Showing papers by "Richard N. Clayton published in 2007"

Primary colorectal tumors fail to express the proapoptotic mediator PTAG and its reexpression augments drug-induced apoptosis.

Abstract: Genes implicated in tumor evolution and progression, including those in apoptotic pathways, are associated with methylation-associated gene silencing in different tumor types. By exploiting differential methylation we recently isolated a novel pituitary tumor derived apoptosis gene (PTAG) that augments drug-induced apoptosis. The importance of PTAG was determined in other tumor types, and these studies show that the majority of primary colorectal tumors fail to express the PTAG gene, indicating an important role for PTAG in colorectal tumorigenesis. The effects of expression of PTAG were examined through stable transfection of the colorectal cell lines HCT116 and SW480. Expression of PTAG, per se, had no discernible effects on cell viability or cell kinetics. In contrast to these findings, in cells subject to drug challenges that engaged either a death-receptor mediated or mitochondrial pathway, all of the experiments indicated a role for PTAG in the intrinsic pathway of apoptosis. Loss of PTAG therefore contributes to a blunted apoptotic response and is likely to predispose cells toward malignant transformation and resistance to chemotherapeutic interventions.

Spontaneous pregnancy after trans-sphenoidal surgery in a patient with lymphocytic hypophysitis.

Abstract: Lymphocytic hypophysitis (LH) is a rare but increasingly recognized autoimmune endocrine condition primarily affecting peripartum young women. In the UK, there have been only 28 reported cases so far. 1 The natural history of LH in relation to the incidence and effect of subsequent pregnancies, especially after pituitary surgery is not known. We report a 37-years-old patient who had a spontaneous and uneventful pregnancy following LH that had been treated with transspenoidal surgery. A 37-years-old woman developed progressive visual loss and headache at five weeks after the delivery of her second child. Her pregnancy had previously been uneventful and there was no significant past medical history of note. Physical examination showed bilateral quadrantanopic visual field defects. Laboratory investigations revealed a 9am serum cortisol of 77 nmol/l (280–700), free T4 of 6·7 pmol/l (9–25), TSH of 0·13 mU/l (0·1–5·0) and a serum prolactin of 330 mU/l (up to 700). A magnetic resonant imaging (MRI) scan of the pituitary revealed a pituitary tumour with suprasellar extension and optic chiasmal compression. She underwent transsphenoidal surgery with thyroxine and steroid cover. Histological examination of the resected specimen was consistent with lymphocytic hypophysitis showing intense infiltration of lymphocytes, plasma cells, eosinophils, neutrophils and macrophages, excess fibrous tissue and occasional lymphoid aggregates (Fig. 1). No adenoma was identified. Postoperatively, she developed diabetes insipidus (serum sodium 148 mmol/l, spot serum osmalility 307 mOsm/kg, urine osmalility 95 mOsm/kg) that responded to oral desmopressin. Her headache and visual field defect resolved completely. Subsequent endocrine testing 6 weeks after surgery revealed a subnormal cortisol response to glucagon of 531, 349 and 384 nmol/l at 0, 150 and 180 minutes, respectively, and she was therefore advised to take steroids at times of stress. Peak GH response was also inadequate at 4·9 m μ /l with a low basal IGF level of 5·1units (9·5–40). Free T4 spontaneously improved to 13·6 pmol/l (9–25) and TSH to 1·2 mU/l (0·1–5·0). She continued to have regular periods. Her diabetes insipidus persisted and required regular oral desmopressin. A repeat MRI scan 3 months post hypophysectomy was normal. Three years after her original presentation she got pregnant spontaneously. At 28 weeks of gestation, laboratory investigations revealed that she continued to have adequate thyroid reserve (TSH 1·83) and her morning cortisol was also in the normal range (serum cortisol 544). Her desmopressin requirement did not change throughout this pregnancy. A mid-trimester MRI scan did not show any recurrence of pituitary mass. She delivered spontaneously under steroid cover and a postpartum MRI scan was normal. Her most recent pituitary function tests showed a free T4 of 15 pmol/l, TSH of 0·77 mU/l and an IGF-1 of 14 units. The peak cortisol and GH response to insulin-induced hypoglycaemia were 467 nmol/l and 0·3 mU/l, respectively. Her current treatments include oral hydrocortione 20 mg/day and oral desmopressin 450 μ g/day. She is currently being assessed for suitability for GH replacement. In summary, we present a 37-years-old lady with a spontaneous and uneventful pregnancy after developing partial hypopituitarism and diabetes insipidus that followed a diagnosis of lymphocytic hypophysitis requiring trans-sphenoidal surgery after delivery of her previous child 3 years earlier. Hypophysitis can be primary or secondary. Lymphocytic hypophysitis, granulomatous hypophysitis and xanthomatous hypophysitsis are the three distinct clinicopathalogical entities described in primary hypophysistis, while secondary hypophysitis may be caused by infections, or the pituitary inflammatory process may be a part of systemic disease. 2