Gastro-intestinal stromal tumours (GISTs) - the Pretoria experience and a literature review.

AIM: To analyse the presentation and management of patients with gastrointestinal stromal tumours (GISTs) at Pretoria hospitals. DESIGN: A retrospective study was done in which all available clinical records of primary c-KIT positive GISTs were analysed. SETTING: Secondary and tertiary care institutions in Pretoria, including both private and public hospitals. Subjects. The population studied included all individuals treated at Pretoria hospitals from 17 July 2000 to 1 April 2009 who had a GIST confirmed with immunohistochemical c KIT staining. Patients with incomplete or inaccessible clinical records were excluded. Outcome measures. Patient demographics including gender, age and race; presenting symptoms and signs; results of special investigations; and treatment. RESULTS: Fifty-four cases were identified for inclusion in the study. The age of the subjects ranged from 15 to 83 years. The male-to-female ratio was 1.5:1. The organ most commonly affected was the stomach, and abdominal pain and weight loss were the most common presenting symptoms. Seventy-six per cent of the patients were treated surgically, and 24% received Imatinib. CONCLUSION: GISTs often present late with non-specific symptoms, and are frequently discovered incidentally. Large tumours tend to be malignant.

Health; Well-Being and Wellness: an Anthropological Eco-Systemic Approach

More than two decades ago; Fritjof Capra commended - and indeed advocated - a paradigm shift in health science and care. In his book The Turning Point (1982) he talks of a major shift from the preoccupation with micro-organisms to a careful study of the `host organism and its environment'; of `significant attempts to develop a unified approach to the mind/body system' in Western medicine; of `a new holistic paradigm' (as opposed to `the old biomedical paradigm') regarding the problem of health and healing; of `a holistic and humanistic approach to primary care'; and of `a holistic therapy' as opposed to `the traditional biochemical practice of associating a physical disease with a specific physical cause'. Our concern in this article is with the paradigm shift advocated by Capra in this book and the progress that has since been made

Personality and academic performance of three cohorts of veterinary students in South Africa.

To aid in selecting students for admission to undergraduate veterinary training, admissions procedures often take into account students' previous academic performance as well as the results of an interview. The study reported here investigated the relationship between personality and academic success. Students from three entry cohorts to the second year of study of a six-year BVSc program at the University of Pretoria completed the 16 Personality Factor Questionnaire. A meta-analytic approach was used to estimate the relationship between academic performance in two major final-year subjects and academic performance on entry, an interview score, and the personality factors. The study confirmed the value of previous academic performance and the interview in selecting students for the veterinary degree program. The findings also indicate that the inclusion of a measure of intellectual ability could be of value. The value of various personality characteristics in predicting good study habits and examination performance is highlighted by the study results: students were more successful if they were conscientious, emotionally stable, socially adept, self-disciplined, practical rather than imaginative, and relaxed rather than anxious. It appears worthwhile to consider including an appropriate personality questionnaire in the selection process to improve the accuracy of predictions of students' success. A sound personality make-up will not only increase the likelihood of academic success but should also be beneficial in the successful management of a veterinary practice and in enjoying veterinary science as a career.

Early neoplastic and metastatic mammary tumours of transgenic mice detected by 5-aminolevulinic acid-stimulated protoporphyrin IX accumulation.

A photodynamic technique for human breast cancer detection founded upon the ability of tumour cells to rapidly accumulate the fluorescent product protoporphyrin IX (PpIX) has been applied to transgenic mouse models of mammary tumorigenesis. A major goal of this investigation was to determine whether mouse mammary tumours are reliable models of human disease in terms of PpIX accumulation, for future mechanistic and therapeutic studies. The haeme substrate 5-aminolevulinic acid (5-ALA) (200 mg kg(-1)) was administered to mouse strains that develop mammary tumours of various histological subtypes upon expression of the transgenic oncogenes HRAS, Polyoma Virus middle T antigen, or Simian Virus 40 large T antigen in the mammary gland. Early neoplastic lesions, primary tumours and metastases showed consistent and rapid PpIX accumulation compared to the normal surrounding tissues, as evidenced by red fluorescence (635 nm) when the tumours were directly illuminated with blue light (380-440 nm). Detection of mouse mammary tumours at the stage of ductal carcinoma in situ by red fluorescence emissions suggests that enhanced PpIX synthesis is a good marker for early tumorigenic processes in the mammary gland. We propose the mouse models provide an ideal experimental system for further investigation of the early diagnostic and therapeutic potential of 5-ALA-stimulated PpIX accumulation in human breast cancer patients.

Preoperative esophageal manometry does not predict postoperative dysphagia following anti-reflux surgery.

This prospective study was undertaken to determine the value of manometric studies in predicting postoperative dysphagia in patients undergoing laparoscopic Toupet fundoplication. Two hundred and twenty-nine out of 401 patients (57%) had preoperative dysphagia, and 26 patients had late postoperative dysphagia (6.5%). Eight patients who had no preoperative dysphagia developed dysphagia following surgery. There were no significant differences in esophageal motility for patients without postoperative dysphagia (n = 375) compared with those with postoperative dysphagia (n = 26). Among patients with postoperative dysphagia as a new symptom (n = 8), six had normal preoperative distal esophageal pressures, and none had esophageal hypomotility. In those with both pre- and postoperative dysphagia 15 of 18 had normal esophageal motility and hypomotility was only found in one. The positive predictive values of distal esophageal hypomotility and other measures for postoperative dysphagia are poor. In conclusion, preoperative manometry does not predict postoperative dysphagia following laparoscopic Toupet partial fundoplication.

Endovascular treatment of intractable epistaxis--results of a 4-year local audit.

OBJECTIVE: Transcatheter embolisation is an accepted and effective treatment for intractable epistaxis. We analysed our success and complication rates and compared these with results from other published series. DESIGN: Retrospective review. SETTING: Unitas Interventional Unit, Centurion. METHODS: Case record review (57 procedures) and telephonic interviews (36 traceable respondents). OUTCOME MEASURES: A numerical audit of the success and complication rates for embolisation procedures performed during the 4-year period between July 1999 and June 2003. RESULTS: A total of 57 endovascular embolisation procedures were performed for intractable epistaxis in 51 patients during this period. Eight patients (15.7%) developed a re-bleed between 1 and 33 days after embolisation, of whom 5 were reembolised, giving a primary short-term success rate of 86.3% and secondary assisted success rate of 94.1%. Thirty-five of 36 respondents (97.2%) reported no further epistaxis during the long-term follow-up period of 1-47 months. The mortality rate was 0%, the major morbidity rate was 2% (1 stroke) and the minor morbidity rate was 25%. CONCLUSION: Our success and complication rates are acceptable and compare favourably with those reported in other large series.

Ciliary motility in bovine oviducts for sensing rapid non-genomic reactions upon exposure to progesterone.

Based on the expression of hormone receptors, oviductal cells receive a series of signals to control the conduit and transport of gametes. Most cells in the inner oviductal mucosa have motile cilia, and the mucociliary system of oviducts represents a prominent object of study for rapid feedback after application of steroid hormones. Using a high-speed reflectometry method, we investigated effects on the ciliary beat frequency (CBF) of bovine oviductal explants after progesterone treatment. To classify changes of CBF as either classic or non-classic reactions, we pretreated primary tissue cultures with mifepristone, an antagonist to the classic progesterone receptor in a second experimental series. In contrast to classical genomic reactions, non-classic or non-genomic reactions are characterized by fast effects, insensitive to the classic receptor antagonist. We observed inhibitory effects on the ciliary beat frequency as soon as 15 minutes after application of progesterone (20 microM), reaching a plateau of about 11 % after 90 minutes. Pretreatment with mifepristone (20 microM) for two hours did not induce significant differences in short-term reactions. However, the inhibitory influence of progesterone after 24 hours could be effectively prevented. Our data confirmed the short-term reaction of CBF as non-genomic or non-classic.

Photodynamic detection of diseased axillary sentinel lymph node after oral application of aminolevulinic acid in patients with breast cancer.

Benign as well as malignant tumour tissues of the breast demonstrate higher fluorescence intensity (FI) than normal breast tissue after application of a photosensitiser. As a follow-up study, we evaluated the FI of metastatic sentinel lymph nodes and metastatic axillary lymph nodes compared to nonmetastatic sentinel and axillary lymph nodes in patients with breast cancer. In all, 11 patients received 30 mg 5-aminolevulinic acid (ALA) kg(-1) bodyweight orally 3 h prior to surgery. The sentinel lymph node was marked with Nanocoll preoperatively and with a blue dye intraoperatively. Tumour excision, excision of the sentinel lymph node and an axillary lymph node dissection were performed during the same surgical session. The operation site was illuminated with blue light (400 nm) to obtain macroscopic tissue characterisation of fluorescence. Tissue samples were stored protected from light, and analysed using a fluorescence microscope. Results were correlated with histopathology. In all, 14 sentinel lymph nodes, seven axillary lymph nodes and seven primary tumours were analysed. Metastatic sentinel lymph nodes demonstrated a statistically significant higher FI than nonmetastatic sentinel lymph nodes (2630 vs 526, P<0.0001). The FI of metastatic sentinel lymph nodes, of metastatic axillary lymph nodes and of the primary tumour were comparably high, and were statistically significantly higher compared to the normal mammary tissue. Intraoperatively, only in a few cases, it was possible to recognise the metastatic sentinel lymph node macroscopically with blue light. Our study indicates that photodynamic diagnosis with ALA has a potential in the diagnosis and detection of the sentinel lymph node in patients with breast cancer, and is worth to be further investigated and developed for intraoperative photodynamic diagnosis and possibly therapy.

The Arthritis, Diet and Activity Promotion Trial (ADAPT): design, rationale, and baseline results.

Osteoarthritis (OA) of the knee leads to restrictions of physical activity and ability to perform activities of daily living. Obesity is a risk factor for knee OA and it appears to exacerbate knee pain and disability. The Arthritis, Diet, and Activity Promotion Trial (ADAPT) was developed to test the efficacy of lifestyle behavioral changes on physical function, pain, and disability in obese, sedentary older adults with knee OA. This controlled trial randomized 316 sedentary overweight and obese older adults in a two-by-two factorial design into one of four 18-month duration intervention groups: Healthy Lifestyle Control; Dietary Weight Loss; Structured Exercise; or Combined Exercise and Dietary Weight Loss. The weight-loss goal for the diet groups was a 5% loss at 18 months. The intervention was modeled from principles derived from the group dynamics literature and social cognitive theory. Exercise training consisted of aerobic and strength training for 60 minutes, three times per week in a group and home-based setting. The primary outcome measure was self-report of physical function using the Western Ontario and McMaster University Osteoarthritis Index. Other measurements included timed stair climb, distance walked in 6 minutes, strength, gait, knee pain, health-related quality of life, knee radiographs, body weight, dietary intake, and cost-effectiveness of the interventions. We report baseline data stratified by level of overweight and obesity focusing on self-reported physical function and physical performance tasks. The results from ADAPT will provide approaches clinicians should recommend for behavioral therapies that effectively reduce the incidence of disability associated with knee OA.

Photodynamic therapy of DNA mismatch repair-deficient and -proficient tumour cells.

Loss of DNA mismatch repair is a common finding in hereditary nonpolyposis colon cancer as well as in many types of sporadic human tumours. DNA mismatch repair-deficient cells have been reported to be resistant to many chemotherapeutic agents and to radiotherapy, and to have the potential of rapidly acquiring additional mutations leading to tumour progression. Photodynamic therapy is a new treatment modality using light to activate a photosensitiser that preferentially localises in tumour cells. An oxygen dependent photochemical reaction ensues, resulting in selective tumour necrosis. The effect of loss of DNA mismatch repair activity on the sensitivity to photodynamic therapy was tested using pairs of cell lines proficient or deficient in mismatch repair due to loss of either MLH1 or MSH2 protein function. Cells were incubated with the photosensitiser 5,10,15,20-meta-tetra(hydroxyphenyl)chlorin and exposed to laser light at 652 nm with various optical doses ranging from 0-1 J cm(-2). Cell survival was assessed using the clonogenic assay. Loss of MLH1 or MSH2 function was not associated with resistance to photodynamic therapy. MCF-7 cells repeatedly treated with photodynamic therapy expressed parental levels of MLH1, MSH2, MSH6, and PMS2. DNA mismatch repair-deficient and -proficient cells showed similar subcellular distributions of meta-tetra(hydroxyphenyl)chlorin as analysed by laser scanning and fluorescence microscopy. Therefore, repeated exposure of tumour cells to photodynamic therapy does not seem to result in loss of DNA mismatch repair, and loss of mismatch repair, in turn, does not seem to contribute to resistance to photodynamic therapy. Our results suggest recommending photodynamic therapy as a strategy for circumventing resistance due to loss of DNA mismatch repair.

Skin protection for photosensitized patients.

BACKGROUND AND OBJECTIVE: The goal of this study was to evaluate various creams for their capability to protect photosensitized skin from visible light. STUDY DESIGN/MATERIALS AND METHODS: Two cover creams and creams containing various combinations of Vaseline with TiO(2), ZnO, and Fe(2)O(3) were used to measure the reduced light transmission and the light absorption spectrum. In vitro and in vivo tests were performed to assess the protection from light by above mentioned compounds. RESULTS: The cover creams and the 50% TiO(2) cream showed similar efficacy in reducing light transmission, while the sunscreen was less efficient by a factor of 5. Cell protection by 25% TiO(2)+25% ZnO, TiO(2), or the cover creams was more efficient than protection by the sunscreen or other compounds. In vivo, the dark cover cream protected the skin by a factor of 3.4 better than the sunscreen. CONCLUSION: The dark cover cream has acceptable properties to protect photosensitized skin.

Primary ciliary dyskinesia with situs inversus totalis, hydrocephalus internus and cardiac malformations in a dog.

A nine-month-old golden retriever bitch was presented with exercise intolerance and recurrent nasal discharge. Based on clinical, radiographic and ultrasonographic examination, a diagnosis of rhinitis, situs inversus totalis and tricuspid valve insufficiency was established. The results of video- and electron microscopy studies of the respiratory epithelium were compatible with primary ciliary dyskinesia (PCD). However, no evidence of a primary ultrastructural defect of the cilia was found. The dog was euthanased because of the poor prognosis. At necropsy, a hydrocephalus internus and a subaortic stenosis were additionally diagnosed. PCD, in combination with situs inversus, has been previously reported in golden retrievers, but without a concomitant hydrocephalus internus. Furthermore, concomitant occurrence of internal cardiac malformation and PCD has not previously been reported in the dog.

Resistance to topoisomerase poisons due to loss of DNA mismatch repair.

Sporadic breast carcinomas demonstrate microsatellite instability, reflecting the presence of DNA mismatch repair-deficient cells, in about one fourth of cases at the time of diagnosis. Loss of DNA mismatch repair has been reported to result in resistance not only to cisplatin and alkylating agents but also to the topoisomerase II poison doxorubicin, suggesting an association between DNA mismatch repair and topoisomerase II poison-induced cytotoxicity. Our study investigates the relationship between loss of MSH2 or MLH1 function and sensitivity to the topoisomerase I and II poisons, and to the taxanes, 2 classes of cytotoxic drugs commonly used in breast cancer. Two pairs of cell lines proficient and deficient in mismatch repair due to loss of either MSH2 or MLH1 function were used. Loss of either MSH2 or MLH1 function resulted in resistance to the topoisomerase II poisons doxorubicin, epirubicin and mitoxantrone, whereas only loss of MLH1 function was associated with low-level resistance to the topoisomerase I poisons camptothecin and topotecan. In contrast, there was no resistance to docetaxel and paclitaxel. Our data support the hypothesis that both MSH2 and MLH1 are involved in topoisomerase II poison-mediated cytotoxicity, whereas only MLH1 is involved in topoisomerase I poison-mediated cytotoxicity. Since our study shows that loss of DNA mismatch repair does not result in resistance to the taxanes, these drugs can be recommended for use in breast cancer deficient in mismatch repair.

Photodynamic therapy of locoregional breast cancer recurrences using a chlorin-type photosensitizer.

Chest wall recurrences are a frequent problem in patients treated by mastectomy for breast cancer. Surgery and ionizing radiation are established treatment modalities in these cases. Photodynamic therapy (PDT) provides an alternative treatment modality using a photosensitizer and laser light to induce selective tumor necrosis. PDT was performed as compassionate use in 7 patients aged 57.6 years (+/-12.6 SD). A total of 89 metastatic skin nodes were treated in 11 PDT sessions. As photosensitizer meta-tetra(hydroxyphenyl)chlorin (m-THPC) was applied intravenously. Patients (n = 3) photosensitized with a drug dose of 0.10 mg/kg bodyweight were irradiated 48 hr after drug application at a lightdose of 5 J/cm(2). Patients (n = 4) were illuminated by an optical dose of 10 J/cm(2) 96 hr after photosensitization with 0.15 mg/kg. Laser light at a wavelength of 652 nm was generated by a diode laser and applied by a front lens light diffuser using a fluence rate of 20--25 mW/cm(2). PDT using m-THPC resulted in complete response in all patients. Response to treatment did not differ when using the 2 different drugdose protocols. Healing time depended mainly on the size of the illumination field but not on the lightdose. Pain score usually raised 1 day after PDT and lasted at higher levels for about 10 days. Healing time usually ranged between 8--10 weeks. Photodynamic technique offers a minimal-invasive, outpatient treatment modality for recurrent breast cancer on the chest wall with few side effects, high patient's satisfaction and with possible repetitive application.

Photodynamic diagnosis of breast tumours after oral application of aminolevulinic acid.

Photodynamic diagnosis is of increasing interest for diagnosis in oncology. It is based on a more intense incorporation of a fluorescent dye in tumours compared to normal tissue. As a feasibility study we investigated the effectiveness of oral application of 5-aminolevulinic acid for photodynamic diagnosis of human primary mammary tumours. The study included 16 patients with palpable breast tumours. Aminolevulinic acid was administered at a concentration of 40 mg kg(-1)bodyweight 150-420 min prior to tumourectomy. Intraoperatively blue light (405 nm) was applied to the operation site. Sections of the excised tumour and some lymph nodes were prepared and analysed with a fluorescent microscope. All primary mammary tumour tissues showed significantly higher fluorescence intensity than surrounding normal mammary tissue. Fluorescence of the mammary tumours could also be discriminated macroscopically and intraoperatively. Fluorescence intensity in nonmetastatic lymph node tissue was higher in 2 out of 3 patients than in primary tumour tissue. By photodynamic diagnosis using aminolevulinic acid we were able to reliably distinguish primary mammary tumours from normal mammary tissue microscopically and macroscopically in all our patients. We suggest that photodynamic diagnosis with aminolevulinic acid for breast tumours should be further investigated and developed for intraoperative use and may well be a simple tool for better intraoperative diagnosis and recognition of tumour margins. We hypothesize that lymph node metastasis of breast tumours will not be detectable by this method.

Hypercalcemic-type of small cell carcinoma of the ovary: characterization of a new tumor line.

BACKGROUND: The aim of this study was to develop and characterize a mouse xenograft model for the hypercalcemic-type of small cell carcinoma of the ovary (HTSCCO). PATIENTS AND METHODS: Tumor fragments were removed from a patient and cultured in six subsequent generations of nude mice. Histology, comparative genomic hybridization (CGH), electron microscopy and serum calcium levels were investigated. RESULTS: Morphology remained the same from the primary tumor of the patient through the 6th passage in the mouse. Serum calcium levels were significantly higher in the tumor-bearing mice compared to controls. CGH of the HTSCCO did not show evidence of a close relationship to either a germ cell tumor or an epithelial ovarian cancer. CONCLUSION: Some evidence was provided that the HTSCCO is an inhomogeneous tumor that is neither related to a germ cell tumor nor to an epithelial ovarian cancer, but is a distinct tumor entity.

PEG-m-THPC-mediated photodynamic effects on normal rat tissues.

Photodynamic therapy (PDT) of malignancies uses light to activate a photosensitizer preferentially accumulated in cancer cells. The first pegylated photosensitizer, tetrakis-(m-methoxypolyethylene glycol) derivative of 7,8-dihydro-5,10,15,20-tetrakis(3-hydroxyphenyl)-21-23-[H]-porphyrin (PEG-m-THPC), was evaluated in non-tumor-bearing rats. The aim of this study was to assess the photodynamic threshold for damage and its sequelae in normal rat tissue. Thirty-five Fischer rats were sensitized with 3, 9 or 30 mg/kg body weight PEG-m-THPC. Colon, vagina and perineum were irradiated with laser light of 652 nm wavelength and an optical dose of 50, 150 or 450 J/cm fiber length. Temperature in the pelvis was measured during PDT. Three days following PDT the effect on skin, vagina, colon, striated muscle, connective tissue, nerves and blood vessels was assessed by histology. The healing of the above-mentioned tissues was assessed on two rats 3 and 8 weeks after PDT using 9 mg/kg PEG-m-THPC activated with 450 J/cm laser light. No dark toxicity was observed. PDT using 30 mg/kg PEG-m-THPC induced severe necrosis irrespective of the optical dose. Body weight of 9 or 3 mg/kg activated with less than 450 J/cm induced moderate or no damage. No substantial increase in body temperature was seen during PDT. Tissues with severe PDT-induced damage seem to have a good tendency to regenerate. We conclude that within the dose required for tumor treatment PEG-m-THPC is a safe photosensitizer with promising properties. PDT of the colon mucosa below 9 mg/kg PEG-m-THPC and 150 J/cm seems to be safe. All other tissues can be exposed to 9 mg/kg PEG-m-THPC activated with less than 450 J/cm laser light with little side effects.