Metronomic Chemotherapy with Vinorelbine Produces Clinical Benefit and Low Toxicity in Frail Elderly Patients Affected by Advanced Non-Small Cell Lung Cancer

Lung cancer is the leading cause of death worldwide. The treatment choice for advanced stage of lung cancer may depend on histotype, performance status (PS), age, and comorbidities. In the present study, we focused on the effect of metronomic vinorelbine treatment in elderly patients with advanced unresectable non-small cell lung cancer (NSCLC). Methods. From January 2016 to December 2016, 44 patients affected by non-small cell lung cancer referred to our oncology day hospital were progressively analyzed. The patients were treated with oral vinorelbine 30 mg x 3/wk or 40 mg x 3/wk meaning one day on and one day off. The patients were older than 60, stage IIIB or IV, ECOG PS ≥ 1, and have at least one important comorbidity (renal, hepatic, or cardiovascular disease). The schedule was based on ECOG-PS and comorbidities. The primary endpoint was progression-free survival (PFS). PFS was used to compare patients based on different scheduled dosage (30 or 40 mg x3/weekly) and age (more or less than 75 years old) as exploratory analysis. We also evaluated as secondary endpoint toxicity according to Common Toxicity Criteria Version 2.0. Results. Vinorelbine showed a good safety profile at different doses taken orally and was effective in controlling cancer progression. The median overall survival (OS) was 12 months. The disease control rate (DCR) achieved 63%. The median PFS was 9 months. A significant difference in PFS was detected comparing patients aged below with those over 75, and the HR value was 0.72 (p<0.05). Not significant was the difference between groups with different schedules. Conclusions. This study confirmed the safety profile of metronomic vinorelbine and its applicability for patients unfit for standard chemotherapies and adds the possibility of considering this type of schedule not only for very elderly patients

Fagliazione normale attiva lungo il versante occidentale del Monte Morrone (Appennino Centrale, Italia)

L’Appennino Centrale è interessato da sistemi attivi di faglie normali potenzialmente responsabili di terremoti di elevata magnitudo (fino a 7). Alcuni forti terremoti storici avvenuti in questo settore di catena appenninica sono stati attribuiti all’attivazione di alcune di questi sistemi di faglia, mediante analisi paleosismologiche e il confronto fra la distribuzione del danneggiamento associato a tali eventi sismici e la distribuzione spaziale delle faglie attive. Ad alcune di queste strutture tettoniche attive, invece, non è possibile associare alcun evento sismico storico noti da catalogo e per questo esse vengono considerate come strutture sismogenetiche silenti. Pertanto, a queste faglie è comunemente attribuita un’elevata pericolosità sismica. Il presente studio è mirato a caratterizzare l’attività tardo-Quaternaria di una queste faglie silenti, nello specifico quella che borda il versante occidentale del Monte Morrone (nell’Appennino abruzzese), cercando di definirne 1) la cinematica, 2) il tasso di movimento e 3) la massima magnitudo attesa da un evento di attivazione. Le analisi (comprendenti rilevamento geologico, geomorfologico e strutturale, nonché datazioni al 14C e determinazioni tefrostratigrafiche) effettuate lungo l’espressione in superficie di questa struttura tettonica, costituita da due segmenti di faglia paralleli, orientati NW-SE, hanno permesso di confermare che essa è prevalentemente caratterizzata da una cinematica normale, con una minore componente obliqua sinistra. Tale cinematica sarebbe consistente con un’estensione orientata circa N 20°. Il tasso di movimento del segmento di faglia occidentale è stato definito mediante l’individuazioni di depositi (prevalentemente conoidi alluvionali), cronologicamente vincolati, dislocati dall’attività di tale segmento. Lo slip rate è risultato essere dell’ordine di 0.4±0.07 mm/anno. Per quanto concerne il segmento orientale, la sua attività tardopleistocenica – olocenica è indicata dalla dislocazione lungo di esso di depositi di versante attribuiti all’UMG. Tuttavia, la mancanza di sedimenti e/o morfologie coevi nel blocco di letto ha impedito di valutare il tasso di movimento di questo segmento. Tuttavia, le analisi geologico-strutturali effettuate, unite ad una revisione critica della letteratura disponibile sui modelli evolutivi dei sistemi di faglie normali, hanno permesso di ipotizzare per il segmento di faglia orientale uno tasso di movimento >0 ma inferiore a quello definito per il segmento occidentale, ossia <0.4±0.07 mm/anno. Questo consente di definire per l’intero sistema di faglie del Monte Morrone uno slip rate compreso fra 0.4±0.07 e 0.8±0.09 mm/anno. Infine, applicando le equazioni empiriche proposte da Wells e Coppersmith (1994) che legano la magnitudo momento e i) la lunghezza in superficie della struttura tettonica e ii) il rigetto (massimo e medio) per evento di attivazione – considerando un tempo di ricorrenza di circa 2000anni – è stato possibile definire che la massima magnitudo attesa da un terremoto originato lungo il sistema di faglie normali del Monte Morrone (lungo circa 23 km) è dell’ordine di 6.6-6.7

40Ar/39Ar and 14C geochronology of the Albano maar deposits: Implications for 2 defining the age and eruptive style of the most recent explosive activity at Colli 3 Albani Volcanic District, Central Italy

New 40Ar/39Ar and 14C ages have been found for the Albano multiple maar pyroclastic units and underlying 25 paleosols to document the most recent explosive activity in the Colli Albani Volcanic District (CAVD) near 26 Rome, Italy, consisting of seven eruptions (Albano 1 27 ^ = ^ oldest). Both dating methodologies have been applied on several proximal units and on four mid-distal fall/surge deposits, the latter correlated, according to two 28 current different views, to either the Albano or the Campi di Annibale hydromagmatic center. The 40Ar/39Ar 29 ages on leucite phenocrysts from the mid-distal units yielded ages of ca. 72 ka, 73 ka, 41 ka and 36 ka BP, 30 which are indistinguishable from the previously determined 40Ar/39Ar ages of the proximal Albano units 1, 2, 31 5 and 7, thus confirming their stratigraphic correspondence. 32 Twenty-one 14C ages of the paleosols beneath Albano units 3, 5, 6 and 7 were found for samples collected 33 from 13 proximal and distal sections, some of which were the same sections sampled for 40Ar/39Ar 34 measurements. The 14C ages were found to be stratigraphically inconsistent and highly scattered, and were 35 systematically younger than the 40Ar/39Ar ages, ranging 36 ^ from 35 ka ^ to 3 ka. Considering the significant consistence of the 40Ar/39Ar chronological framework, we interpret the scattered and contradictory 14C ages 37 to be the result of a variable contamination of the paleosols by younger organic carbon deriving from the 38 superficial soil horizons. 39 These results suggest that multiple isotopic systems anchored to a robust stratigraphic framework may need 40 to be employed to determine accurately the geochronology of the CAVD as well as other volcanic districts. 4

Fagliazione normale attiva e deformazioni gravitative profonde di versante: il caso del versante occidentale del Monte Morrone (Appennino Centrale, Italia)

Questo lavoro ha l’obiettivo di indagare la relazione fra l’attività tettonica e l’innesco di deformazioni gravitative profonde lungo i versanti montuosi. In base alla letteratura esistente, la tettonica può svolgere un duplice ruolo nell’influenzare l’evoluzione in senso gravitativo dei versanti: i) un ruolo passivo, legato all’influenza sull’assetto strutturale dei versanti che può essere ereditato da una fase tettonica non più attiva; ii) un ruolo attivo, rappresentato dalle modifiche che essa può determinare sui versanti, producendo incrementi dell’energia del rilievo e dello stress tensionale subito dai volumi di roccia. In quest’ottica è stato effettuato uno studio lungo il versante occidentale del Monte Morrone, rilievo che delimita ad oriente il bacino di Sulmona, nell’Appennino abruzzese, e che costituisce un’anticlinale da thrust formatasi durante il Mio-Pliocene. Questo versante del rilievo è interessato da un sistema attivo di faglie normali (orientato NW-SE), lungo circa 23 km, costituito da due segmenti di faglia paralleli, uno localizzato nel settore intermedio del versante e uno localizzato alla base del rilievo. Lungo questo versante sono state riconosciute in passato alcune morfologie – quali trincee, depressioni allungate, scarpate in contropendenza – indicanti l’occorrenza di movimenti gravitativi profondi (tipo sackung). Sono state condotte osservazioni geomorfologico-strutturali atte a mappare tutti gli elementi morfologici legati ai movimenti gravitativi profondi. Sono stati altresì realizzati 4 scavi geognostici all’interno di due trincee gravitative per cercare di ottenere elementi utili alla caratterizzazione dell’evoluzione recente di questi fenomeni gravitativi (Fig.1). Le analisi condotte hanno permesso di definire che tali fenomeni gravitativi di grande scala sono determinati dall’incremento dell’energia del rilievo prodotta dall’attività del segmento di faglia occidentale. La faglia orientale, invece, viene esclusivamente utilizzata, nella sua porzione più superficiale, come superficie di scivolamento delle masse rocciose. L’innesco dei fenomeni gravitativi sarebbe dunque avvenuto successivamente all’inizio dell’attività del segmento di faglia occidentale che, secondo Gori et al. (2007), avrebbe avuto luogo in un momento successivo all’attivazione del segmento orientale, dopo il Pleistocene Inferiore. Questo quadro evolutivo è suggerito dal fatto che la formazione di alcune delle trincee gravitative ha dislocato brecce di versante attribuite al Pleistocene Inferiore. Queste, infatti, si sono depositate su un paleo-paesaggio, attualmente individuabile fra i due segmenti di faglia, sospeso sulla piana attuale, che era localizzato alla base della scarpata di faglia relativa al segmento orientale, quando quello occidentale non era ancora attivo. La realizzazione di scavi geognostici all’interno di due trincee gravitative ha permesso di individuare la dislocazione dei depositi di riempimento lungo le scarpate che delimitano tali depressioni e lungo piani di taglio gravitativi secondari. I depositi messi alla luce dagli scavi sono prevalentemente costituiti da detrito di versante, sedimenti di origine colluviali e paleosuoli. Datazioni radiometriche effettuate su campioni di materiale organico prelevato dai paleosuoli e su frammenti di carbone contenuti nelle unità colluviali, indicano che i movimenti lungo le scarpate delle trincee è proseguito anche nel corso del tardo Olocene, nello specifico successivamanete a 10660-10540 cal. a.C./10430-9910 cal. a.C.. Questo indicherebbe che le deformazioni gravitative che interessano il versante occidentale del Monte Morrone possono considerarsi attive. Infine, anche se non sono state riconosciute chiare evidenze che mettano in relazione eventi di attivazione del sistema di faglie normali del M. Morrone con episodi di accelerazione dei movimenti gravitativi, questo non può essere escluso e, anzi, deve essere considerato come probabile

Time intervals to assess active and capable faults for engineering practices in Italy

The time span necessary to define a fault as ‘active and capable’ can mainly be derived from the framework of the regulations and the literature produced since the 1970s on risk estimation in engineering planning of strategic buildings. Within this framework, two different lines of thought can be determined, which have mainly developed in the USA. On the one side, there is a tendency to produce ‘narrow’ chronological definitions. This is particularly evident in the regulatory acts for the planning of nuclear reactors. The much more effective second line of thought anchors the chronological definitions of the terms ‘active’ and, therefore ‘capable’, to the concept of ‘seismotectonic domain’. As the domains are different in different regions of the World, the chronological definition cannot be univocal; i.e., different criteria are needed to define fault activity, which will depend on the characteristics of the local tectonic domain and of the related recurrence times of fault activation. Current research on active tectonics indicates that methodological aspects can also condition the chronological choice to define fault activity. Indeed, this practice implies the use of earth science methods, the applications of which can be inherently limited. For example, limits and constraints might be related to the availability of datable sediments and landforms that can be used to define the recent fault kinematic history. For the Italian territory, we consider two main tectonic domains: (a) the compressive domain along the southern margin of the Alpine chain and the northern and northeastern margins of the Apennines, which is characterised by the activity of blind thrusts and reverse faults; and (b) the extensional domain of the Apennines and the Calabria region, which is often manifest through the activity of seismogenic normal and normal-oblique faults. In case (a), the general geomorphic and subsurficial evidence of recent activity suggests that a reverse blind fault or a blind thrust should be considered active and potentially capable if showing evidence of activity during the Quaternary (i.e., over the last 2.6 Myr), unless information is available that documents its inactivity since at least the Last Glacial Maximum (LGM) (ca. 20 ka). The choice of the LGM period as the minimum age necessary to define fault inactivity is related to practical aspects (the diffusion of the LGM deposits and landforms) and to the evidence that ca. 20 kyr to assess fault inactivity precautionarily includes a number of seismic cycles. In the extensional domains of the Apennines and Calabria region, the general geological setting suggests that the present tectonic regime has been active since the beginning of the Middle Pleistocene. Therefore, we propose that a normal fault in the Italian extensional domain should be considered active and capable if it displays evidence of activation in the last 0.8 Myr, unless it is sealed by deposits or landforms not younger than the LGM. The choice of the LGM as the minimum age to ascertain fault inactivity follows the same criteria described for the compressive tectonic domain

The late MIS 5 Mediterranean tephra markers: A reappraisal from peninsular Italy terrestrial records

We present new tephrostratigraphic records from the late MIS 5 (ca 110e80 ka) terrestrial sediments from southern and central Italy. On the one hand, the central Italy record consists of an outcropping lacustrine sequence from the Sulmona intermountain basin that contains four trachyticephonolitic tephra layers (POP3, POP2a, POP2b, POP1), all of which show a K-alkaline affinity that is typical for the Roman co-magmatic Province. The POP3 and POP1 layers were dated by 40Ar/39Ar method at 106.2 1.3 ka (2s) and 92.4 4.6 ka (2s), respectively. The sequence in southern Italy, on the other hand, is represented by post-Tyrrhenian coastal deposits of the Cilento area, Campania, which contain two trachytic layers (CIL2, CIL1) that show the same K-alkaline affinity. Based on their chemical compositions and radiometric ages, POP3 and POP1 are firmly correlated with the marine tephra layers X-5 (105 2 ka) and C-22 (ca 90 ka), which, in turn, match tephras TM-25 and TM-23-11, respectively, in the lacustrine sequence of Lago Grande di Monticchio (southern Italy). Of note, the POP1 layer also matches the Adriatic Sea tephra PRAD 2517 that was previously correlated with the older X-5 layer. The tephra couplet POP2a and POP2b (ca 103 and 103.5 ka, extrapolated ages) are compatible with the TM- 24b and TM-24-3 tephras in Monticchio, which match both the stratigraphic positions and the chemical compositions. In the Cilento area, as well as the already described X-6 layer (ca 108 ka) (CIL2), we recognise a new stratigraphic superimposed layer (CIL1) that matches the POP3/TM-25/C-27/X-5 Mediterranean marker(s). In summary, the data presented here provide new chemical and 40Ar/39Ar chronological constraints towards a robust late MIS 5 tephrostratigraphy of the central Mediterranean, although at the same time, they also reveal how the tephrostratigraphy itself might be flawed when dealing with tephra markers that are not adequately constrained and characterised.Published31-451V. Storia eruttivaJCR Journa

Deep-seated gravitational slope deformation, large-scale rock failure, and active normal faulting along Mt. Morrone (Sulmona basin, Central Italy): Geomorphological and paleoseismological analyses.

Active faulting is one of the main factors that induce deep-seated gravitational slope deformations (DGSDs). In this study, we investigate the relationships between the tectonic activity of the NW–SE normal fault system along Mt. Morrone, central Apennines, Italy, and the evolution of the associated sackung-type DGSD. The fault system is considered to be the source of M 6.5–7 earthquakes. Our investigations have revealed that the DGSD began to affect the Mt. Morrone SW slope after the Early Pleistocene. This was due to the progressive slope instability arising from the onset of the younger western fault, with the older eastern fault acting as the preferred sliding zone. Paleoseismological investigations based on the excavation of slope deposits across gravitational troughs revealed that the DGSD was also responsible for the displacement of Late Pleistocene–Holocene sediments accumulated in the sackung troughs. Moreover, we observed that the investigated DGSD can evolve into large-scale rock slides. Therefore, as well as active normal faulting, the DGSD should be considered as the source of a further geological hazard. Overall, our approach can be successfully applied to other contexts where active normal faults control the inception and evolution of a DGSD

Co/Ni element ratio in the galactic cosmic rays between 0.8 and 4.3 GeV/nucleon

In a one-day balloon flight of the Trans-Iron Galactic Element Recorder (TIGER) in 1997, the instrument achieved excellent charge resolution for elements near the Fe peak, permitting a new measurement of the element ratio Co/Ni. The best fit to the data, extrapolated to the top of the atmosphere, gives an upper limit for this ratio of 0.093±0.037 over the energy interval 0.8 to 4.3 GeV/nucleon; because a Co peak is not seen in the data, this result is given as an upper limit. Comparing this upper limit with calculations by Webber & Gupta suggests that at the source of these cosmic rays a substantial amount of the electron-capture isotope 59Ni survived. This conclusion is in conflict with the clear evidence from ACE/CRIS below 0.5 GeV/nucleon that there is negligible 59Ni surviving at the source. Possible explanations for this apparent discrepancy are discussed

Mid-distal occurrences of the Albano Maar pyroclastic deposits and their relevance for reassessing the eruptive scenarios of the most recent activity at the Colli Albani Volcanic District, Central Italy

The Late Pleistocene Albano Maar hosted the most recent volcanic activity of the Colli Albani Volcanic District, represented at nearvent sections by a thick pyroclastic succession of seven units clustered in two main eruptive cycles dated at around 70–68 and 41–36 ka B.P., respectively. Recent stratigraphic investigations allowed us to recognise a pyroclastic succession comprising four eruptive units widely spread in the northeastern sectors of the Colli Albani volcano, up to 15km eastward from the Albano Maar. Integrated tephrostratigraphic, morpho-pedostratigraphic, archaeological, petrological and geochemical analyses enable us to recognise them as distal deposits of the first, third, fifth and seventh Albano Maar eruptions, enlarging significantly their previously supposed dispersion area. Further tephrostratigraphic studies in central Apennine area, allowed us to identify the Albano Maar products in Late Pleistocene deposits of several intermountain basins, extending still further the dispersion area of distal ash fallout as far as 100–120km from the vent. On the basis of the identification and the study of these previously unrecognised mid-distal Albano Maar deposits, a reappraisal of the eruptive scenarios and related energetic parameters is proposed