Phase II study of eribulin in combination with gemcitabine for the treatment of patients with locally advanced or metastatic triple negative breast cancer (ERIGE trial). Clinical and pharmacogenetic results on behalf of the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC).

BACKGROUND: The combination of a microtubule inhibitor (eribulin) with a nucleoside analog (gemcitabine) may synergistically induce tumor cell death, particularly in triple negative breast cancer (TNBC) characterized by high cell proliferation, aggressive behavior, and chemo-resistance. PATIENTS AND METHODS: This is an open-label, multicenter phase II study evaluating the combination of eribulin (0.88 mg/m2) plus gemcitabine (1000 mg/m2) on days 1 and 8 of a 21-day cycle as either first- or second-line treatment of locally advanced or metastatic TNBC. The primary endpoint was the objective response for evaluable patients. A prospective, molecular correlative study was carried out to assess the role of germinal BRCA pathogenic variants and single nucleotide polymorphisms (SNPs) in predicting efficacy and toxicity of the combination regimen. RESULTS: From July 2013 to September 2016, 83 evaluable patients were enrolled. They received a median number of six cycles of treatment. An overall response rate (ORR) of 37.3% (31 patients) was observed, with a complete response rate of 2.4% and a partial response rate of 34.9%; the clinical benefit rate was 48.8%. With a median follow-up of 28.8 months, the median response duration was 6.6 months, the median progression-free survival (PFS) was 5.1 months, and the median overall survival (OS) was 14.5 months. The most common grade 3-4 adverse events were aminotransferase elevation (in 25% of the patients) and neutropenia (in 23.8%). Women with BRCA1/2 pathogenic variants were associated with worse ORR, PFS, and OS than BRCA1/2 wild-type carriers. CYP3A4 and FGD4 SNPs were associated with increased risk of liver toxicity. Three different SNPs in CDA∗2, RRM1, and CYP2C8 genes were significantly associated with poorer OS. CONCLUSIONS: The combination of eribulin and gemcitabine showed promising activity and a moderate toxicity profile in metastatic TNBC. BRCA status and pharmacogenetics tests may help identify patients with high probability of response with negligible toxicity. EUDRACT NUMBER: 2012-003505-10.

Baseline radionuclide and heavy metal concentrations in sediments of Sabaki River estuary (Kenya, Indian Ocean).

Baseline study of natural (7Be, 210Pb, 226Ra, 234Th, 228Ra, 40K) and anthropogenic (137Cs) radionuclides was carried out in two cores collected from Sabaki River estuary (Kenya, Indian Ocean). There was no exponential decrease of excess 210Pb down the cores, which did not allow dating and determination of heavy metal pollution history. The use of 137Cs as a time marker was not possible due to its low fallout rates in East Africa. The short-lived radioisotope 7Be, a tracer of river floods, confirmed 2018 flood in Sabaki River estuary. Heavy metal concentration in the two cores showed nonsystematic trends with depth. Only Pb concentration in Sabaki River estuary was higher than the background levels. Application of the "Environmental Risk from Ionising Contaminants Assessment and management" (ERICA) tool confirmed that the potential dose rates to biota from the sediment radioactivity concentrations are unlikely to pose appreciable ecological risks.

From radiometry to chronology of a marine sediment core: A 210Pb dating interlaboratory comparison exercise organised by the IAEA.

Laboratories from 14 countries (with different levels of expertise in radionuclide measurements and 210Pb dating) participated in an interlaboratory comparison exercise (ILC) related to the application of 210Pb sediment dating technique within the framework of the IAEA Coordinated Research Project. The laboratories were provided with samples from a composite sediment core and were required to provide massic activities of several radionuclides and an age versus depth model from the obtained results, using the most suitable 210Pb dating model. Massic concentrations of Zn and Cu were also determined to be used for chronology validation. The ILC results indicated good analytical performances while the dating results didn't demonstrate the same degree of competence in part due to the different experience in dating of the participant laboratories. The ILC exercise enabled evaluation of the difficulties faced by laboratories implementing 210Pb dating methods and identified some limitations in providing reliable chronologies.

Transport and fate of 137Cs in the Mediterranean and Black Seas system during 1945-2020 period: A modelling study.

The compartment model POSEIDON-R with an embedded dynamic food web model was used to assess 137Cs distributions in the Mediterranean and Black Seas during 1945-2020 due to the weapon testing and accident at the Chernobyl nuclear power plant. Three maximums of contamination of surface waters can be identified from 1950 in the Mediterranean Sea system. Two of them (in 1959 and 1963) were caused by atmospheric deposition due to the nuclear weapon testing. Third maximum in 1986 was related with the Chernobyl accident. Maximum of inventory of 137Cs in the Mediterranean Sea (11461 TBq) was achieved in 1968, whereas secondary maximum caused by Chernobyl accident in 1986 was almost the same (11460 TBq). The corresponding maximum in the Black Sea (3703 TBq) was reached in 1986. It is approximately two times larger than nuclear weapon tests maximum. The results of simulations conducted with generic parameters agreed well with measurements of 137Cs concentrations in the water, bottom sediments, and in marine organisms. The inventory in the Mediterranean Sea is most sensitive to the global deposition, whereas water exchange with Atlantic Ocean and the Black Sea plays minor role. The cumulative individual dose for the period 1945-2020 from consumption of marine products contaminated by 137Cs was in the range 41-130 µSv in the Mediterranean Sea and 213-274 µSv in the Black Sea. The dose increased up to 40% due to Chernobyl accident in the Mediterranean countries and 66-103% in the Black Sea countries comparatively with dose from the global deposition. A useful application of the modelling for monitoring purposes was selection of representative regions in the Mediterranean Sea (5 regions) and in the Black Sea (4 regions) using "etalon" method for classification.

Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study‡.

Background: Chemotherapy plus 1-year trastuzumab is the standard adjuvant treatment of HER2-positive breast cancer. The efficacy of less extended trastuzumab exposure is under investigation. The short-HER study was aimed to assess the non-inferiority of 9 weeks versus 1 year of adjuvant trastuzumab combined with chemotherapy. Patients and methods: HER2-positive breast cancer patients with node-positive or, if node negative, with at least one risk factor (pT>2 cm, G3, lympho-vascular invasion, Ki-67 > 20%, age ≤35 years, or hormone receptor negativity) were randomly assigned to receive sequential anthracycline-taxane combinations plus 1-year trastuzumab (arm A, long) or plus 9 weeks trastuzumab (arm B, short). This study was designed as a non-inferiority trial with disease-free survival (DFS) as primary end point. A DFS hazard ratio (HR) <1.29 was chosen as the non-inferiority margin. Analyses according to the frequentist and Bayesian approach were planned. Secondary end points included 2-year failure rate and cardiac safety. Results: A total of 1254 patients from 82 centers were randomized (arm A, long: n = 627; arm B, short: n = 626). Five-year DFS is 88% in the long and 85% in the short arm. The HR is 1.13 (90% CI 0.89-1.42), with the upper limit of the CI crossing the non-inferiority margin. According to the Bayesian analysis, the probability that the short arm is non-inferior to the long one is 80%. The 5-year overall survival (OS) is 95.2% in the long and 95.0% in the short arm (HR 1.07, 90% CI 0.74-1.56). Cardiac events are significantly lower in the short arm (risk-ratio 0.33, 95% CI 0.22-0.50, P < 0.0001). Conclusions: This study failed to show the non-inferiority of a shorter trastuzumab administration. One-year trastuzumab remains the standard. However, a 9-week administration decreases the risk of severe cardiac toxicity and can be an option for patients with cardiac events during treatment and for those with a low risk of relapse. Trial Registration: EUDRACT number: 2007-004326-25; NCI ClinicalTrials.gov number: NCT00629278.

Faunal activity rhythms influencing early community succession of an implanted whale carcass offshore Sagami Bay, Japan.

Benthic community succession patterns at whale falls have been previously established by means of punctual submersible and ROV observations. The contribution of faunal activity rhythms in response to internal tides and photoperiod cues to that community succession dynamism has never been evaluated. Here, we present results from a high-frequency monitoring experiment of an implanted sperm whale carcass in the continental slope (500 m depth) offshore Sagami Bay, Japan. The benthic community succession was monitored at a high frequency in a prolonged fashion (i.e. 2-h intervals for 2.5 months) with a seafloor lander equipped with a time-lapse video camera and an acoustic Doppler profiler to concomitantly study current flow dynamics. We reported here for the first time, to the best of our knowledge, the occurrence of strong 24-h day-night driven behavioral rhythms of the most abundant species (Simenchelys parasitica; Macrocheira kaempferi, and Pterothrissus gissu). Those rhythms were detected in detriment of tidally-controlled ones. Evidence of a diel temporal niche portioning between scavengers and predators avoiding co-occurrence at the carcass, is also provided. The high-frequency photographic and oceanographic data acquisition also helped to precisely discriminate the transition timing between the successional stages previously described for whale falls' attendant communities.

Efficacy and safety of Everolimus and Exemestane in hormone-receptor positive (HR+) human-epidermal-growth-factor negative (HER2-) advanced breast cancer patients: New insights beyond clinical trials. The EVA study.

BACKGROUND: The BOLERO-2 trial reported efficacy and safety of Everolimus (EVE) and Exemestane (EXE) combination in HR+ advanced breast cancer (ABC) patients. The BALLET trial further evaluated the safety of EVE-EXE in HR+ ABC patients, without reporting efficacy data. Aim of the EVA real-life study was to collect data of efficacy and safety of EVE-EXE combination in the clinical setting, as well as exploring efficacy according to EVE Dose-Intensity (DI) and to previous treatment with Fulvestrant. PATIENTS AND METHODS: This study aimed to describe the outcome of ABC pts treated with EVE-EXE combination in terms of median duration of EVE treatment and ORR in a real-life setting. RESULTS: From July 2013 to December 2015, the EVA study enrolled 404 pts. Median age was 61 years (33-83). Main metastatic sites were: bone (69.1%), soft tissue (34.7%) and viscera (33.2%). Median number of previous treatments was 2 (1-7). 43.3% of the pts had received Fulvestrant. Median exposure to EVE was 31.0 weeks (15.4-58.3) in the whole population. No difference was observed in terms of EVE exposure duration according to DI (p for trend = 0.27) or type of previous treatments (p = 0.33). ORR and Disease Control Rate (DCR) were observed in 31.6% and 60.7% of the patients, respectively, with the lowest ORRs confined in CHT pre-treated patients or in those who received the lowest DI of EVE. Grade 3-4 adverse events (AEs) were reported in 37.9% of the patients. Main AEs were: stomatitis (11.2%), non-infectious pneumonitis - NIP (3.8%), anaemia (3.8%) and fatigue (3.2%). CONCLUSIONS: The EVA study provided new insights in the use of EVE-EVE combination in HR+ ABC pts many years after the publication of the pivotal trial. The combination is safe and the best response could be obtained in patients receiving the full dose of EVE and/or after hormone-therapy as Fulvestrant in ABC.

Inertial bioluminescence rhythms at the Capo Passero (KM3NeT-Italia) site, Central Mediterranean Sea.

In the deep sea, the sense of time is dependent on geophysical fluctuations, such as internal tides and atmospheric-related inertial currents, rather than day-night rhythms. Deep-sea neutrino telescopes instrumented with light detecting Photo-Multiplier Tubes (PMT) can be used to describe the synchronization of bioluminescent activity of abyssopelagic organisms with hydrodynamic cycles. PMT readings at 8 different depths (from 3069 to 3349 m) of the NEMO Phase 2 prototype, deployed offshore Capo Passero (Sicily) at the KM3NeT-Italia site, were used to characterize rhythmic bioluminescence patterns in June 2013, in response to water mass movements. We found a significant (p < 0.05) 20.5 h periodicity in the bioluminescence signal, corresponding to inertial fluctuations. Waveform and Fourier analyses of PMT data and tower orientation were carried out to identify phases (i.e. the timing of peaks) by subdividing time series on the length of detected inertial periodicity. A phase overlap between rhythms and cycles suggests a mechanical stimulation of bioluminescence, as organisms carried by currents collide with the telescope infrastructure, resulting in the emission of light. A bathymetric shift in PMT phases indicated that organisms travelled in discontinuous deep-sea undular vortices consisting of chains of inertially pulsating mesoscale cyclones/anticyclones, which to date remain poorly known.

Sediment reworking rates in deep sediments of the Mediterranean Sea.

Different pelagic areas of the Mediterranean Sea have been investigated in order to quantify physical and biological mixing processes in deep sea sediments. Herein, results of eleven sediment cores sampled at different deep areas (> 2000 m) of the Western and Eastern Mediterranean Sea are presented. ²¹°Pb(xs) and ¹³7Cs vertical profiles, together with ¹4C dating, are used to identify the main processes characterising the different areas and, finally, controlling mixing depths (SML) and bioturbation coefficients (D(b)). Radionuclide vertical profiles and inventories indicate that bioturbation processes are the dominant processes responsible for sediment reworking in deep sea environments. Results show significant differences in sediment mixing depths and bioturbation coefficients among areas of the Mediterranean Sea characterised by different trophic regimes. In particular, in the Oran Rise area, where the Almeria-Oran Front induces frequent phytoplankton blooms, we calculate the highest values of sediment mixing layers (13 cm) and bioturbation coefficients (0.187 cm² yr⁻¹), and the highest values of ²¹°Pb(xs) and ¹³7Cs inventories. Intermediate values of SML and D(b) (~6 cm and ~0.040 cm² yr⁻¹, respectively) characterise the mesothrophic Algero-Balearic basin, while in the Southern Tyrrhenian Sea mixing parameters (SML of 3 cm and D(b) of 0.011 cm² yr⁻¹ are similar to those calculated for the oligotrophic Eastern Mediterranean (SML of 2 cm and D(b) of ~0.005 cm² yr⁻¹).

A comparative study of protein immobilization techniques for optical immunosensors.

This paper presents the results of a study of a number of antibody immobilization techniques for application to optical immunosensors. In particular, well-known methods such as covalent binding and physical adsorption have been extended to the Langmiur-Blodgett method in an attempt to improve the density and possibly the uniformity of orientation of monoclonal antibodies on an optical surface. The surface density of active immobilized antibodies was determined from enzyme immunoassay and their thickness and refractive index were deduced from ellipsometry. It is shown that, although high surface densities (500 ng/cm2) of antibody can be obtained, the major obstacle to the detection of low concentrations of antigens or haptens is the non-specific binding of foreign molecules to the sensing surface.