Integrating X-ray computed tomography with chemical imaging to quantify mineral re-crystallization from granulite to eclogite metamorphism in the Western Italian Alps (Sesia-Lanzo Zone)

Metamorphic transformations and fabric evolution are the consequence of thermo-dynamic processes, lasting from thousands to millions of years. Relative mineral percentages, their grain size distribution, grain orientation, and grain boundary geometries are first-order parameters for dynamic modeling of metamorphic processes. To quantify these parameters, we propose a multidisciplinary approach integrating X-ray computed microtomography (\u3bc-CT) with X-ray chemical mapping obtained from an Electron MicroProbe Analyzer (EMPA). We used a metapelitic granulite sample collected from the Alpine HP-LT metamorphic rocks of the Mt. Mucrone (Eclogitic Micaschists Complex, Sesia-Lanzo Zone, Western Alps, Italy). The heterogeneous Alpine deformation and metamorphism allowed the preservation of pre-alpine structural and mineralogical features developed under granulite-facies conditions. The inferred granulitic mineral association is Grt + Bt + Sil + Pl + Qtz \ub1 Ilm \ub1 Kfs \ub1 Wm. The subsequent pervasive static eclogite-facies re-equilibration occurred during the alpine evolution. The inferred alpine mineral association is Wm + Omp \ub1 Ky + Qtz + Grt though local differences may occur, strongly controlled by chemistry of microdomains. X-ray \u3bc-CT data extracted from centimeter-sized samples have been analyzed to quantify the volumetric percentage and shape preferred orientation (SPO) for each mineral phase. By combining tomographic phase separation with chemical variation and microstructures (i.e., different grain-size classes for the same phase and morphology of different pre-alpine microdomains) the pre-alpine mineralogical phases from the alpine overprint have been distinguished and quantified. Moreover, the sample preserves 100% of the pre-alpine granulite fabric, which surprisingly corresponds to less than 22% of the corresponding pre-alpine metamorphic assemblages, while the alpine eclogitic static assemblage corresponds to 78% though no new fabric is developed. This contribution demonstrates that the combined use of EMPA X-ray chemical mapping with the X-ray \u3bc-CT shape analysis permits a dynamic approach to constrain the chemistry of the mineral phases linked to the development of metamorphic-related static and dynamic fabrics

PSMA PET/CT in Castration-Resistant Prostate Cancer: Myth or Reality?

Background: prostate-specific membrane antigen (PSMA) ligand PET has been recently incorporated into international guidelines for several different indications in prostate cancer (PCa) patients. However, there are still some open questions regarding the role of PSMA ligand PET in castration-resistant prostate cancer (CRPC). The aim of this work is to assess the clinical value of PSMA ligand PET/CT in patients with CRPC. Results: PSMA ligand PET has demonstrated higher detection rates in comparison to conventional imaging and allows for a significant reduction in the number of M0 CRPC patients. However, its real impact on patients’ prognosis is still an open question. Moreover, in CRPC patients, PSMA ligand PET presents some sensitivity and specificity limitations. Due to its heterogeneity, CRPC may present a mosaic of neoplastic clones, some of which could be PSMA−/FDG+, or vice versa. Likewise, unspecific bone uptake (UBU) and second primary neoplasms (SNPs) overexpressing PSMA in the neoangiogenic vessels represent potential specificity issues. Integrated multi-tracer imaging (PSMA ligand and [18F]FDG PET) together with a multidisciplinary discussion could allow for reaching the most accurate evaluation of each patient from a precision medicine point of view

Dynamics in the Sesia HP terrane: Combined petrochronological and structural analysis

HP terranes dominated by continental crust represent the end result of a sequence of processes that operate at lithosphere scale, i.e. rifting, subduction/accretion, return flow/exhumation. To under\uacstand the dynamics of the subduction channel in complex terranes of this kind, the effects from each stage must be investigated separately, linking the observations and data from kilometers down to micrometer scale. This task recommends an integrative approach. Here we focus on the assembly of the Sesia Zone (SZ), a key element of the internal Western Alps. This terrane comprises two main polymetamorphic base\uacment units and thin trails of a cover sequence that includes post-Permian syn- to post-rift metasediments; the latter show no pre-Alpine metamorphic imprint. The tectonic scenario of Babist et al. (2006) recognizes five main phases in the Alpine structural evolution; their model helped us select areas for detailed structural work and sampling. Our first goal was to relate the early convergent structures (D1, D2) to the P-T evolution and to establish a robust time-frame for the HP-dynamics within and between the tectonic slices. Within the subduction/extrusion channel, problems addressed include the question of tectonic mixing, i.e. temporal and spatial scales of relative and absolute movement of the slices, and the conditions and timing of their final juxtaposition prior to the rapid exhumation of the Sesia Zone as a whole. Mono- and polymetamorphic sediments from different slices display unequivocal evidence of several HP-stages separated in time. Successive stages under eclogite facies conditions occurred between 86 \u2013 65 Ma, as shown by LA-ICP-MS and SHRIMP data on growth zones in accessory allanite, monazite, zircon, and titanite. By using mutual inclusions and overgrowth relationships, the age-data on allanite and monazite can be tied to the multistage evolution of an individual sample. For different rocks, these (over)growth stages can be related to D1- and D2-deformation when micro-, meso- and megastructural observations are combined. Thermobarometry indicates intermittant decompression by ~0.8 GPa between HP phases, hence pressure cycling (aka yo-yo tectonics, Rubatto et al., 2011). This tectonic mobility occurred prior to the final juxtaposition of slices and their exhumation, which involved at least two major deformation phases and lead to widespread retrogression at amphibolite to green-schist facies conditions. Our approach combining structural, petrological, and geochronological techniques yields some field-based constraints on the duration and rates of the dynamics within a subduction channel. It may be useful to compare these to insights from numerical models, provided the latter take into account the specific conditions of the plate convergence, which turns out to have been highly oblique in the present case

correlation between immuno related adverse events iraes occurrence and clinical outcome in metastatic renal cell carcinoma mrcc patients treated with nivolumab iraene trial an italian multi institutional retrospective study

n/

Milk flow pattern, somatic cell count and teat apex score in primiparous dairy cows at the beginning of lactation

The aim of the study was to investigate the relationships between milk flow traits, milk Somatic Cell Count (SCC) and teat apex score in primiparous cows during the first 120 days of lactation. A total of 82 primiparous Holstein cows were randomly selected in 6 herds characterized by different milking machines and management. The cows were monitored monthly during the first 120 days of lactation. Each month, milk flow curves of the whole udder of each primiparous cow were registered with continuous electronic milk flow meters (Lactocorder), quarter milk samples were aseptically collected, somatic cells were counted, and teat apex scores were assessed. Quarter milk samples were divided in two groups according to SCC: 200,000 cells/ml, respectively. At udder level each cow was classified as low SCC (LSCC) when all quarters had 10 SCC; P<0.05). Moreover, primiparous cows with at least one HSCC control had a significant increase in peak milk flow during the first four months of lactation, while the other cows showed only a slight increase. Teat apex scores significantly increased in both groups of primiparous cows as lactation progressed but values in subjects always classified as LSCC animals were constantly lower with respect to cows with at least one HSCC control. The results obtained in this study support the relationship between SCC, teat apex score and milk flow traits

Bladder metastases of appendiceal mucinous adenocarcinoma: a case presentation

<p>Abstract</p> <p>Background</p> <p>Appendiceal adenocarcinoma is rare with a frequency of 0.08% of all surgically removed appendices. Few cases of appendiceal carcinoma infiltrating the bladder wall for spatial contiguity have been documented.</p> <p>Case Presentation</p> <p>A case is reported of a 45-years old woman with mucinous cystadenocarcinoma of the appendix with bladder metastasis. Although ultrasonography and voided urinary cytology were negative, abdomen computed tomography (CT) scan and cystoscopy and subsequent pathological examination revealed a mass exclusively located in the anterior wall of the bladder. Histopathology of the transurethral bladder resection revealed a bladder adenocarcinoma [6 cm (at the maximum diameter) × 2,5 cm; approximate weight: 10 gr] with focal mucinous aspects penetrating the muscle and perivisceral fat. Laparotomy evidenced the presence of a solid mass of the appendix (2,5 cm × 3 cm × 2 cm) extending to the loco-regional lymph nodes. Appendectomy and right hemicolectomy, linfoadenectomy and partial cystectomy were performed. The subsequent pathological examination revealed a mucinous cystadenocarcinoma of the appendix with metastatic cells colonising the anterior bladder wall and several colic lymph nodes.</p> <p>Conclusions</p> <p>The rarity of the appendiceal carcinoma invading the urinary bladder and its usual involvement of nearest organs and the posterior bladder wall, led us to describe this case which demonstrates the ability of the appendiceal cancer to metastasize different regions of urinary bladder.</p

Long-term benefit of lurbinectedin as palliative chemotherapy in progressive malignant pleural mesothelioma (MPM): final efficacy and translational data of the SAKK 17/16 study.

BACKGROUND The SAKK 17/16 study showed promising efficacy data with lurbinectedin as second- or third-line palliative therapy in malignant pleural mesothelioma. Here, we evaluated long-term outcome and analyzed the impact of lurbinectedin monotherapy on the tumor microenvironment at the cellular and molecular level to predict outcomes. MATERIAL AND METHODS Forty-two patients were treated with lurbinectedin in this single-arm study. Twenty-nine samples were available at baseline, and seven additional matched samples at day one of cycle two of treatment. Survival curves and rates between groups were compared using the log-rank test and Kaplan-Meier method. Statistical significance was set at P value <0.05. RESULTS Updated median overall survival (OS) was slightly increased to 11.5 months [95% confidence interval (CI) 8.8-13.8 months]. Thirty-six patients (85%) had died. The OS rate at 12 and 18 months was 47% (95% CI 32.1% to 61.6%) and 31% (95% CI 17.8% to 45.0%), respectively. Median progression-free survival was 4.1 months (95% CI 2.6-5.5 months). No new safety signals were observed. Patients with lower frequencies of regulatory T cells, as well as lower tumor-associated macrophages (TAMs) at baseline, had a better OS. Comparing matched biopsies, a decrease of M2 macrophages was observed in five out of seven patients after exposure to lurbinectedin, and two out of four patients showed increased CD8+ T-cell infiltrates in tumor. DISCUSSION Lurbinectedin continues to be active in patients with progressing malignant pleural mesothelioma. According to our very small sample size, we hypothesize that baseline TAMs and regulatory T cells are associated with survival. Lurbinectedin seems to inhibit conversion of TAMs to M2 phenotype in humans

Impact of hypoxia on chemoresistance of mesothelioma mediated by the proton-coupled folate transporter, and preclinical activity of new anti-LDH-A compounds

BACKGROUND: Expression of proton-coupled folate transporter (PCFT) is associated with survival of mesothelioma patients treated with pemetrexed, and is reduced by hypoxia, prompting studies to elucidate their correlation. METHODS: Modulation of glycolytic gene expression was evaluated by PCR arrays in tumour cells and primary cultures growing under hypoxia, in spheroids and after PCFT silencing. Inhibitors of lactate dehydrogenase (LDH-A) were tested in vitro and in vivo. LDH-A expression was determined in tissue microarrays of radically resected malignant pleural mesothelioma (MPM, N = 33) and diffuse peritoneal mesothelioma (DMPM, N = 56) patients. RESULTS: Overexpression of hypoxia marker CAIX was associated with low PCFT expression and decreased MPM cell growth inhibition by pemetrexed. Through integration of PCR arrays in hypoxic cells and spheroids and following PCFT silencing, we identified the upregulation of LDH-A, which correlated with shorter survival of MPM and DMPM patients. Novel LDH-A inhibitors enhanced spheroid disintegration and displayed synergistic effects with pemetrexed in MPM and gemcitabine in DMPM cells. Studies with bioluminescent hypoxic orthotopic and subcutaneous DMPM athymic-mice models revealed the marked antitumour activity of the LDH-A inhibitor NHI-Glc-2, alone or combined with gemcitabine. CONCLUSIONS: This study provides novel insights into hypoxia/PCFT-dependent chemoresistance, unravelling the potential prognostic value of LDH-A, and demonstrating the preclinical activity of LDH-A inhibitors

Impact of hypoxia on chemoresistance of mesothelioma mediated by the proton-coupled folate transporter, and preclinical activity of new anti-LDH-A compounds

Background: Expression of proton-coupled folate transporter (PCFT) is associated with survival of mesothelioma patients treated with pemetrexed, and is reduced by hypoxia, prompting studies to elucidate their correlation. Methods: Modulation of glycolytic gene expression was evaluated by PCR arrays in tumour cells and primary cultures growing under hypoxia, in spheroids and after PCFT silencing. Inhibitors of lactate dehydrogenase (LDH-A) were tested in vitro and in vivo. LDH-A expression was determined in tissue microarrays of radically resected malignant pleural mesothelioma (MPM, N = 33) and diffuse peritoneal mesothelioma (DMPM, N = 56) patients. Results: Overexpression of hypoxia marker CAIX was associated with low PCFT expression and decreased MPM cell growth inhibition by pemetrexed. Through integration of PCR arrays in hypoxic cells and spheroids and following PCFT silencing, we identified the upregulation of LDH-A, which correlated with shorter survival of MPM and DMPM patients. Novel LDH-A inhibitors enhanced spheroid disintegration and displayed synergistic effects with pemetrexed in MPM and gemcitabine in DMPM cells. Studies with bioluminescent hypoxic orthotopic and subcutaneous DMPM athymic-mice models revealed the marked antitumour activity of the LDH-A inhibitor NHI-Glc-2, alone or combined with gemcitabine. Conclusions: This study provides novel insights into hypoxia/PCFT-dependent chemoresistance, unravelling the potential prognostic value of LDH-A, and demonstrating the preclinical activity of LDH-A inhibitors