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.

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.

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.

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.

Technological devices in peripheral percutaneous interventions.

New innovations and novel approaches to peripheral arterial occlusive disease have brought enormous benefits to the vascular patient. Diseases that were once manageable only by surgical intervention are now easily and successfully treated by minimally invasive procedures. While the early days of percutaneous intervention were filled with inventions of new devices, today the focus centers on using modern technology and manufacturing to further improve upon these devices. Advances in guidewires and catheters have allowed us to visualize and treat lesions in nearly any vessel, and technology is guiding us towards specialized applications for specific lesions in specific vessels. However, one of the big hurdles remaining in treating arterial occlusive diseases is the rate of restenosis and the need for reinterventions. The location and architecture of these vessels make them uniquely difficult to treat, and call for new technology to address these challenges. Current developments of drug-eluting and bioabsorbable stents are at the forefront of new advancements specifically directed at improving current patency and restenosis rates; perhaps the next step in percutaneous intervention will rely on nanotechnology and the molecular surface engineering that may achieve a new era of devices that are able to target specific cell ligands or proteins to prevent the inflammatory and proliferative response from vessels. The present review will focus on the current literature regarding technological devices in peripheral percutaneous interventions and clinical applications. Future advancements in materials engineering and biotechnology will continue to improve the current standard of percutaneous intervention for peripheral arterial occlusive diseases.

Computational study of haemodynamic effects of entry- and exit-tear coverage in a DeBakey type III aortic dissection: technical report.

OBJECTIVES: Outcome prediction in DeBakey Type III aortic dissections (ADs) remains challenging. Large variations in AD morphology, physiology and treatment exist. Here, we investigate if computational fluid dynamics (CFD) can provide an initial understanding of pressure changes in an AD computational model when covering entry and exit tears and removing the intra-arterial septum (IS). DESIGN: A computational mesh was constructed from magnetic resonance images from one patient (one entrance and one exit tear) and CFD simulations performed (scenario #1). Additional meshes were derived by virtually (1) covering the exit tear (false lumen (FL) thrombus progression) (scenario #2), (2) covering the entrance tear (thoracic endovascular treatment, TEVAR) (scenario #3) and (3) completely removing the IS (fenestration) (scenario #4). Changes in flow patterns and pressures were quantified relative to the initial mesh. RESULTS: Systolic pressures increased for #2 (300 Pa increase) with largest inter-luminal differences distally (2500 Pa). In #3, false lumen pressure decreased essentially to zero. In #4, systolic pressure in combined lumen reduced from 2400 to 800 Pa. CONCLUSIONS: CFD results from computational models of a DeBakey type III AD representing separate coverage of entrance and exit tears correlated with clinical experience. The reported results present a preliminary look at a complex clinical problem.

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.

Patterning the vertebrate neuraxis.

Neuraxial patterning is a continuous process that extends over a protracted period of development. During gastrulation a crude anteroposterior pattern, detectable by molecular markers, is conferred on the neuroectoderm by signals from the endomesoderm that are largely inseparable from those of neural induction itself. This coarse-grained pattern is subsequently reinforced and refined by diverse, locally acting mechanisms. Segmentation and long-range signaling from organizing centers are prominent among the emerging principles governing regional pattern.

Homeotic transformation of rhombomere identity after localized Hoxb1 misexpression.

Segmentation of the hindbrain and branchial region is a conserved feature of head development, involving the nested expression of Hox genes. Although it is presumed that vertebrate Hox genes function as segment identifiers, responsible for mediating registration between elements of diverse embryonic origin, this assumption has remained untested. To assess this, retroviral misexpression was combined with orthotopic grafting in chick embryos to generate a mismatch in Hox coding between a specific rhombomere and its corresponding branchial arch. Rhombomere-restricted misexpression of a single gene, Hoxb1, resulted in the homeotic transformation of the rhombomere, revealed by reorganization of motor axon projections.

Target control of collateral extension and directional axon growth in the mammalian brain.

Individual neurons in the brain send their axons over considerable distances to multiple targets, but the mechanisms governing this process are unresolved. An amenable system for studying axon outgrowth, branching, and target selection is the mammalian corticopontine projection. This major connection develops from parent corticospinal axons that have already grown past the pons, by a delayed interstitial budding of collateral branches that then grow directly into their target, the basilar pons. When cocultured with explants of developing cortex in three-dimensional collagen matrices, the basilar pons elicits the formation and directional growth of cortical axon collaterals across the intervening matrix. This effect appears to be target-specific and selectively influences neurons in the appropriate cortical layer. These in vitro findings provide evidence that the basilar pons becomes innervated by controlling at a distance the budding and directed ingrowth of cortical axon collaterals through the release of a diffusible, chemotropic molecule.

Rhombomere-specific origin of the contralateral vestibulo-acoustic efferent neurons and their migration across the embryonic midline.

The bilateral efferent supply to the inner ear receptor fields is located in the hindbrain. In ovo injections of Dil into the common facial/vestibulo-acoustic nerve root at 3 days of chick development (stage 16) followed by analysis at 7 days has revealed the origin of the contralateral efferent neurons of the inner ear and their relation to the transient hindbrain rhombomeres. These neurons have a rhombomere 4-specific origin and form their commissure not by axonal outgrowth but, unusually, by transmedian cell migration into the contralateral rhombomere 4 and rhombomere 5. Neurons first project their axons from the ipsilateral basal plate through the VII/VIIIth nerve exit point and then migrate in the opposite direction, crossing the floor plate at stage 19-21. This rhombomere-specific cell behavior provides evidence at the cellular level that segmentation is intimately involved in establishing the pattern of this region of the CNS.

Dorsal spinal cord neuroepithelium generates astrocytes but not oligodendrocytes.

There is evidence that oligodendrocytes in the spinal cord are derived from a restricted part of the ventricular zone near the floor plate. An alternative view is that oligodendrocytes are generated from all parts of the ventricular zone. We reinvestigated glial origins by constructing chick-quail chimeras in which dorsal or ventral segments of the embryonic chick neural tube were replaced with equivalent segments of quail neural tube. Ventral grafts gave rise to both oligodendrocytes and astrocytes. In contrast, dorsal grafts produced astrocytes but not oligodendrocytes. In mixed cultures of ventral and dorsal cells, only ventral cells generated oligodendrocytes, whereas both ventral and dorsal cells generated astrocytes. Therefore, oligodendrocytes are derived specifically from ventral neuroepithelium, and astrocytes from both dorsal and ventral.

Selective adhesion of cells from different telencephalic regions.

We asked whether specifications of different regions of the rodent and avian telencephalon during development involved the acquisition of differential adhesive properties. Cells from different regions were aggregated in a short-term aggregation assay, and their segregation was analyzed. Both neurons and precursor cells from cortex segregate from striatal cells at early, but not later, stages, whereas cells from rodent neocortex and hippocampus segregated only during later stages. Segregation was abolished when Ca2+-dependent but not Ca2+-independent adhesion molecules were selectively removed. Thus, selective adhesion appears to be a conserved mechanism that restricts cellular mixing and might serve to maintain positional information during forebrain development. A candidate for mediating the Ca2+-dependent segregation is the CD15 (Lewis(x)) carbohydrate epitope, which is selectively expressed by mammalian cortex but not striatum.

Axon guidance in the vertebrate central nervous system.

The development of connections in the central nervous system depends on the ability of the tips of growing axons to find their appropriate, often distant, target field. Factors that regulate axon outgrowth may be distinct from those that influence direction finding. Tissue culture methods have helped to distinguish between possible in vivo mechanisms and, in some cases, have identified candidate molecules.

Segmental specification of GABAergic inhibition during development of hindbrain neural networks.

A primordial rhythm-generating neural network emerges during the segmental period of vertebrate hindbrain development, suggesting a common genetic basis to both the structure and network activity of the region. We show here that segmentation influenced a postsegmental developmental step by which a GABAergic rhythm generator was incorporated into the primordial network and increased rhythm frequency to near mature values. This process depended on specifications in r3 and r5 that controlled, on the basis of a two-segment repeat, later maturation of GABAergic inhibition.

Neural development. A 'LIM code' for motor neurons?

Combinatorial expression of LIM homeobox genes in subsets of embryonic motor neurons defines early stages in the topographic and functional organization of the spinal cord motor columns.

Independent assignment of antero-posterior and dorso-ventral positional values in the developing chick hindbrain.

BACKGROUND: Cell patterning in the developing central nervous system seem to involve a coordinate system of positional information, in which specific fates are assigned to multipotent precursor cells by positional signals acting on the antero-posterior and dorso-ventral axes of the neural tube. Before neurons differentiate in the hindbrain, it becomes subdivided antero-posteriorly into a series of developmental compartments, the rhombomeres. When the rhombomeres are delineated from each other by interfaces at which cell mixing is transiently restricted, they are determined for expression of specific selector Hox genes that may encode aspects of their individual identity. To assess whether the phenotypic identities of the rhombomeres are also determined at this stage, we have analyzed the capacity of individual rhombomeres to realize specific neuronal fates when grafted heterotopically along both antero-posterior and dorso-ventral axes. RESULTS: When rhombomere 4 (r4) is grafted unilaterally to the r2 position, both facial motor neurons and contralateral vestibulo-acoustic efferent neurons differentiate, as normal, in the ventral region of the graft. These aspects of phenotypic identity therefore appear to have been determined at or before the time of grafting. When r4 is grafted to the r2 position with its dorso-ventral polarity inverted, both types of neuron again develop, but in the ventral region of the graft, in a position appropriate to the dorso-ventral pattern of the host, rather than their original dorso-ventral position. The change in fate of these cells is restricted, however, to the repertoire characteristic of the antero-posterior position of origin, in this case r4. CONCLUSIONS: Cells seem to 'know' details of their presumptive fate before more general features. At this stage of development, precursor cells in r4 seem to have been assigned an 'r4 fate', but remain multipotent in their choice of r4-specific cell type. Precursor cells seem to be committed to their fates according to position on an orthogonal grid, the coordinates of which are set (or read) independently and sequentially. Thus, at the 7-10 somite stage, dorso-ventral positional values are still labile, whereas antero-posterior values are already fixed.

Cell mixing between the embryonic midbrain and hindbrain.

Segmentation is a mechanism that controls spatial organization along the anteroposterior axis of the neural tube and is particularly well characterized for the hindbrain region [1]. The generation of distinct and regionally specific structures from each rhombomere is achieved with the almost complete absence of cell mixing between neighboring rhombomeres [2, 3]. Here, we have examined cell mingling at the isthmus, where Otx2-expressing midbrain cells abut Gbx2-expressing hindbrain cells [4]. The sharp line of demarcation between the two expression domains suggests that this interface would be a compartment boundary, with no intermixing of cells, but this has not been directly tested. We have used short-term reaggregation assays to compare the adhesive properties of cells derived from midbrain and anterior hindbrain and cell labeling in vivo directly to monitor cell behavior at the midbrain/hindbrain boundary. Interestingly, our data demonstrate that, in contrast to the rhombomeres, differential adhesion does not seem to operate between the midbrain and anterior hindbrain and that cells move between the two territories. We conclude that these two subdivisions are not maintained by cell lineage restriction but by cells maintaining labile fates.

Rostral optic tectum acquires caudal characteristics following ectopic engrailed expression.

BACKGROUND: Expression of the homeobox-containing gene Engrailed (En) in an increasing rostral-to-caudal gradient in the dorsal mesencephalon is the earliest known marker for polarity of the chick optic tectum. In heterotopic transplantation experiments, En protein expression correlates well with the subsequent gradient of cytoarchitecture as well as the pattern of retinotectal projections. The En gradient also correlates with the expression of two putative retinal axon-guidance molecules, RAGS and ELF-1, which are Eph-like receptor tyrosine kinase ligands that may function in the establishment of retinotopic projections by excluding temporal axons from the caudal tectum. RESULTS: To examine the function of En in determining tectal polarity, we used the replication-competent retroviral vector RCAS to misexpress mouse En-1 throughout the chick tectal primordium. Our results show that the rostral portion of the tectum adopts a caudal phenotype: the gradient of cytoarchitectonic differentiation is abolished, and the molecular markers RAGS and ELF-1 are strongly expressed rostrally. In addition, cell membranes from rostral tectum of RCAS En-1-infected embryos preferentially repel temporal axons in in vitro membrane stripe assays. CONCLUSIONS: These results are consistent with a role for En in determining rostrocaudal polarity of the developing tectum. The demonstration that both RAGS and ELF-1 are upregulated following En misexpression provides a molecular basis for understanding the previous observation, also based on retrovirus-mediated En misexpression, that nasal axons form ectopic connections in rostral tectum, from which temporal axons are excluded.