Demographics, natural history and treatment outcomes of non-molar gestational choriocarcinoma: a UK population study.

OBJECTIVE: To investigate the demographics, natural history and treatment outcomes of non-molar gestational choriocarcinoma. DESIGN: A retrospective national population-based study. SETTING: UK 1995-2015. POPULATION: A total of 234 women with a diagnosis of gestational choriocarcinoma, in the absence of a prior molar pregnancy, managed at the UKs two gestational trophoblast centres in London and Sheffield. METHODS: Retrospective review of the patient's demographic and clinical data. Comparison with contemporary UK birth and pregnancy statistics. MAIN OUTCOMES: Incidence statistics for non-molar choriocarcinoma across the maternal age groups. Cure rates for patients by FIGO prognostic score group. RESULTS: Over the 21-year study period, there were 234 cases of non-molar gestational choriocarcinoma, giving an incidence of 1:66 775 relative to live births and 1:84 226 to viable pregnancies. For women aged under 20, the incidence relative to viable pregnancies was 1:223 494, for ages 30-34, 1:80 227, and for ages 40-45, 1:41 718. Treatment outcomes indicated an overall 94.4% cure rate. Divided by FIGO prognostic groups, the cure rates were low-risk group 100%, high-risk group 96% and ultra-high-risk group 80.5%. CONCLUSIONS: Non-molar gestational choriocarcinoma is a very rare diagnosis with little prior detailed information on the demographics and natural history. The data in this study give age-related incidence data based on a large national population study. The results also demonstrated the widely varying natural history of this rare malignancy and the marked correlation of disease incidence with rising maternal age. TWEETABLE ABSTRACT: National gestational choriocarcinoma database indicates a close association between increasing maternal age and incidence.

Revising the role of the androgen receptor in breast cancer.

Breast cancer (BC) is traditionally viewed as an oestrogen-dependent disease in which the androgen receptor (AR) is inhibitory, counteracting the oncogenic activity of oestrogen receptor α (ERα (ESR1)). Most probably as a result of this crosstalk, the AR has prognostic value in ER-positive disease, with AR positivity reported to correlate with a better prognosis. Activation of the AR pathway has been previously used as a therapeutic strategy to treat BC, but its usage declined following the introduction of the anti-oestrogen tamoxifen. More recently, it has been demonstrated that a subset of triple-negative BCs (molecular apocrine) are dependent upon androgen signalling for growth and therapies that inhibit androgen signalling, currently used for the treatment of prostate cancer, e.g. the antiandrogen bicalutamide and the CYP17 inhibitor abiraterone acetate are undergoing clinical trials to investigate their efficacy in this BC subtype. This review summarises the current knowledge of AR activity in BC.

Uterine artery pulsatility index improves prediction of methotrexate resistance in women with gestational trophoblastic neoplasia with FIGO score 5-6.

OBJECTIVE: The Uterine Artery Pulsatility Index (UAPI) is an ultrasound measure of tumour vascularity. In this study, we hypothesised that a UAPI ≤ 1 (high vascularity) would identify women with gestational trophoblastic neoplasia (GTN) at increased risk of resistance to first-line single-agent methotrexate (MTX-R). DESIGN: Single-centre cohort study. SETTING: Charing Cross Hospital, a UK national centre for the treatment of trophoblastic disease. POPULATION: All women with a GTN FIGO score 5-6 treated with methotrexate (n = 92), between 1999 and 2011, at Charing Cross Hospital. METHODS: UAPI was measured before the start of chemotherapy, and women were monitored for the development of MTX-R. MAIN OUTCOME MEASURES: Frequency of MTX-R in women with UAPI ≤ 1 compared with UAPI >1. RESULTS: UAPI was measured before chemotherapy in 73 of 92 women with GTN FIGO score 5-6. UAPI ≤ 1 predicted MTX-R independent of the FIGO score (hazard ratio 2.9, P = 0.04), with an absolute risk of MTX-R in women with a UAPI ≤ 1 of 67% (95% CI 53-79%) compared with 42% (95% CI 24-61%) with a UAPI >1 (P = 0.036). CONCLUSION: Our results suggest UAPI is an independent predictor of MTX-R in women with FIGO 5-6 GTN.

The relationship of maternal age to molar pregnancy incidence, risks for chemotherapy and subsequent pregnancy outcome.

The national registration and treatment service for molar pregnancies in the UK allows for the collection of accurate data on this relatively rare diagnosis. In England and Wales, between 2000 and 2009, 5,793 patients with complete moles and 7,790 with partial moles were registered, compared with a total of 8,242,511 conceptions. The overall molar pregnancy incidence was 1 for every 607 conceptions (complete mole 1:1,423; partial mole 1:1,058), but with major variations with age. For complete moles, the risk varied from < 1:1,000 for ages 18-40, to 1:156 for women aged 45 and 1:8 for those aged 50 and above. The overall risk of requiring chemotherapy after a complete mole was 13.6% and 1.1% for partial mole, while the risk of a further molar pregnancy in the next conception was 1:68 but each of these figures have considerable variations with age. These modern statistics on molar pregnancy risks and outcomes should be of value to clinicians and their patients, while discussing this rare diagnosis.

Circulating microRNAs as potential new biomarkers for prostate cancer.

Since they were first described in the 1990s, circulating microRNAs (miRNAs) have provided an active and rapidly evolving area of current research that has the potential to transform cancer diagnostics and therapeutics. In particular, miRNAs could provide potential new biomarkers for prostate cancer, the most common cause of cancer in UK men. Current diagnostic tests for prostate cancer have low specificity and poor sensitivity. Further, although many prostate cancers are so slow growing as not to pose a major risk to health, there is currently no test to distinguish between these and cancers that will become aggressive and life threatening. Circulating miRNAs are highly stable and are both detectable and quantifiable in a range of accessible bio fluids, thus have the potential to be useful diagnostic, prognostic and predictive biomarkers. This review aims to summarise the current understanding of circulating miRNAs in prostate cancer patients and their potential role as biomarkers.

Treatment outcomes for 618 women with gestational trophoblastic tumours following a molar pregnancy at the Charing Cross Hospital, 2000-2009.

BACKGROUND: Post-molar pregnancy gestational trophoblastic tumours (GTT) have been curable with chemotherapy treatment for over 50 years. Because of the rarity of the diagnosis, detailed structured information on prognosis, treatment escalations and outcome is limited. METHODS: We have reviewed the demographics, prognostic variables, treatment course and clinical outcomes for the post-mole GTT patients treated at Charing Cross Hospital between 2000 and 2009. RESULTS: Of the 618 women studied, 547 had a diagnosis of complete mole, 13 complete mole with a twin conception and 58 partial moles. At the commencement of treatment, 94% of patients were in the FIGO low-risk group (score 0-6). For patients treated with single-agent methotrexate, the primary cure rate ranged from 75% for a FIGO score of 0-1 through to 31% for those with a FIGO score of 6. CONCLUSION: In the setting of a formal follow-up programme, the expected cure rate for GTT after a molar pregnancy should be 100%. Prompt treatment and diagnosis should limit the exposure of most patients to combination chemotherapy. Because of the post-treatment relapse rate of 3% post-chemotherapy, hCG monitoring should be performed routinely.

Advances in the treatment of pancreatic neuroendocrine tumours.

Pancreatic neuroendocrine tumours (pNETs) are relatively rare and generally felt to follow an indolent course. But poorly differentiated tumours can behave aggressively with 5-year survival ranging from 31% to 48%. Recent data suggest that patients with pNETs may derive benefit from treatment targeting the molecular changes expressed in this tumour group. This article describes advances in the treatment of unresectable pNETs that have led to a doubling of progression free survival.

Reducing prohibitin increases histone acetylation, and promotes androgen independence in prostate tumours by increasing androgen receptor activation by adrenal androgens.

Prostate cancers (PCs), initially responsive to anti-androgen therapies, often advance to a hormone-refractory 'castrate-resistant' PC (CRPC) stage. However, the androgen receptor (AR) pathway remains active and key for cell growth and gene expression within tumours, even in the apparent absence of hormone. Proposed mechanisms to explain progression, including AR amplification/mutation, are insufficient to completely explain CRPC and possible roles of AR cofactors such as prohibitin (PHB) are poorly understood. We investigated whether PHB loss could sensitise PC cells and tumours to adrenal gland-derived androgens, which persist even after androgen ablation, hence contribute to development of CRPC. Using a pair of PC cell lines, inducibly expressing ectopic cDNA or RNAi for PHB, responses to different androgens and hormone concentrations were studied both in vitro and in vivo. PHB was found at the promoters of several genes, both AR and non-AR-regulated, and knockdown increased histone acetylation at these promoters. Further, PHB knockdown increased the rate of AR ligand-induced chromatin binding, and binding rate and occupancy of AR upon the PSA promoter. This resulted in increased cell growth and AR activity in response to all androgens, including promoting a response to the weaker adrenal androgens previously absent at physiological concentrations. In vivo this had functional consequences such that PHB knockdown resulted in androstenedione being sufficient to promote tumour growth, under conditions mimicking those in patients undergoing androgen ablation therapy. We conclude that reduction in PHB levels is sufficient to lower the threshold of AR activity in vitro and in vivo; this may be via a general increase in histone acetylation that could potentially affect signalling by other transcription factors. PHB loss may provide a mechanism for progression to CRPC by sensitising PC cells to 'castrate' conditions-that is, low levels of testicular androgens in the continued presence of weak adrenal and dietary androgens.

Regression of melanoma metastases following treatment with the n-bisphosphonate zoledronate and localised radiotherapy.

We report a case of regression of pulmonary and bony metastases in a patient with malignant melanoma following palliative treatment with systemic zoledronate and localised radiotherapy to the bone. Zoledronate is a potent new bisphosphonate used for the treatment of metabolic bone diseases including bone metastases due to its inhibitory effect on osteoclasts. In the context of metastatic cancer zoledronate is routinely used to improve bone pain and reduce the frequency of skeletal events. There is also an increasing body of evidence suggesting that bisphosphonates exhibit anti-tumour properties. Bisphosphonates are able to activate Vgamma9Vdelta2 gamma-delta T cells which can be key players in the immune defence against malignant cells. Furthermore bisphosphonates have direct anti-proliferative, anti-metastatic and pro-apoptotic effects on tumour cells. These actions, together with their low side effect profile, may prove to be useful therapeutic tools in the treatment of cancer even in the absence of bone metastases. On the basis of this case report we here review the current literature on present preclinical and clinical studies using bisphosphonates for the treatment of cancer.

Reactivation of tuberculosis and vitamin D deficiency: the contribution of diet and exposure to sunlight.

BACKGROUND: As well as its role in the regulation of calcium metabolism, vitamin D is an immunoregulatory hormone. Epidemiological evidence also suggests a link between vitamin D deficiency and tuberculosis (TB). A study was undertaken to examine serum vitamin D concentrations before treatment in patients with active TB and their contacts from the same ethnic and social background and to investigate the relative contributions of diet and sunlight exposure. METHODS: Serum vitamin D concentrations were measured before treatment in 178 patients with active TB and 130 healthy contacts. The prevalence of vitamin D deficiency and its relation to skin colour, month of estimation and TB diagnosis were determined. 35 patients and 35 frequency-matched contacts completed dietary and sun exposure questionnaires to determine the relative contribution of these to serum vitamin D concentrations. RESULTS: There was a statistically significant difference in serum vitamin D concentrations between patients and contacts (20.1 vs 30.8 nmol/l, 95% CI 7.1 to 14.3; p<0.001) and significantly more patients had severely deficient concentrations (<21 nmol/l) than controls (114/178 (64%) vs 40/130 (31%), p<0.001). There was no association between serum concentrations of vitamin D and skin pigmentation. The healthy contacts showed a predictable seasonal pattern, rising to peak concentrations in the summer months, but this response was absent in patients with TB. Dietary intake was the same in both patients with TB and contacts matched for age, sex and skin colour, but patients with TB displayed a stronger correlation between serum vitamin D concentrations and dietary intake (r = 0.42, p = 0.016) than controls (r = 0.13, p>0.1). There was no difference in sunlight exposure between the groups. CONCLUSIONS: Patients with active TB have lower serum vitamin D concentrations than contacts from similar ethnic and social backgrounds and with comparable dietary intake and sun exposure, and do not show the expected seasonal variation. These observations indicate that other factors are contributing to vitamin D deficiency in patients with TB and suggest abnormal handling of this vitamin.