Centralised multidisciplinary management of breast cancer occurs in KwaZulu-Natal, South Africa and requires a diagnostic and staging pathway at the referring hospital. Delays in this pathway are unknown. This study, conducted at a referring hospital, R K Khan (RKK), quantifies and analyses these delays. A retrospective folder review included all patients with breast cancer diagnosed at RKK from January 2008 to January 2009. Data extraction included demographic data, time to diagnosis and initial staging using a standardised datasheet. Specific care steps were identified, namely delays to initial imaging with mammography, pathology confirmation, staging workup and eventual referral to a centralised breast clinic.

Normal physiological functioning is highly dependent of calcium and the concentration range is very narrow. Normal calcium levels are so crucial to survival that the body will de-mineralize bone if the levels are insufficient. A prerequisite for normal calcium uptake is a normal Vitamin D level. Insufficient levels of Vitamin D are associated to several diseases. The aims of this thesis were to study the relationship between pregnancies and hyperparathyroidism (pHPT) (I), between pHPT and pregnancy with preeclampsia (II) and also to determine if disturbances in calcium homeostasis with vitamin D deficiency are apparent in preeclamptic women (III).  The aim was also to study calciumhomeostasis in obese patients before and after bariatric surgery (IV and V) with emphasis on vitamin D status, parathyroid secretion and bone mineral density (BMD). A correlation was found between a history of pHPT and pregnancy with preeclampsia, with an odds ratio of 6,89 ( 95% CI 2.30, 20.58).  Parathyroid hormone was significantly raised in preeclamptic pregnancies but vitamin D deficiency was present both in preeclamptic and healthy pregnancies. A certain polymorphism of the Vitamin D receptor (baT haplotype), overrepresented in pHPT, was not over expressed in preeclampsia. Hypovitaminosis D was present in more than 70% of bariatric patients preoperatively, which did not change after surgery, despite great weight loss and start of Vitamin D supplementation. BMD was significantly lower in bariatric patients with a negative correlation to the time elapsed since surgery. A small increase in BMD could be noted 10-13 years after bariatric surgery, possibly due to gradual weight gain. CiCa-clamping in obese patients demonstrated a disturbed calcium homeostasis with a left-shifted calcium-PTH relationship and a lower set-point of calcium. This disturbance persisted one year postoperatively. In conclusion, derangements in calcium homeostasis with decreased levels of Vitamin D are present in preeclampsia and obesity. A history of pHPT should be viewed as a risk factor for preeclampsia. Life long follow-up is necessary after bariatric surgery, and an individually adjusted high dose Vitamin D substitute is probably needed to avoid a development of osteoporosis.

Endocrine tumors arise from endocrine glands. Most endocrine tumors are benign but malignant variants exist. Several endocrine neoplasms display loss of parts of chromosome 11 or 18, produce hormones and responds poorly to conventional chemotherapeutics. The multiple endocrine neoplasia syndromes are mainly confined to endocrine tumors. This opens the question if there exists a single or several endocrine tumor genes. The aim of the study was to describe genetic derangements in endocrine tumors. Paper I: Investigation of mutational status of SDHAF2 in parathyroid tumors. SDHAF2 is located in the proximity of 11q13, a region that frequently displays loss in parathyroid tumors. We established that mutations in SDHAF2 are infrequent in parathyroid tumors. Paper II: Study of SDHAF2 gene expression in a cohort of benign pheochromocytomas (PCC) (n=40) and malignant PCC (n=10). We discovered a subset of  benign PCC (28/40) and all malignant PCC (10/10) with significantly lower SDHAF2 expression. Benign PCC with low SDHAF2 expression and malignant tumors consistently expressing low levels of SDHAF2 were methylated in the promoter region. SDHAF2 expression was restored in vitro after treatment with 5- aza-2-deoxycytidine. Paper III: HumanMethylation27 array (Illumina) covering 27578 CpG sites spanning over 14495 genes were analyzed in a discovery cohort of 10 primary small neuroendocrine tumors (SI-NETs) with matched metastases. 2697 genes showed different methylation pattern between the primary tumor and its metastasis. We identified several hypermethylated genes in key regions. Unsupervised clustering of the tumors identified three distinct clusters, one with a highly malignant behavior. Paper IV: Loss of chromosome 18 is the most frequent genetic aberration in SI-NETs. DNA from SI-NETs were subjected to whole exome capture sequencing and high resolution SNP array. Genomic profiling revealed loss of chromosome 18 in 5 out of 7 SI-NETs. No tumor-specific somatic mutation on chromosome 18 was identified which suggests involvement of other mechanisms than point mutations in SI-NET tumorigenesis. Paper V: The cost for diagnostic genetic screening of common susceptibility genes in PCC is expensive and labor intensive. Three PCC from three patients with no known family history were chosen for exome capture sequencing. We identified three variants in known candidate genes. We suggest that exome-capture sequencing is a quick and cost-effective tool.