Pituitary hCG production and cerebral tuberculosis mimicking disease progression during chemotherapy for an advanced ovarian germ cell tumour.

BACKGROUND: Ovarian germ cell tumours (OGCT) are rare but are usually curable with chemotherapy, even when presenting with advanced disease. The majority of OGCT produce the tumour markers, hCG and/or AFP which can be helpful in the diagnosis and monitoring the response to treatment. CASE PRESENTATION: In this case of a 36 year old woman, the elevated hCG level at presentation was helpful in making a clinical diagnosis of OGCT in a patient too unwell to permit a tissue diagnosis. Cisplatin based combination chemotherapy produced an initial normalisation of the hCG level, but later in treatment the patient developed new cerebral lesions and a rising serum hCG suggestive of disease progression. Further investigations suggested that the CNS lesions were cerebral TB and that the low levels of hCG elevations was likely to be pituitary in origin. Chemotherapy treatment was continued along with anti-tuberculous therapy and 24 months after successful completion of therapy the patient remains disease free. CONCLUSIONS: In the treatment of cancer patients it may be helpful to consider the potential non-malignant causes of new CNS lesions and that low hCG elevations may result from physiology rather than pathology in selected cases.

Elevated NCOR1 disrupts PPARalpha/gamma signaling in prostate cancer and forms a targetable epigenetic lesion.

The loss of anti-proliferative responsiveness in prostate cancer cell lines toward ligands for vitamin D receptor, retinoic acid receptors/retinoid X receptors and peroxisome proliferator activated receptor (PPAR)alpha/gamma may entail underlying epigenetic events, as ligand insensitivity reflects significantly altered messenger RNA expression of corepressors and histone-modifying enzymes. Expression patterns were dependent on phases of the cell cycle and associated with repressed basal gene expression of vitamin D receptor and PPARalpha/gamma target genes, for example CDKN1A [encodes p21((waf1/cip1))]. Elevated nuclear corepressor 1 (NCOR1) and nuclear corepressor 2/silencing mediator of retinoic acid and thyroid hormone receptor protein levels were detected in prostate cancer cell lines compared with non-malignant counterparts. Knockdown of the corepressor NCOR1 significantly elevated basal expression of a cohort of target genes, including CDKN1A. Both chemical [histone deacetylases inhibitor (HDACi)] and NCOR1 knockdown targeting enhanced anti-proliferative sensitivity toward PPARalpha/gamma ligands in prostate cancer cell lines. Pursuing PPARalpha/gamma signaling, microarray approaches were undertaken to identify pathways and genes regulated uniquely by a combination of PPARalpha/gamma activation and HDAC inhibition. Again, HDACi and knockdown approaches demonstrated that elevated NCOR1 expression and activity distorted PPARalpha/gamma gene targets centered on, for example cell cycle control, including CDKN1A and TGFBRAP1. Quantitative real time polymerase chain reaction validation and chromatin immunoprecipitation assays both confirmed that elevated NCOR1 disrupted the ability of PPARalpha/gamma to regulate key target genes (CDKN1A and TGFBRAP1). Interrogation of these relationships in prostate cancer samples using principal component and partial correlation analyses established significant interdependent relationships between NCOR1-PPARalpha/gamma and representative target genes, independently of androgen receptor expression. Therefore, we conclude that elevated NCOR1 distorts the actions of PPARalpha/gamma selectively and generates a potential epigenetic lesion with diagnostic and prognostic significance.