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Assessing the covariance of human biological and cultural evolution with major climate fluctuations requires independent, precise, and accurate chronologies documenting environmental change in association with rare fossils and archaeology. This thesis aims to improve and diversify geochronological tools and associated paleoenvironmental characterization of paleoanthropological sequences using two of the most precise and accurate chronometers applicable in the Quaternary Period, 40Ar/39Ar and U-Series (i.e., 230Th) geochronology, combined with light stable isotopes, to reconstruct timescales and terrestrial paleoenvironments at paleoanthropological sites.The first chapter refines the age of the Alder Creek sanidine (ACs) fluence monitor which is frequently utilized to determine 40Ar/39Ar ages of volcanic rocks in association with hominid fossil-bearing and archaeological deposits in eastern Africa. The age of ACs is significantly different if anchored by astronomical tuning (tACs = 1.1848 ± 0.0006 Ma, σ) than if anchored solely by constraints from radioactive decay (tACs = 1.1891 ± 0.0008 Ma), possibly due to 1) leads and lags in the deposition of astronomically tuned sequences, 2) inaccuracy of decay constants, and/or 3) assumptions inherent to each dating method. The second chapter outlines the use of C, N, and O stable isotopes of ostrich eggshells to reconstruct local paleoenvironments at African archaeological sites. Combined with novel 230Th burial dating of ostrich eggshells, these may provide precisely dated paleoenvironmental records for sites up to ~ 500 ka. The light stable isotope composition of ostrich eggshells from two eastern African archaeological sites ~50 – 4 ka, which include diachronous occurrences of the Middle to Later Stone Age transition, suggest a mosaic of local environments through time and space that is not apparent from global or regional paleoenvironmental records. In the third chapter, I apply 230Th dating to coral abrader artifacts from a stratified archaeological sequence at Tangatatau Rockshelter, Mangaia (Cook Islands). I compare the results with a recent Bayesian 14C chronology for the site and develop screening criteria to identify reliable 230Th dates from buried contexts at other sites in an effort to develop more precise ways of dating Polynesian expansion. Precise 230Th dates from coral abraders support early Polynesian arrival to Mangaia (1011.6 ± 5.8 CE) and the arrival of the sweet potato (Ipomoea batatas) to no later than 1361–1466 CE, indicating that trans-Pacific voyaging had introduced this South American native plant to the Cook Islands by that time. The techniques used in this thesis demonstrate the power of integrative research in isotope geochemistry to address questions about geological processes and human evolution.

Introduction: 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). Material and methods: 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). Results: 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). Conclusion: 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.

The 40Ar/39Ar dating method is among the most versatile of geochronometers, having the potential to date a broad variety of K-bearing materials spanning from the time of Earth’s formation into the historical realm. Measurements using modern noble-gas mass spectrometers are now producing 40Ar/39Ar dates with analytical uncertainties of ~0.1%, thereby providing precise time constraints for a wide range of geologic and extraterrestrial processes. Analyses of increasingly smaller subsamples have revealed age dispersion in many materials, including some minerals used as neutron fluence monitors. Accordingly, interpretive strategies are evolving to address observed dispersion in dates from a single sample. Moreover, inferring a geologically meaningful “age” from a measured “date” or set of dates is dependent on the geological problem being addressed and the salient assumptions associated with each set of data. We highlight requirements for collateral information that will better constrain the interpretation of 40Ar/39Ar data sets, including those associated with single-crystal fusion analyses, incremental heating experiments, and in situ analyses of microsampled domains. To ensure the utility and viability of published results, we emphasize previous recommendations for reporting 40Ar/39Ar data and the related essential metadata, with the amendment that data conform to evolving standards of being findable, accessible, interoperable, and reusable (FAIR) by both humans and computers. Our examples provide guidance for the presentation and interpretation of 40Ar/39Ar dates to maximize their interdisciplinary usage, reproducibility, and longevity.

Due to the high soft tissue resolution, magnetic resonance imaging (MRI) could improve the accuracy of pancreatic tumor delineation in radiation treatment planning. A multi-institutional study was proposed to evaluate the impact of MRI on inter-observer agreement in gross tumor volume (GTV) and duodenum delineation for pancreatic cancer compared with computer tomography (CT).Two clinical cases of borderline resectable (Case 1) and unresectable (Case 2) pancreatic cancer were selected. In two sequential steps, diagnostic contrast-enhanced CT scan and MRI sequences were sent to the participating centers. CT-GTVs were contoured while blinded to MRI data sets. DICE index was used to evaluate the spatial overlap accuracy.Thirty-one radiation oncologists from different Institutions submitted the delineated volumes. CT- and MRI-GTV mean volumes were 21.6 ± 9.0 cmDiagnostic MRI resulted in smaller GTV in borderline resectable case with a substantial agreement between observers, and was comparable to CT scan in interobserver variability, in both cases. The greater variability in the unresectable case underlines the critical issues related to the outlining when vascular structures are more involved. The integration of MRI with contrast-enhancement CT, thanks to its high definition of tumor relationship with neighboring vessels, could offer a greater accuracy of target delineation.

Africa’s Middle Stone Age preserves sporadic evidence for novel behaviours among early modern humans, prompting a range of questions about the influence of social and environmental factors on patterns of human behavioural evolution. Here we document a suite of novel adaptations dating approximately 92–80 thousand years before the present at the archaeological site Varsche Rivier 003 (VR003), located in southern Africa’s arid Succulent Karoo biome. Distinctive innovations include the production of ostrich eggshell artefacts, long-distance transportation of marine molluscs and systematic use of heat shatter in stone tool production, none of which occur in coeval assemblages at sites in more humid, well-studied regions immediately to the south. The appearance of these novelties at VR003 corresponds with a period of reduced regional wind strength and enhanced summer rainfall, and all of them disappear with increasing winter rainfall dominance after 80 thousand years before the present, following which a pattern of technological similarity emerges at sites throughout the broader region. The results indicate complex and environmentally contingent processes of innovation and cultural transmission in southern Africa during the Middle Stone Age. acceptedVersion

Significance Understanding the evolution, dispersals, behaviors, and ecologies of early African Homo sapiens requires accurate geochronological placement of fossils and artifacts. We introduce open-air occurrences of such remains in sediments of the Middle Awash study area in Ethiopia. We describe the stratigraphic and depositional contexts of our discoveries and demonstrate the effectiveness of recently developed uranium-series dating of ostrich eggshell at validating and bridging across more traditional radioisotopic methods (14C and 40Ar/39Ar). Homo sapiens fossils and associated Middle Stone Age artifacts are placed at >158 and ∼96 ka. Later Stone Age occurrences are dated to ∼21 to 24 ka and ∼31 to 32 ka, firmly dating the upper portion of one of the longest records of human evolution., 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 230Th/U burial dating of OES to bridge the temporal gap between radiocarbon (14C) and 40Ar/39Ar ages for the MSA and provide 14C ages to constrain the younger LSA archaeology and fauna to ∼24 to 21.4 ka. Paired 14C and 230Th/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 40Ar/39Ar age. Associated fauna, flora, and Homo sapiens fossils are thereby now fixed between 106 ± 20 ka and 96.4 ± 1.6 ka (all errors 2σ). Additional 40Ar/39 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 H. sapiens 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.

40Ar/39Ar geochronology constraints to aggradational phases and grainsize variations show that the sedimentary filling of the Liri fluvial-lacustrine basin (central Italy) recorded the occurrence of deglaciation events associated with global meltwater pulses. Integrating these data with those from the Tiber River catchment basin, 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. 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 occurred 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.

PURPOSE/OBJECTIVE(S): stereotactic ablative radiotherapy (SABR) has been shown to increase survival rates in oligometastatic disease (OMD), but local control of colorectal metastases still remains poor. We aimed to identify potential predictive factors of SBRT response through a multicenter large retrospective database and to investigate how lung SBRT can impact on the progression to the polymetastatic disease (PMD). MATERIALS/METHODS: the study involved 22 centers, and was approved by the Ethical Committee (Prot. Negrar 2019-ZT). 1023 lung metastases treated with SBRT in 622 patients were reported. The median BED was 105 Gy10. Lesion diameter GTV, PTV volume, dose, fractionations, and site of primary tumor were evaluated as potential predictive marker for SBRT response for the primary end-point local progression-free survival (LPFS). EGFR, KRAS, NRAS, BRAF, and MSI were also evaluated. Secondary end-point was the time to the polymetastatic conversion (ttPMC). RESULTS: the median follow-up was 26 months (range 3-117 months). The median lesion diameter was 13 mm (range 4-58 mm). The 2- and 3-year LPFS were 75.6% and 71%, respectively. At the univariate analysis, BED ≥125Gy10 was associated with improved LPFS (2-year: 94.1% versus 72.6%; P = < 0.0001), single fraction SBRT correlated with better LPFS in the overall population (2-year: 80.6% versus 73.7%; P = 0.03), but no significant difference was observed when considering the population treated with BED > 100 Gy10. Lesion diameter ≤19 mm correlated with improved LPFS (2-year 80% versus 60%; P = < 0.0001). The median ttPMC was 26 months, and the 2-year ttPMC was 54.5%. The median PFS was 11.3 months. After SABR, 36% patients had polymetastatic relapse, 39.5% patients had an oligometastatic relapse, and 24.5% patients had no further relapse. CONCLUSION: 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. Several biological and clinical predictive factors were identified to assure the highest local control, on the basis of which a decisional algorithm will be derived.

Background/aim The aim of the study was to investigate boost volume definition, doses, and delivery techniques for rectal cancer dose intensification. Patients and methods An online survey was made on 25 items (characteristics, simulation, imaging, volumes, doses, planning and treatment). Results Thirty-eight radiation oncologists joined the study. Twenty-one delivered long-course radiotherapy with dose intensification. Boost volume was delineated on diagnostic magnetic resonance imaging (MRI) in 18 centres (85.7%), and computed tomography (CT) and/or positron emission tomography-CT in 9 (42.8%); 16 centres (76.2%) performed co-registration with CT-simulation. Boost dose was delivered on gross tumor volume in 10 centres (47.6%) and on clinical target volume in 11 (52.4%). The most common total dose was 54-55 Gy (71.4%), with moderate hypofractionation (85.7%). Intensity-modulated radiotherapy (IMRT) was used in all centres, with simultaneous integrated boost in 17 (80.8%) and image-guidance in 18 (85.7%). Conclusion A high quality of treatment using dose escalation can be inferred by widespread multidisciplinary discussion, MRI-based treatment volume delineation, and radiation delivery relying on IMRT with accurate image-guided radiation therapy protocols.