treat therapy-related adverse events. Patients should also be followed-up after completion of therapy cycles for monitoring of long-term toxicities and response assessment. CONCLUSION: PRRT is a safe and effective therapy option in patients with differentiated NETs. Its use in appropriate patients is associated with a survival benefit.

Sonar guided focused parathyroidectomy under cervical block.

BACKGROUND: Presentation of hyperparathyroidism varies and is highly non-specific. The automated calcium analyzer has made the diagnosis easy. Similarly, the advent of Sestamibi scan has paved the way to minimally invasive parathyroidectomy indicated for parathyroid adenoma. There is no uniformity in the extent of minimally invasive parathyroidectomy that is done through limited incision under radio or sonar guidance and endoscopically. In this study, we are presenting the focused parathyroidectomy performed under sonar guidance and superficial cervical block (SCB). The prerequisite is concordant preoperative Sestamibi and ultrasound imaging. METHOD: A two-year review of parathyroidectomies performed between January 2013 and December 2014. OBJECTIVE: To reflect on the result of sonar-guided focused parathyroidectomy under SCB. RESULTS: There was good correlation between the pre-operative imaging, the intra-operative findings and the postoperative histology result of the 15 cases analysed. CONCLUSION: The focused parathyroidectomy under SCB yielded a good result with concordant preoperative Sestamibi and ultrasound findings.

Acquired cholesteatoma: summary of the cascade of molecular events.

BACKGROUND: Cholesteatoma is considered a benign, gradually expanding and destructive epithelial lesion of the temporal bone. The pathogenesis of different classifications of cholesteatoma is marked by similar underlying cellular and molecular processes. Stepwise explanations of the histopathogenesis have been described previously. The current paper focuses on expounding the molecular events of cholesteatoma. METHOD AND RESULTS: Cholesteatoma pathogenesis encompasses a complex network of signalling pathways during: epidermal hyperplasia, perimatrix-matrix interactions and mucosal disease. This paper presents a review of the molecular events driven by inflammatory mediators and enzymes during: cholesteatoma growth (cell proliferation and apoptosis); maintenance and deterioration (angiogenesis and hypoxia, oxidative stress and toxicity); and complications (bone erosion and hearing loss). The cascade of molecular events applicable to atelectasis and cholesteatoma that coexist with chronic otitis media and bone erosion as sequelae is summarised. CONCLUSION: The role of lipids in this disease is relatively unexplored, but there is evidence in support of fatty acid role-players that needs confirmation. Future directions in lipid research to delineate molecular mechanisms are proposed.

Rationale for adjuvant fatty acid therapy to prevent radiotherapy failure and tumor recurrence during early laryngeal squamous cell carcinoma.

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.

Ex vivo study of MAPK profiles correlated with parameters of apoptosis during cervical carcinogenesis.

Cervical cancer is a leading cause of death in developing countries and is the second highest occurring cancer in women all over the world. The progression of cancer is a multistep process affecting aspects of cellular function such as proliferation, differentiation and apoptosis. Mitogen activated protein kinases (MAPKs), which include p38-MAPK, c-Jun NH(2)-terminal kinase (JNK) and extracellular signal-regulated kinases (ERKs) are closely associated with cell proliferation and apoptosis and the balance between them could determine a cell's fate. Despite the expanding research effort in vitro, little is known about MAPK activation in clinical specimens of cervical cancer. Therefore, the aim of this ex vivo study was to correlate the phosphorylation status (activity) of MAPKs (p38-MAPK, JNK and ERK), as well as poly (ADP-ribose) polymerase (PARP) and caspase-3 (two cellular markers of apoptosis), during the different stages of cervical carcinogenesis, to observe whether correlations between MAPK activities and apoptosis during the disease process exist. Decreased p38-MAPK phosphorylation was found in the carcinoma (Ca) group) compared to the normal tissues, as well when the low grade squamous intraepithelial lesion--LSIL) group and high grade squamous intraepithelial lesion--HSIL) group were compared with the Ca group. Interestingly, a significant decrease in ERK44 phosphorylation was observed in Ca when compared to LSIL and HSIL. There was also a significant decrease in JNK phosphorylation in Ca when compared with normal tissue and HSIL. As expected, caspase-3 activation and PARP cleavage was significantly lower in Ca when compared with normal tissue. Our results present the first evidence of in vivo involvement of MAPKs in cervical cancer and indicate a possible correlation between MAPK activities and apoptosis in the disease process.

Keloids in rural black South Africans. Part 1: general overview and essential fatty acid hypotheses for keloid formation and prevention.

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.

Keloids in rural black South Africans. Part 3: a lipid model for the prevention and treatment of keloid formations.

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.

Comparison of the fatty acid compositions in intraepithelial and infiltrating lesions of the cervix: part I, total fatty acid profiles.

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.

Comparison of the fatty acid compositions in intraepithelial and infiltrating lesions of the cervix: part II, free fatty acid profiles.

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.

Comparison of the fatty acid compositions in intraepithelial and infiltrating lesions of the cervix: part III, saturated and unsaturated fatty acid profiles.

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.

Correlation between histopathology and linoleic acid levels in five meningioma types.

The total fatty acid compositions of neoplastic tissues in 5 different meningioma types (meningotheliomatous, transitional, vascular, fibroblastic, atypical), analysed by gas-liquid chromatography, are presented in correlation with their histopathology. The benign meningioma types (first 3) had higher relative percentages of linoleic acid, compared to the apparently malignant meningioma types (fibroblastic, atypical). From these results it is suggested that a high relative percentage of linoleic acid is characteristic of benign neoplastic growth, while a low relative percentage may correlate with increased malignancy.