Mitochondrial DNA mutations in Malaysian female breast cancer patients.

Cancer development has been ascribed with diverse genetic variations which are identified in both mitochondrial and nuclear genomes. Mitochondrial DNA (mtDNA) alterations have been detected in several tumours which include lung, colorectal, renal, pancreatic and breast cancer. Several studies have explored the breast tumour-specific mtDNA alteration mainly in Western population. This study aims to identify mtDNA alterations of 20 breast cancer patients in Malaysia by next generation sequencing analysis. Twenty matched tumours with corresponding normal breast tissues were obtained from female breast cancer patients who underwent mastectomy. Total DNA was extracted from all samples and the entire mtDNA (16.6kb) was amplified using long range PCR amplification. The amplified PCR products were sequenced using mtDNA next-generation sequencing (NGS) on an Illumina Miseq platform. Sequencing involves the entire mtDNA (16.6kb) from all pairs of samples with high-coverage (~ 9,544 reads per base). MtDNA variants were called and annotated using mtDNA-Server, a web server. A total of 18 of 20 patients had at least one somatic mtDNA mutation in their tumour samples. Overall, 65 somatic mutations were identified, with 30 novel mutations. The majority (59%) of the somatic mutations were in the coding region, whereas only 11% of the mutations occurred in the D-loop. Notably, somatic mutations in protein-coding regions were non-synonymous (49%) in which 15.4% of them are potentially deleterious. A total of 753 germline mutations were identified and four of which were novel mutations. Compared to somatic alterations, less than 1% of germline missense mutations are harmful. The findings of this study may enhance the current knowledge of mtDNA alterations in breast cancer. To date, the catalogue of mutations identified in this study is the first evidence of mtDNA alterations in Malaysian female breast cancer patients.

Clinical course after parathyroidectomy in adults with end-stage renal disease on maintenance dialysis.

BACKGROUND: Parathyroidectomy (PTX) is done in cases of secondary hyperparathyroidism from chronic kidney disease to improve renal osteodystrophy. Despite this widespread practice, clinical outcomes regarding the benefits of this procedure are still lacking. Most studies in the literature have opted to report the laboratory outcome instead. Our study aimed to evaluate the postoperative clinical course for patients who had undergone total PTX without autoimplantation. METHODS AND RESULTS: All patients who underwent PTX between January 2010 and February 2014 in a tertiary referral center were included in this study and followed up for 12 months. Laboratory outcome parameters include various preoperative and postoperative serial measurements of laboratory parameters. Patients' hospitalizations and mortality records post-PTX were also retrieved and recorded. In all, 90 patients were included in this study. The mean age was 48 ± 18 years. The majority of the patients (54.4%) were male and 90% were on hemodialysis. The mean duration of dialysis was 8.0 ± 5.0 years. Indications for PTX were symptomatic bone pain (95.6%), fractures (3.3%) and calciphylaxis (1.1%). Mean preoperative values for serum calcium, phosphate, alkaline phosphatase and intact parathyroid hormone (iPTH) were 2.40 ± 0.23mmol/L, 1.92 ± 0.51 mmol/L, 689.60 ± 708.50 U/L and 311.90 ± 171.94 pmol/L, respectively. The majority (92.2%) had all four glands removed and 92.2% of the glands showed hyperplasic changes. One year after PTX, 90 patients (100%) had serum iPTH <8 pmol/L and 28 patients (31%) had unmeasurable iPTH levels. A total of 15% of patients had hospitalizations for various reasons and of these, 50% were within 90 days. The mean hospital stay was 14.4 ± 18.6 days. The mortality rate was 4.4% and of these, 25% were in first 30 days. Causes of death were mainly from sepsis (75%) and acute coronary syndrome (25%). One patient (1.1%) had a relapse. CONCLUSIONS: Even though PTX markedly reduces postoperative serum iPTH levels, it carries with it significant risk of morbidity and mortality.

PRKAR1A-negative familial Cushing's syndrome: two case reports.

INTRODUCTION: Determining the etiology of Cushing's syndrome is very challenging to endocrinologists, with most of the difficulty arising from subtype differentiation of adrenocorticotropic hormone-dependent Cushing's syndrome. We present the pitfalls of evaluating a rare cause of adrenocorticotropic hormone-independent Cushing's syndrome in the transition period between adolescence and adulthood. CASE PRESENTATION: A sibling pair with familial isolated primary pigmented nodular adrenocortical disease is described. The index case, a 20-year-old Chinese woman, presented with premenopausal osteoporosis with T12 compression fracture and young hypertension. Biochemical analysis confirmed adrenocorticotropic hormone-independent Cushing's syndrome (elevated 0800 h plasma cortisol 808 nmol/L with suppressed adrenocorticotropic hormone level <5 pg/ml). Computed tomography of her adrenal glands revealed a 0.7-cm left adrenal hypodense nodule. After a left adrenalectomy, she had residual hypercortisolism (progressive weight gain, new T10 compression fracture, and not glucocorticoid-dependent postoperatively). Completion of contralateral adrenalectomy was performed upon recognition of typical histologic characteristics of primary pigmented nodular adrenocortical disease found in an initial left adrenalectomy specimen. Similarly, her younger brother developed adrenocorticotropic hormone-independent Cushing's syndrome at age 18 years, with typical cushingoid habitus, but no osteoporosis or hypertension. His adrenal computed tomographic scans showed micronodularities over bilateral adrenal glands. He was successfully treated with bilateral adrenalectomy. Screening for Carney's complex and PRKAR1A gene mutation was negative. Signs and symptoms of Cushing's syndrome resolved after bilateral adrenalectomy for both patients. They were placed on lifelong glucocorticoid and mineralocorticoid replacement therapy and long-term surveillance for Carney's complex. CONCLUSIONS: The cases of these two patients illustrate the difficulties involved in diagnosing primary pigmented nodular adrenocortical disease, a variant of adrenocorticotropic hormone-independent Cushing's syndrome that is managed with bilateral adrenalectomy. A high index of suspicion for this disease is needed, especially in adolescents with adrenocorticotropic hormone-independent Cushing's syndrome who have a significant family history, features of Carney's complex, and no resolution of Cushing's syndrome after unilateral adrenalectomy. Patients with primary pigmented nodular adrenocortical disease can either have bilateral/multiple adrenal nodules or normal adrenal glands visualized by computed tomography. Long-term surveillance is imperative in patients with confirmed Carney's complex and in those who have not undergone complete genetic testing to exclude this hereditary disorder.

Gastric band erosion in 63 cases: endoscopic removal and rebanding evaluated.

BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) remains the most popular bariatric procedure performed in Australia and Europe. Gastric band erosion is a significant complication that results in band removal. The aim of this study is to assess the prevalence of band erosion and its subsequent management with a particular focus on rebanding results. METHODS: Patients who underwent LAGB in a prospective cohort study from August 1996 to October 2010 were evaluated. Patients that developed band erosion were identified and clinical presentations, band characteristics and subsequent management were evaluated. RESULTS: One thousand eight hundred seventy-four morbidly obese patients underwent LAGB. Band erosion developed in 63 patients (3.4%). Median preoperative BMI was 41.5 kg/m(2) (range 30-61 kg/m(2)). Median time from operation to diagnosis was 39 months (range 6-132 months). Twenty nine patients (46%) were asymptomatic (sudden loss of restriction, weight gain, turbid fluid, or absence of fluid). Symptoms included abdominal pain in 24 (38%), obstruction in 7 (11%), recurrent port infection in 5 (8%), reflux symptoms in 2 (3%) and sepsis in 2 (3%). Fourteen patients (22%) had discolouration of the fluid in their band. Endoscopic removal was attempted in 50 patients with successful removal in 46 (92%). Median number of endoscopies prior to removal was 1.0 (range 1-5). The median duration of the procedure was 46 min (range 17-118 min). Rebanding was performed in 29 patients and 5 (17%) experienced a second erosion. Mean percentage excess weight loss was 54% in the remaining 22 patients with at least 3 months follow-up. CONCLUSIONS: Band erosion prevalence was 3.4%. Endoscopic removal of eroded gastric bands was proven safe and effective. Band erosion is now preferably managed endoscopically in our institution. Rebanding following erosion results in acceptable weight loss but an unacceptable reerosion rate.