SINGLE AND DUAL-DOMAIN MODELS TO ASSESS THE EFFECTS OF HETEROGENEITY ON THE SOLUTE TRANSPORT IN ALLUVIAL AQUIFERS

Groundwater contamination is a fundamental environmental concern, since aquifers are a major source of drinking water in many regions of the world. The effects of different sources of pollutants on water quality can be investigated through the modeling of water flow and solute transport in the aquifers. An important issue to be addressed in the development of such models is the heterogeneity of the aquifers, which can occur at different spatial scales. The fine scale heterogeneity significantly affects the transport of contaminants at the scales of interest for practical applications. The primary objective of this thesis is to implement some models to effectively describe non-reactive solute transport in heterogeneous alluvial aquifers, by considering the porous medium as either an equivalent homogeneous volume (single-domain model) or a superposition of two domains (dual-domain models). Specifically, the dual-porosity model assumes that water flows in only one of the two domains, which can exchange solute by diffusion. The dual-permeability models assume that water flows in both domains, which have different hydrodispersive parameters and can be coupled, i.e., they can exchange solute, or uncoupled. These models are applied for the interpretation of some numerical tracer tests performed in portions of aquifers with different degrees of heterogeneity and at different scales: from a laboratory test on a decimeter-scale sand column, to numerical transport experiments on meter- and decameter-scale blocks of sediments, to an hectometer-scale field tracer test performed at the Cape Cod site. The effective model parameters are linked to the heterogeneity pattern of the different tests and the ability of the different models to describe the effects of structured heterogeneity on the solute transport is compared. The uncoupled dual-permeability model is shown to be the best one for alluvial aquifers characterized by the presence of preferential flow paths, which are connected bands of high-permeability sediments

Model calibration for ice sheets and glaciers dynamics: a general theory of inverse problems in glaciology

Numerical modelling of the dynamic evolution of ice sheets and glaciers requires the solution of discrete equations which are based on physical principles (e.g. conservation of mass, linear momentum and energy) and phenomenological constitutive laws (e.g. Glen\u2019s and Fourier\u2019s laws). These equations must be accompanied by information on the forcing term and by initial and boundary conditions (IBCs) on ice velocity, stress and temperature; on the other hand the constitutive laws involve many physical parameters, some of which depend on the ice thermodynamical state. The proper forecast of the dynamics of ice sheets and glaciers requires a precise knowledge of several quantities which appear in the IBCs, in the forcing terms and in the phenomenological laws. As these quantities cannot be easily measured at the study scale in the field, they are often obtained through model calibration by solving an inverse problem (IP). The objective of this paper is to provide a thorough and rigorous conceptual framework for IPs in cryospheric studies and in particular: to clarify the role of experimental and monitoring data to determine the calibration targets and the values of the parameters that can be considered to be fixed; to define and characterise identifiability, a property related to the solution to the forward problem; to study well-posedness in a correct way, without confusing instability with ill-conditioning or with the properties of the method applied to compute a solution; to cast sensitivity analysis in a general framework and to differentiate between the computation of local sensitivity indicators with a one-at-a-time approach and first-order sensitivity indicators that consider the whole possible variability of the model parameters. The conceptual framework and the relevant properties are illustrated by means of a simple numerical example of isothermal ice flow, based on the shallow-ice approximation

Platinum-Fluoropyrimidine and Paclitaxel-Based Chemotherapy in the Treatment of Advanced Anal Cancer Patients.

Background Although treatment of localized anal cancer (AC) is well established, very little evidence is available to inform the management of advanced tumors, and the prognosis of these patients remains poor. We have analyzed treatment pathways and outcomes of a single-institution series of advanced AC patients in order to provide insight into the management of this rare condition.Materials and methods Inclusion criteria included epidermoid histology, inoperable locally recurrent or metastatic disease, and availability of full medical records. The primary objective was overall survival (OS). Prognostic factors were analyzed in univariate models.Results Sixty-four patients (1997-2014) were included: 16 (25.0%) with inoperable locally advanced and 48 (75.0%) with metastatic tumors. Fifty-one (79.7%) received at least one line of chemotherapy; of these, 37% underwent multimodality treatment. A combination of a platinum agent plus a fluoropyrimidine was the most common first-line regimen (74.5%), with an objective response rate (ORR) of 34.4% (95% confidence interval [CI], 18.6%-53.2%). Paclitaxel-based chemotherapy was used in 15 patients as front-line or salvage treatment, and the overall ORR was 53.3% (95% CI, 26.6%-78.7%). Median progression-free survival (PFS) after first- and second-line chemotherapy was 5.8 (interquartile range [IQR], 2.8-7.6) and 3.2 (IQR, 2.5-7.1) months, respectively. Five-year OS in the overall population was 15% (95% CI, 7.0%-25.0%). Age ≤65 years and liver metastases were predictive of better PFS (hazard ratio [HR], 0.39; 95% CI, 0.16-0.97; p = .04) and worse OS (HR, 2.25; 95% CI, 1.25-4.03; p = .01), respectively.Conclusion A platinum agent plus a fluoropyrimidine and paclitaxel-based chemotherapy are active regimens for advanced AC. Clinical trials are needed to standardize treatment pathways, investigate the potential of novel therapeutics, and improve the poor prognosis of this rare condition. The Oncologist 2017;22:402-408Implications for Practice: Because of the lack of randomized trials, the optimal management of advanced anal cancer is uncertain. Despite its retrospective analysis and relatively small sample size, this is the second largest study ever conducted in this setting, and, as such, it has the potential to serve as a valuable source of information for everyday clinical practice. These findings suggest that chemotherapy with a platinum agent plus a fluoropyrimidine or paclitaxel-containing regimens are reasonable treatment options for patients with inoperable locally recurrent or metastatic anal carcinoma

A conceptual framework for discrete inverse problems in geophysics

In geophysics, inverse modelling can be applied to a wide range of goals, including, for instance, mapping the distribution of rock physical parameters in applied geophysics and calibrating models to forecast the behaviour of natural systems in hydrology, meteorology and climatology. A common, thorough conceptual framework to define inverse problems and to discuss their basic properties in a complete way is still lacking. The main goal of this paper is to propose a step forward toward such a framework, focussing on the discrete inverse problems, that are used in practical applications. The relevance of information and measurements (real world data) for the definition of the calibration target and of the objective function is discussed, in particular with reference to the Bayesian approach. Identifiability of model parameters, posedness (uniqueness and stability) and conditioning of the inverse problems are formally defined. The proposed framework is so general as to permit rigorous definitions and treatment of sensitivity analysis, adjoint-state approach, multi-objective optimization

Surrogate Endpoints in Second-Line Trials of Targeted Agents in Metastatic Colorectal Cancer : A Literature-Based Systematic Review and Meta-Analysis

The purpose of this study was to evaluate progression-free survival (PFS) and objective response rate (ORR) as surrogate endpoints of overall survival (OS) in modern clinical trials investigating the efficacy of targeted agents in the second-line treatment of metastatic colorectal cancer (mCRC). Materials and Methods A systematic search of literature pertaining to randomized phase II and III trials evaluating targeted agents as second-line treatments for mCRC was performed. The strength of the correlation between both PFS and ORR and OS was assessed based on the Pearson's correlation coefficient (R) and the coefficient of determination (R2). Results Twenty trials, including a total of 7,571 patients, met the search criteria. The median duration of post-progression survival (PPS) was 7.6 months. The median differences between experimental and control arms were 0.65 months (range, -2.4 to 3.4) for the median PFS and 0.7 months (range, -5.8 to 3.9) for the median OS. PFS and ORR showed moderate (R=0.734, R2=0.539, p < 0.001) and poor correlation (R=0.169, R2=0.029, p=0.476) with OS, respectively. No differences between anti-angiogenic agents and other drugs were evident. Conclusion Targeted agents investigated in the second-line treatment of mCRC provided minimal PFS gains translating into modest OS improvements. Considering both the moderate correlation between PFS and OS and the short duration of PPS, the OS should remain the preferred primary endpoint for randomized clinical trials in the second-line treatment of mCRC

Systemic Chemotherapy as Salvage Treatment for Locally Advanced Rectal Cancer Patients Who Fail to Respond to Standard Neoadjuvant Chemoradiotherapy.

Background The potential of chemotherapy as salvage treatment after failure of neoadjuvant chemoradiotherapy for locally advanced rectal cancer (LARC) has never been explored. We conducted a single-center, retrospective analysis to address this question.Patients and methods Patients with newly diagnosed LARC who were inoperable or candidates for extensive (i.e., beyond total mesorectal excision [TME]) surgery after long-course chemoradiotherapy and who received salvage chemotherapy were included. The primary objective was to estimate the proportion of patients who became suitable for TME after chemotherapy.Results Forty-five patients were eligible (39 candidates for extensive surgery and 6 unresectable). Previous radiotherapy was given concurrently with chemotherapy in 43 cases (median dose: 54.0 Gy). Oxaliplatin- and irinotecan-based salvage chemotherapy was administered in 40 (88.9%) and 5 (11.1%) cases, respectively. Eight patients (17.8%) became suitable for TME after chemotherapy, 10 (22.2%) ultimately underwent TME with clear margins, and 2 (4.4%) were managed with a watch and wait approach. Additionally, 13 patients had extensive surgery with curative intent. Three-year progression-free survival and 5-year overall survival in the entire population were 30.0% (95% confidence interval [CI]: 15.0-46.0) and 44.0% (95% CI: 26.0-61.0), respectively. For the curatively resected and "watch and wait" patients, these figures were 52.0% (95% CI: 27.0-73.0) and 67.0% (95% CI: 40.0-84.0), respectively.Conclusion Systemic chemotherapy may be an effective salvage strategy for LARC patients who fail to respond to chemoradiotherapy and are inoperable or candidates for beyond TME surgery. According to our study, one out of five patients may become resectable or be spared from an extensive surgery after systemic chemotherapy.Implications for practice High-quality evidence to inform the optimal management of rectal cancer patients who are inoperable or candidates for beyond total mesorectal excision surgery following standard chemoradiotherapy is lacking. We show for the first time that systemic chemotherapy may be beneficial and result in one out of five poor prognosis patients becoming resectable or being spared from an extensive surgical approach. Although mores studies are needed to confirm these data, administering salvage systemic chemotherapy in this setting may have the potential to minimize morbidity associated with extensive surgical procedures and improve long-term oncological outcome

Novel CCL21-Vault Nanocapsule Intratumoral Delivery Inhibits Lung Cancer Growth

Based on our preclinical findings, we are assessing the efficacy of intratumoral injection of dendritic cells (DC) transduced with an adenoviral vector expressing the secondary lymphoid chemokine (CCL21) gene (Ad-CCL21-DC) in a phase I trial in advanced non-small cell lung cancer (NSCLC). While this approach shows immune enhancement, the preparation of autologous DC for CCL21 genetic modification is cumbersome, expensive and time consuming. We are evaluating a non-DC based approach which utilizes vault nanoparticles for intratumoral CCL21 delivery to mediate antitumor activity in lung cancer.Here we describe that vault nanocapsule platform for CCL21 delivery elicits antitumor activity with inhibition of lung cancer growth. Vault nanocapsule packaged CCL21 (CCL21-vaults) demonstrated functional activity in chemotactic and antigen presenting activity assays. Recombinant vaults impacted chemotactic migration of T cells and this effect was predominantly CCL21 dependent as CCL21 neutralization abrogated the CCL21 mediated enhancement in chemotaxis. Intratumoral administration of CCL21-vaults in mice bearing lung cancer enhanced leukocytic infiltrates (CXCR3(+)T, CCR7(+)T, IFNγ(+)T lymphocytes, DEC205(+) DC), inhibited lung cancer tumor growth and reduced the frequencies of immune suppressive cells [myeloid derived suppressor cells (MDSC), T regulatory cells (Treg), IL-10 T cells]. CCL21-vaults induced systemic antitumor responses by augmenting splenic T cell lytic activity against parental tumor cells.This study demonstrates that the vault nanocapsule can efficiently deliver CCL21 to sustain antitumor activity and inhibit lung cancer growth. The vault nanocapsule can serve as an "off the shelf" approach to deliver antitumor cytokines to treat a broad range of malignancies

Multi-laboratory efforts for the standardization of performance assessment of diffuse optics instruments - The BitMap Exercise

A multi-laboratory exercise, involving 29 diffuse optical instruments, aimed at performance assessment of diffuse optics instruments on standardized protocols is presented. The overarching methodology and future actions will also be discussed

A multi-laboratory comparison of photon migration instruments and their performances – the BitMap Exercise

Performance assessment and standardization are indispensable for instruments of clinical relevance in general and clinical instrumentation based on photon migration/diffuse optics in particular. In this direction, a multi-laboratory exercise was initiated with the aim of assessing and comparing their performances. 29 diffuse optical instruments belonging to 11 partner institutions of a European level Marie Curie Consortium BitMap1 were considered for this exercise. The enrolled instruments covered different approaches (continuous wave, CW; frequency domain, FD; time domain, TD and spatial frequency domain imaging, SFDI) and applications (e.g. mammography, oximetry, functional imaging, tissue spectroscopy). 10 different tests from 3 well-accepted protocols, namely, the MEDPHOT2, the BIP3, and the nEUROPt4 protocols were chosen for the exercise and the necessary phantoms kits were circulated across labs and institutions enrolled in the study. A brief outline of the methodology of the exercise is presented here. Mainly, the design of some of the synthetic descriptors, (single numeric values used to summarize the result of a test and facilitate comparison between instruments) for some of the tests will be discussed.. Future actions of the exercise aim at deploying these measurements onto an open data repository and investigating common analysis tools for the whole dataset