Intensive induction chemotherapy with C-BOP/BEP for intermediate- and poor-risk metastatic germ cell tumours (EORTC trial 30948)

New chemotherapy regimens are continuously explored in patients with high-risk malignant germ cell tumours (MGCTs). This multicentre phase II trial assessed the efficacy and toxicity of C-BOP/BEP chemotherapy in intermediate and poor prognosis MGCT (IGCCCG criteria). C-BOP/BEP treatment consisted of cycles of cisplatin, vincristine, bleomycin and carboplatin, followed by one cycle of vincristine and bleomycin and three cycles of BEP (bleomycon, etoposide, cisplatin). The trial was designed to demonstrate a 1-year progression-free survival rate of 80%, that is, to exclude a 1-year rate of 70% or less, with a one-sided significance level of 5%. Secondary end points included toxicity, overall survival and the postchemotherapy complete response rate. In total, 16 European hospitals entered 66 eligible patients (intermediate prognosis group: 37; poor prognosis group: 29). A total of 45 patients (68.2%, 95% confidence interval (95% CI): 56.9–79.4%) achieved a complete response (intermediate prognosis: 30; poor prognosis: 15). After a median observation time of 40.4 months (range: 13.7–66.3), the 1-year progression-free survival rate was 81.8% 95% CI: 72.5–91.1%). The 2-year overall survival was 84.5% (95% CI: 75.6–93.3%). In all, 51 patients experienced at least one episode of WHO grade 3/4 leucopenia, and at least one event of grade 3/4 thrombocytopenia occurred in 30 patients. There was no toxic death. With an 82% 1-year progression-free survival and a lower limit of the 95% CI above 70%, the efficacy of C-BOP/BEP is comparable to that of published alternative chemotherapy schedules in high-risk MGCT patients. The treatment's toxicity is manageable in a multicentre setting. In poor prognosis patients, C-BOP/BEP should be compared to standard chemotherapy of four cycles of BEP

GAMEC – a new intensive protocol for untreated poor prognosis and relapsed or refractory germ cell tumours

There is no consensus as to the management of untreated poor prognosis or relapsed/refractory germ cell tumours. We have studied an intensive cisplatin-based regimen that incorporates high-dose methotrexate (HD MTX) and actinomycin-D and etoposide every 14 days (GAMEC). Sixty-two patients were enrolled in a phase 2 study including 27 who were untreated (IGCCCG, poor prognosis) and 35 with progression despite conventional platinum based chemotherapy. The pharmacokinetics of the drugs were correlated with standard outcome measures. Twenty of the untreated patients were progression free following GAMEC and appropriate surgery, as were 18 individuals in the pretreated group. None of the established prognostic factors for therapy for pretreated patients could identify a poor-prognosis group. Five out of nine late relapses to prior chemotherapy were progression free following GAMEC and appropriate surgery. All patients had at least one episode of febrile neutropenia and there were five (8%) treatment-related deaths. PK values were not predictive of efficacy or toxicity, although the dose intensity in the pretreated group of patients, especially of HD MTX, was significantly correlated with progression-free survival (PFS). GAMEC is a novel intensive regimen for this group of patients producing encouraging responses, although with significant toxicity. For those in whom it fails, further therapy is still possible with durable responses being seen

The relationship between eruptive activity, flank collapse, and sea level at volcanic islands: A long-term (>1 Ma) record offshore Montserrat, Lesser Antilles

Hole U1395B, drilled southeast of Montserrat during Integrated Ocean Drilling Program Expedition 340, provides a long (>1 Ma) and detailed record of eruptive and mass-wasting events (>130 discrete events). This record can be used to explore the temporal evolution in volcanic activity and landslides at an arc volcano. Analysis of tephra fall and volcaniclastic turbidite deposits in the drill cores reveals three heightened periods of volcanic activity on the island of Montserrat (?930 ka to ?900 ka, ?810 ka to ?760 ka, and ?190 ka to ?120 ka) that coincide with periods of increased volcano instability and mass-wasting. The youngest of these periods marks the peak in activity at the Soufrière Hills volcano. The largest flank collapse of this volcano (?130 ka) occurred towards the end of this period, and two younger landslides also occurred during a period of relatively elevated volcanism. These three landslides represent the only large (>0.3 km3) flank collapses of the Soufrière Hills edifice, and their timing also coincides with periods of rapid sea-level rise (>5 m/ka). Available age data from other island arc volcanoes suggests a general correlation between the timing of large landslides and periods of rapid sea-level rise, but this is not observed for volcanoes in intra-plate ocean settings. We thus infer that rapid sea-level rise may modulate the timing of collapse at island arc volcanoes, but not in larger ocean-island settings

Submarine record of volcanic island construction and collapse in the Lesser Antilles arc: First scientific drilling of submarine volcanic island landslides by IODP Expedition 340

IODP Expedition 340 successfully drilled a series of sites offshore Montserrat, Martinique and Dominica in the Lesser Antilles from March to April 2012. These are among the few drill sites gathered around volcanic islands, and the first scientific drilling of large and likely tsunamigenic volcanic island-arc landslide deposits. These cores provide evidence and tests of previous hypotheses for the composition and origin of those deposits. Sites U1394, U1399, and U1400 that penetrated landslide deposits recovered exclusively seafloor-sediment, comprising mainly turbidites and hemipelagic deposits, and lacked debris avalanche deposits. This supports the concepts that i/ volcanic debris avalanches tend to stop at the slope break, and ii/ widespread and voluminous failures of pre-existing low-gradient seafloor sediment can be triggered by initial emplacement of material from the volcano. Offshore Martinique (U1399 and 1400), the landslide deposits comprised blocks of parallel strata that were tilted or micro-faulted, sometimes separated by intervals of homogenized sediment (intense shearing), while Site U1394 offshore Montserrat penetrated a flat-lying block of intact strata. The most likely mechanism for generating these large-scale seafloor-sediment failures appears to be propagation of a decollement from proximal areas loaded and incised by a volcanic debris avalanche. These results have implications for the magnitude of tsunami generation. Under some conditions, volcanic island landslide deposits comprised of mainly seafloor sediment will tend to form smaller magnitude tsunamis than equivalent volumes of subaerial block-rich mass flows rapidly entering water. Expedition 340 also successfully drilled sites to access the undisturbed record of eruption fallout layers intercalated with marine sediment which provide an outstanding high-resolution dataset to analyze eruption and landslides cycles, improve understanding of magmatic evolution as well as offshore sedimentation processes. This article is protected by copyright. All rights reserved

The present and future of serum diagnostic tests for testicular germ cell tumours.

Testicular germ cell tumours (GCTs) are the most common malignancy occurring in young adult men and the incidence of these tumours is increasing. Current research priorities in this field include improving overall survival for patients classified as being 'poor-risk' and reducing late effects of treatment for patients classified as 'good-risk'. Testicular GCTs are broadly classified into seminomas and nonseminomatous GCTs (NSGCTs). The conventional serum protein tumour markers α-fetoprotein (AFP), human chorionic gonadotrophin (hCG) and lactate dehydrogenase (LDH) show some utility in the management of testicular malignant GCT. However, AFP and hCG display limited sensitivity and specificity, being indicative of yolk sac tumour (AFP) and choriocarcinoma or syncytiotrophoblast (hCG) subtypes. Furthermore, LDH is a very nonspecific biomarker. Consequently, seminomas and NSGCTs comprising a pure embryonal carcinoma subtype are generally negative for these conventional markers. As a result, novel universal biomarkers for testicular malignant GCTs are required. MicroRNAs are short, non-protein-coding RNAs that show much general promise as biomarkers. MicroRNAs from two 'clusters', miR-371-373 and miR-302-367, are overexpressed in all malignant GCTs, regardless of age (adult or paediatric), site (gonadal or extragonadal) and subtype (seminomas, yolk sac tumours or embryonal carcinomas). A panel of four circulating microRNAs from these two clusters (miR-371a-3p, miR-372-3p, miR-373-3p and miR-367-3p) is highly sensitive and specific for the diagnosis of malignant GCT, including seminoma and embryonal carcinoma. In the future, circulating microRNAs might be useful in diagnosis, disease monitoring and prognostication of malignant testicular GCTs, which might also reduce reliance on serial CT scanning. For translation into clinical practice, important practical considerations now need addressing.The authors would like to acknowledge grant funding from CwCUK/GOSHCC (M.J.M. N.C. grant W1058), SPARKS (M.J.M. N.C. grant 11CAM01), CRUK (N.C. grant A13080) MRC (M.J.M. grant MC_EX_G0800464) and National Health Service funding to the Royal Marsden/Institute of Cancer Research National Institute for Health Research Biomedical Research Centre for Cancer (R.A.H.). The authors also thank the Max Williamson Fund, the Josh Carrick Foundation and The Perse Preparatory School, Cambridge for support.This is the author accepted manuscript. The final version is available fromNature Publishing Group via https://doi.org/10.1038/nrurol.2016.17