Late Relapse and Follow-up Protocols in Testicular Germ Cell Tumours: The Edinburgh Cancer Centre Experience and Review of the Literature

Aims To identify clinicopathological features and outcomes in patients with late relapse (LR) of testicular germ cell tumours (GCTs) in order to guide follow-up policy. Materials and Methods The Edinburgh Cancer Centre (ECC) database identified all patients diagnosed with testicular GCT between 1988 and 2002. Of 703 patients, six relapsed more than 24 months after their initial treatment. A retrospective casenote review was performed to extract clinical, pathological, treatment and outcome data. Results Six patients (0.85%) underwent late relapse. All patients presented initially with stage I disease and five were classified as good risk (International Germ Cell Consensus Classification, IGCCC). Median time to LR was 31 months. Two patients had previously relapsed less than 24 months from initial diagnosis. Markers at the time of relapse were normal in all patients. In all cases of late relapse disease was confined to axial lymphadenopathy. Three patients were treated with chemotherapy alone, two patients underwent surgical resection and one patient received combined treatment. All patients obtained a complete response and all remain disease free with a median follow-up of 52 months. Conclusions The incidence of late relapse in this series is low. Chemo-naive patients with LR were successfully salvaged with chemotherapy alone and patients previously exposed to cisplatin-based chemotherapy were salvaged with complete surgical excision. The optimal length of follow-up in patients with testicular germ cell tumours is not known and practice varies widely. In this cohort of 703 patients, only one patient who relapsed was picked up by additional clinic follow-up between 5 and 10 years. Thus, on the basis of this small series, the authors suggest that follow-up after five years may not be justified

Measuring the effects of fractionated radiation therapy in a 3D prostate cancer model system using SERS nanosensors.

Multicellular tumour spheroids (MTS) are three-dimensional cell cultures that possess their own microenvironments and provide a more meaningful model of tumour biology than monolayer cultures. As a result, MTS are becoming increasingly used as tumor models when measuring the efficiency of therapies. Monitoring the viability of live MTS is complicated by their 3D nature and conventional approaches such as fluorescence often require fixation and sectioning. In this paper we detail the use of Surface Enhanced Raman Spectroscopy (SERS) to measure the viability of MTS grown from prostate cancer (PC3) cells. Our results show that we can monitor loss of viability by measuring pH and redox potential in MTS and furthermore we demonstrate that SERS can be used to measure the effects of fractionation of a dose of radiotherapy in a way that has potential to inform treatment planning.EaStCHEM, NHS Lothian, Jamie King Cancer Research FundThis is the final version of the article. It first appeared from the Royal Society of Chemistry via http://dx.doi.org/10.1039/C6AN01032

Cross-talk between signalling pathways and the multidrug resistant protein MDR-1

The multidrug resistant protein MDR-1 has been associated with the resistance to a wide range of anti-cancer drugs. Taxol is a substrate for this transporter system and is used in the treatment of a wide range of human malignancies including lung, breast and ovarian cancer. We have generated a series of ovarian cell lines resistant to this compound, all of which overexpress MDR-1 through gene amplification. We present novel evidence that a constitutive activation of the ERK1/2 MAP kinase pathway was also observed although the level of active JNK and p38 remained unchanged. Inhibition of the ERK1/2 MAP kinase pathway using UO126 or PD098059 re-sensitised the Taxol resistant cells at least 20-fold. Importantly, when Mdr-1 cDNA was stably expressed in the wild-type cell line to generate a highly Taxol-resistant sub-line, 1847/MDR5, ERK1/2 MAP kinases again became activated. This result demonstrated that the increased activity of the signalling pathway in the Taxol-resistant lines was directly attributable to MDR-1 overexpression and was not due to the effects of Taxol itself. Additionally, we demonstrated that inhibition of the P13K pathway with LY294002 sensitised the MDR-1-expressing 1847/TX0.5 cells and 1847/MDR5 cells at least 10-fold but had no effect in the wild-type cells. This finding suggests a possible role for this pathway, also, in the generation of resistance to Taxol. © 2001 Cancer Research Campaign  http://www.bjcancer.co

Post-glacial sea-level change along the Pacific coast of North America

Sea-level history since the Last Glacial Maximum on the Pacific margin of North America is complex and heterogeneous owing to regional differences in crustal deformation (neotectonics), changes in global ocean volumes (eustasy) and the depression and rebound of the Earth\u27s crust in response to ice sheets on land (isostasy). At the Last Glacial Maximum, the Cordilleran Ice Sheet depressed the crust over which it formed and created a raised forebulge along peripheral areas offshore. This, combined with different tectonic settings along the coast, resulted in divergent relative sea-level responses during the Holocene. For example, sea level was up to 200 m higher than present in the lower Fraser Valley region of southwest British Columbia, due largely to isostatic depression. At the same time, sea level was 150 m lower than present in Haida Gwaii, on the northern coast of British Columbia, due to the combined effects of the forebulge raising the land and lower eustatic sea level. A forebulge also developed in parts of southeast Alaska resulting in post-glacial sea levels at least 122 m lower than present and possibly as low as 165 m. On the coasts of Washington and Oregon, as well as south-central Alaska, neotectonics and eustasy seem to have played larger roles than isostatic adjustments in controlling relative sea-level changes

A post-glacial sea level hinge on the central Pacific coast of Canada

Post-glacial sea level dynamics during the last 15,000 calendar years are highly variable along the Pacific coast of Canada. During the Last Glacial Maximum, the Earth\u27s crust was depressed by ice loading along the mainland inner coast and relative sea levels were as much as 200 m higher than today. In contrast, some outer coastal areas experienced a glacial forebulge (uplift) effect that caused relative sea levels to drop to as much as 150 m below present levels. Between these inner and outer coasts, we hypothesize that there would have been an area where sea level remained relatively stable, despite regional and global trends in sea level change. To address this hypothesis, we use pond basin coring, diatom analysis, archaeological site testing, sedimentary exposure sampling, and radiocarbon dating to construct sea level histories for the Hakai Passage region. Our data include 106 newly reported radiocarbon ages from key coastal sites that together support the thesis that this area has experienced a relatively stable sea level over the last 15,000 calendar years. These findings are significant in that they indicate a relatively stable coastal environment amenable to long-term human occupation and settlement of the area. Our results will help inform future archaeological investigations in the region

Targeted SERS nanosensors measure physicochemical gradients and free energy changes in live 3D tumor spheroids.

Use of multicellular tumor spheroids (MTS) to investigate therapies has gained impetus because they have potential to mimic factors including zonation, hypoxia and drug-resistance. However, analysis remains difficult and often destroys 3D integrity. Here we report an optical technique using targeted nanosensors that allows in situ 3D mapping of redox potential gradients whilst retaining MTS morphology and function. The magnitude of the redox potential gradient can be quantified as a free energy difference (ΔG) and used as a measurement of MTS viability. We found that by delivering different doses of radiotherapy to MTS we could correlate loss of ΔG with increasing therapeutic dose. In addition, we found that resistance to drug therapy was indicated by an increase in ΔG. This robust and reproducible technique allows interrogation of an in vitro tumor-model's bioenergetic response to therapy, indicating its potential as a tool for therapy development.Leverhulme Trust (Grant ID: RPG-2012-680), Jamie King Cancer Research FundThis is the final version of the article. It first appeared from the Royal Society of Chemistry via http://dx.doi.org/10.1039/C6NR06031

Convolutional neural networks for automated targeted analysis of gas chromatography-mass spectrometry data

Through their breath, humans exhale hundreds of volatile organic compounds (VOCs) that can reveal pathologies, including many types of cancer at early stages. Gas chromatography–mass spectrometry (GC-MS) is an analytical method used to separate and detect compounds in the mixture contained in breath samples. The identification of VOCs is based on the recognition of their specific ion patterns in GC-MS data, which requires labour-intensive and time-consuming preprocessing and analysis by domain experts. This paper explores the original idea of applying supervised machine learning, and in particular convolutional neural networks (CNNs), to learn ion patterns directly from raw GC-MS data. The method adapts to machine specific characteristics, and once trained, can quickly analyse breath samples bypassing the time-consuming preprocessing phase. The CNN classification performance is compared to those of shallow neural networks and support vector machines. All considered machine learning tools achieved high accuracy in experiments with clinical data from participants. In particular, the CNN-based approach detected the lowest number of false positives. The results indicate that the proposed method is a promising tool to improve accuracy, specificity, and in particular speed in the detection of VOCs of interest in large-scale data analysis

The challenges of the increasing institutionalization of climate security

A rapid and widespread institutionalization of climate security is underway, led by powerful states and international organizations. Recognition of the climate crisis by security actors as a serious threat to humanity is long overdue, but it is imperative that this institutionalization is critically scrutinized. This commentary highlights specific dangers that accompany the institutional mainstreaming of climate security, including a non-reflexive integration into traditional security paradigms, a growing geopolitical separation between discourses emerging from the Global South and North, and policymaking that tends to draw from a narrow view of the science. Science-based and actionable research informed by pluralistic understandings of climate security is needed to counter this trend