Platinum-based chemoradiation (CCRT) is the standard treatment for Locally Advanced Head and Neck Squamous-Cell Carcinoma (LAHNSCC). Cetuximab/RT (CET/RT) is an alternative treatment option to CCRT. ...The efficacy of induction chemotherapy (IC) followed by chemoradiation compared to chemoradiation alone has not been demonstrated in randomized clinical trials. The goals of this phase II-III trial were to assess: (i) the overall survival (OS) of IC versus no-induction (no-IC) and (ii) the Grade 3–4 in-field mucosal toxicity of CCRT versus CET/RT. The present paper focuses on the analysis of efficacy.
Patients with LAHNSCC were randomized to receive concomitant treatment alone CCRT (Arm A1) or CET/RT (Arm A2), or three cycles of induction docetaxel/cisplatin/5 fluorouracil (TPF) followed by CCRT (Arm B1) or followed by CET/RT (Arm B2). The superiority hypothesis of OS comparison of IC versus no-IC (Arms B1 + B2 versus A1 + A2) required 204 deaths to detect an absolute 3-year OS difference of 12% (HR 0.675, with 80% power at two-sided 5% significance level).
414 out of 421 patients were finally analyzed: 206 in the IC and 208 in the no-IC arm. Six patients were excluded because of major violation and one because of metastatic disease at diagnosis. With a median follow-up of 44.8 months, OS was significantly higher in the IC arm (HR 0.74; 95% CI 0.56–0.97; P = 0.031). Complete Responses (P = 0.0028), Progression Free Survival (P = 0.013) and the Loco-regional Control (P = 0.036) were also significantly higher in the IC arm. Compliance to concomitant treatments was not affected by induction TPF.
IC followed by concomitant treatment improved the outcome of patients with LAHNSCC without compromising compliance to the concomitant treatments. The degree of the benefit of IC could be different according to the type of the subsequent concomitant strategy.
NCT01086826, www.clinicaltrials.gov
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•SABR provides high rates of local control to lung oligometastases.•Local control of colorectal lung metastases seems lower compared to other tumors.•We identified predictive factors of SABR response ...and polymetastases development.•Predictive factors of local control are BED ≥125 Gy and lesion diameter ≤20 mm.•Having lesion >20 mm and 4–5 metastases predicted for a polymetastatic evolution.
Stereotactic ablative radiotherapy (SABR) has been shown to increase survival in oligometastatic disease, but local control of colorectal metastases remains poor. We aimed to identify potential predictive factors of SBRT response through a multicenter large retrospective database and to investigate the progression to the polymetastatic disease (PMD).
The study involved 23 centers, and was approved by the Ethical Committee (Prot. Negrar 2019-ZT). 1033 lung metastases were reported. Clinical and biological parameters were evaluated as predictive for freedom from local progression-free survival (FLP). Secondary end-point was the time to the polymetastatic conversion (tPMC).
Two-year FLP was 75.4%. Two-year FLP for lesions treated with a BED < 00 Gy, 100–124 Gy, and ≥125 Gy was 76.1%, 70.6%, and 94% (p = 0.000). Two-year FLP for lesion measuring ≤10 mm, 10–20 mm, and >20 mm was 79.7%, 77.1%, and 66.6% (p = 0.027). At the multivariate analysis a BED ≥125 Gy significantly reduced the risk of local progression (HR 0.24, 95%CI 0.11–0.51; p = 0.000). Median tPMC was 26.8 months. Lesions treated with BED ≥125 Gy reported a significantly longer tPMC as compared to lower BED. The median tPMC for patients treated to 1, 2–3 or 4–5 simultaneous oligometastases was 28.5, 25.4, and 9.8 months (p = 0.035).
The present is the largest series of lung colorectal metastases treated with SABR. The results support the use of SBRT in lung oligometastatic colorectal cancer patients as it might delay the transition to PMD or offer relatively long disease-free period in selected cases. Predictive factors were identified for treatment personalization.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Ar/
Ar geochronology constraints to aggradational phases and grain size variations show that the two large gravel beds occurring in the sedimentary filling of the Liri fluvial-lacustrine basin ...(central Italy) recorded the occurrence of deglaciation events synchronous within uncertainties with global meltwater pulses at ca. 450 and 350 ka. In particular, we find a precise match between the ages of gravel deposition and the occurrence of moderate sea-level rise events which anticipate those more marked during the glacial termination V and IV in the Red Sea relative sea level curve, as already verified by data from the Tiber River catchment basin. Such correspondence suggests that gravel deposition is facilitated by melting of Apennine mountain range glaciers, which provide the water transport energy and a surplus of clastic input to the rivers draining the mountain regions and flowing into the Tyrrhenian Sea. Therefore, the thick gravel beds intercalated in the sedimentary filling of the catchment basins of the major rivers in central Italy may be regarded as an equivalent proxy of large deglaciation events, similar to the ice-rafted debris in northern Atlantic. Consistent with this hypothesis, we also show the close correspondence between the occurrence of particularly mild (warmer) minima of the mean summer insolation at 65° N and these early aggradational phases, as well as with other anomalous early sea-level rises occurring c. 750 ka and 540 ka at the onset of glacial termination VIII and VI, and 40 ka at the onset of the so-called Heinrich events.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The accuracy of 40Ar/39Ar geochronology relies in large part on precise and accurate calibration of the ages and K-Ar isotopic compositions of standards. A widely used standard for Quaternary ...samples, the ∼1.2 Ma Alder Creek sanidine (ACs), has published ages spanning a range of ∼2%. New measurements of ACs co-irradiated with the Fish Canyon sanidine (FCs) standard and sanidines from astronomically dated Miocene tuffs in Crete and Morocco yield results that enable both (i) a direct calibration of ACs relative to FCs, and (ii) stepwise calibrations between these two standards employing the Miocene intermediaries. Results are summarized by the parameter RFCsACs, defined as the ratio of (40Ar*/39ArK) of ACs to FCs, which embodies the fundamental age relationship between these standards that is independent of systematic variables such as decay constants or absolute ages of standards. Our new measurements, executed using three mass spectrometers and various irradiation and analytical protocols, yield a weighted mean RFCsACs = 0.041702 ± 0.000014 (σ). This result can be combined with previously published determinations of R values for ACs relative to the Miocene tuffs and to FCs to yield a recommended interlaboratory value ofRFCsACs = 0.041707 ± 0.000011. The weighted-mean age of ACs using this interlaboratory value, based on astronomically-calibrated ages of FCs and the Miocene intermediary sanidines, is tACs = 1.1848 ± 0.0006 Ma (±0.05%). Applying this result to the most precise published 40Ar/39Ar data for the Matuyama-Brunhes geomagnetic polarity reversal yields tMBB = 780.1 ± 0.8 ka. In addition, these new data for ACs support previous conclusions that U-Pb zircon ages from the Alder Creek rhyolite incorporate ∼13 ka of pre-eruptive residence time.
•Alder Creek sanidine (ACs) is calibrated to astronomically dated Miocene tuffs.•These provide stepwise and direct intercalibration with Fish Canyon sanidine (FCs).•New data yield a weighted mean intercalibration factor RFCsACs=0.041702±0.000014(σ).•Combining with published data yields an interlaboratory RFCsACs=0.041707±0.000011.•These results yield a weighted mean age of tACs = 1.1848 ± 0.0006 Ma (±0.05%).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Proxy records of past climate change spanning beyond the radiocarbon range commonly derive their chronologies from orbital tuning strategies, thus bounding our spatio-temporal reconstructions to a ...priori assumptions that can not be directly tested. Here we present a tephrochronologically constrained framework of past environmental and climatic changes in the central Mediterranean region during the last ca. 190 ka. Our research is based on a high-resolution, multi-proxy study of a sedimentary record (cores F1-F3) retrieved from the Fucino Basin lacustrine succession, central Italy, in 2015. We update the existing tephrostratigraphic framework of the F1-F3 record with the finding of the widespread Campanian Ignimbrite tephra marker layer and produce a robust and independent chronology based on new and published 40Ar/39Ar and 14C dating of 17 tephra layers. Observed palaeoenvironmental changes are tracked in other lacustrine, marine and speleothem records across the Mediterranean and North Atlantic regions via tephrostratigraphic correlations and chronological matching providing a robust assessment of age uncertainties. Results show a complex interplay between local environmental changes and broad-scale climatic processes highlighting a strong orbital forcing on glacial-interglacial changes. Along with these major changes we detect prominent millennial-scale variability. During times of intermediate global ice volumes, Mediterranean mountain ecosystems oscillated around an “interglacial” state suggesting that climatic shifts, although large, did not exceed the local environmental tolerance-resilience threshold. Conversely, during periods of large global ice volume, we observe subdued millennial-scale variability with ecosystems operating in a strictly ruled glacial environment.
•Palaeoenvironmental record of the last 190 ka.•Independent tephrochronology.•Orbital and sub-orbital scale variability.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Here, we report on the Quaternary Volsci Volcanic Field (VVF, central Italy). In light of new
40
Ar/
39
Ar geochronological data and compositional characterization of juvenile eruptive products, we ...refine the history of VVF activity, and outline the implications on the pre-eruptive magma system and the continental subduction processes involved. Different from the nearby volcanic districts of the Roman and Campanian Provinces, the VVF was characterized by small-volume (0.01–0.1 km
3
) eruptions from a network of monogenetic centers (mostly tuff rings and scoria cones, with subordinate lava occurrences), clustered along high-angle faults of lithospheric depth. Leucite-bearing, high-K (HKS) magmas (for which we report for the first time the phlogopite phenocryst compositions) mostly fed the early phase of activity (∼761–539 ka), then primitive, plagioclase-bearing (KS) magmas appeared during the climactic phase (∼424–349 ka), partially overlapping with HKS ones, and then prevailed during the late phase of activity (∼300–231 ka). The fast ascent of primitive magma batches is typical of a tectonically controlled volcanic field, where the very low magma flux is a passive byproduct of regional tectonic strain. We suggest that the dominant compressive stress field acting at depth was accompanied by an extensional regime in the upper crust, associated with the gravity spreading of the Apennine chain, allowing the fast ascent of magma from the mantle source with limited stationing in shallow reservoirs.
The Halibee member of the Upper Dawaitoli Formation of Ethiopia's Middle Awash study area features a wealth of Middle and Later Stone Age (MSA and LSA) paleoanthropological resources in a succession ...of Pleistocene sediments. We introduce these artifacts and fossils, and determine their chronostratigraphic placement via a combination of established radioisotopic methods and a recently developed dating method applied to ostrich eggshell (OES). We apply the recently developed
Th/U burial dating of OES to bridge the temporal gap between radiocarbon (
C) and
Ar/
Ar ages for the MSA and provide
C ages to constrain the younger LSA archaeology and fauna to ∼24 to 21.4 ka. Paired
C and
Th/U burial ages of OES agree at ∼31 ka for an older LSA locality, validating the newer method, and in turn supporting its application to stratigraphically underlying MSA occurrences previously constrained only by a maximum
Ar/
Ar age. Associated fauna, flora, and
fossils are thereby now fixed between 106 ± 20 ka and 96.4 ± 1.6 ka (all errors 2σ). Additional
Ar/
results on an underlying tuff refine its age to 158.1 ± 11.0 ka, providing a more precise minimum age for MSA lithic artifacts, fauna, and
fossils recovered ∼9 m below it. These results demonstrate how chronological control can be obtained in tectonically active and stratigraphically complex settings to precisely calibrate crucial evidence of technological, environmental, and evolutionary changes during the African Middle and Late Pleistocene.
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