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Imaging multimodale in carcinomi sperimentali: il ruolo della componente stromale
No full textI carcinomi presentano una struttura che riproduce quella dei tessuti normali ed è costituita
da due compartimenti distinti ma dipendenti tra loro: il parenchima (formato da cellule neoplastiche
di origine epiteliale) e lo stroma. Lo stroma è interposto tra le cellule maligne ed il tessuto normale
dell’ospite, è essenziale per la crescita e la progressione del tumore, ed è prodotto dall’ospite
mediante interazioni cellula-ospite. Lo stroma comprende tessuto di supporto non maligno che
include plasma e proteine plasmatiche, varo tipo collagene interstiziale e fibrina. Inoltre comprende
tre diversi tipi di cellule: cellule endoteliali, che costituiscono i vasi neoformati, cellule fibroblaste,
che si trovano anche nel tessuto connettivo normale e cellule infiammatorie che provengono dal
circolo sanguigno. I tumori solidi tra loro si differenziano in modo marcato per il contenuto di
stroma e perfino all’interno del singolo tumore ci possono essere significative variazioni del
contenuto stromale da un’area all’altra.
Nel presente lavoro di tesi, diversi modelli di carcinomi sperimentali sono stati analizzati
con tecniche di imaging in vivo - risonanza magnetica (RM) con mezzo di contrasto e tomografia a
emissione di positroni (PET) dopo somministrazione di 2-fluoro-2-deossi-D-glucosio (FDG) –
focalizzando l’attenzione sul compartimento stromale. L’indagine RM con mezzo di contrasto
(sensibile alla vascolarizzazione tumorale) e PET-FDG (sensibile al metabolismo del glucosio) è
stata integrata dall’analisi con tecniche di imaging ex vivo (istologia ed immunoistochimica).
In particolare, la correlazione tra angiogenesi e metabolismo del glucosio è stata studiata per
valutare la complementarietà, recentemente evidenziata nei carcinomi, tra la componente stromale e
quella parenchimale. Infatti, è risaputo che le cellule maligne epiteliali sono caratterizzate da un
metabolismo anaerobico, sia per l’elevato consumo di glucosio (effetto Warburg), sia per la
frequente presenza di condizioni di ipossia. Nello stroma tumorale corrispondente, i fibroblasti
hanno invece evidenziato un metabolismo prevalentemente aerobico, capace quindi di utilizzare i
prodotti di scarto del metabolismo delle cellule tumorali, anche in virtù di una maggiore
disponibilità di ossigeno fornita dalla componente vascolare annessa.
Nel corso dello studio, tale complementarietà metabolica e la relativa diversa captazione alla
PET-FDG è stata confermata dal confronto di due modelli di carcinomi sperimentali caratterizzati
da una diversa estensione del volume stromale1 e validata con tecniche di immunoistochimica (con
marcatori specifici per la neoangiogenesi e per il trasporto del glucosio). Su questi stessi modelli
una diversa perfusione è stata confermata con mezzi di contrasto RM2, peraltro evidenziando anche
un diverso riassorbimento (che avviene prevalentemente per via venosa, e non per via linfatica,
come confermato da un altro studio su modelli di tumore mammario3).
Nei tre modelli di tumore mammario (un carcinoma spontaneo, e un sarcoma ed un
carcinoma sottocutanei derivati dal primo), caratterizzati per la loro differente vascolarizzazione, si
è di nuovo osservato che la perfusione ed il metabolismo presentano caratteristiche di
complementarietà, con zone più perfuse alla RM con mezzo di contrasto ma meno captanti alla
PET-FDG e viceversa4.
Gli effetti di questa organizzazione strettamente connessa con la componente stromale sono
stati segnalati come possibile inconveniente quando si utilizza la PET-FDG da sola per la
definizione dei margini tumorali nella pianificazione del trattamento radioterapico5.
Infine, le caratteristiche della componente stromale sono state analizzate durante un
trattamento anti-angiogenico6. L’analisi RM con mezzo di contrasto e l’analisi istologica hanno
rivelato che la somministrazione prolungata di anti-angiogenici può promuovere lo sviluppo della
componente stromale, che può avere un ruolo nella risposta adattiva del tumore a questi farmaci.
In conclusione, gli studi effettuati su modelli sperimentali hanno evidenziano che la struttura
compartimentale dei carcinomi, ovvero il parenchima delle cellule neoplastiche e la componente
stromale associata, hanno una particolare corrispondenza con due delle due principali tecniche di
imaging oncologico oggi disponibili. La complementarietà evidenziata (la RM con mezzo di
contrasto è sensibile alla perfusione della componente stromale e la PET-FDG è sensibile al
metabolismo della componente parenchimale) ne suggerisce un uso combinato.
Inoltre, con la RM perfusionale è stato possibile studiare sia meccanismi di riassorbimento
del mezzo di contrasto, sia le trasformazioni emerse durante terapia antiangiogenica.
Si prevede che le osservazioni riportate, se confermate in ambito clinico, possano avere
sviluppi nella diagnosi, nella definizione del trattamento e nel monitoraggio terapeutico dei
carcinomi, e possano comunque essere utilizzate in ambito sperimentale visto il ruolo emergente
che sta assumendo la componente stromale per comprendere la progressione tumorale e quindi per
sviluppare nuovi e specifici trattamenti farmacologici.Carcinomas have a distinct structure which mimics that of normal tissues and comprises two
distinct but interdependent compartments: the parenchyma (neoplastic cells) and the stroma. Stroma
is interposed between malignant cells and normal host tissues and is essential for tumor growth.
Stroma is largely a product of the host and its development is induced by tumor cell-host
interactions. Thus, it comprises nonmalignant supporting tissue and includes leaked plasma and
plasma proteins, interstitial collagens and fibrin. Moreover it includes three types of cells:
endothelial cells forming new blood vessels, fibroblasts that reside also in normal connective tissue,
and inflammatory cells that are derived from the blood. Tumors markedly differ from each other in
quantitative stromal content, with significant variations in stromal composition from one area to
another even within a single tumor.
In this thesis different carcinoma models were analyzed in vivo - by contrast enhanced
magnetic resonance imaging (MRI), and by (18)F-fluorodeoxy-glucose (FDG) positron emission
tomography (PET) - focusing on the role of the stromal compartment. Since contrast enhanced MRI
and FDG-PET are sensitive to tumor angiogenesis and glucose metabolism respectively, our studies
investigated the correlation between perfusion and glucose metabolism. The same tumor models
were also evaluated ex vivo - by histology and immunohistochemistry techniques.
It is well known that cancer cells are characterized by anaerobic metabolism with high
glucose consumption, both in hypoxic condition and even in high oxygen tension (Warburg effect).
On the other hand, it has been recently reported that in carcinomas a complementary metabolism
does exist between the epithelial neoplastic cells and the stromal fibroblasts. In fact, stromal
fibroblasts have shown aerobic metabolism, consistent with higher oxygen availability due to the
associated vascular supply, and the capability of buffering and recycling products of anaerobic
metabolism to sustain cancer cell survival.
In the present thesis, the complementary stromal/epithelial metabolism was confirmed by
the resulting different FDG-uptake in two carcinoma models characterized by a markedly different
stromal content1. These findings were also supported by immunohistochemical examination with
markers specific for neoangiogenesis and glucose transporters. On the same experimental models, a
corresponding different perfusion was observed by contrast enhanced MRI2. The different
distribution of the contrast agents proved to be related to stromal content, which presumably
produced also a different washout pattern of the contrast agent itself. Consistently, in an additional
study on experimental mammary tumors, we demonstrated that the washout of the contrast agents
mainly occurs by the venous system and not by lymphatic vessels3.
Moreover, three different breast tumor models (a spontaneous and an implanted carcinoma,
and a mesenchymal tumor), characterized by different vascularization, were evaluated. In these
models perfusion and metabolism resulted to be complementary: tumors (and tumor areas) that
were characterized by higher MR contrast enhancement showed lower FDG-uptake and vice-versa4.
Such effect could constitute a potential risk of tumor volume underestimation when FDGPET
is used as a single imaging modality to assess tumor boundaries and to delineate the target
volume in radiotherapy planning5.
Finally, tumor stroma evolution was assessed during antiangiogenic therapy6. Contrast
enhanced MRI and histology revealed that prolonged treatment could promote an abnormal stromal
development at the periphery of carcinomas, suggesting that cancer-associated stroma can have a
role in the adaptive response to treatment.
In conclusion, the reported studies on experimental models showed that the compartmental
architecture of carcinomas, i.e. the neoplastic cell and the cancer-associated stroma, affects the
sensitivity of two major cancer imaging methods, contrast enhanced MRI and FDG-PET. Contrast
enhanced MRI appeared more sensitive to the presence of cancer-associated stroma due to
perfusion. FDG-PET appeared more sensitive to the presence of cancer cells, due to glucose
metabolism. This “complementary sensitivity” suggests a combined application of the two
modalities for a comprehensive evaluation of carcinomas.
Furthermore, the contrast enhanced MRI modality allowed to evaluate both washout
mechanisms and the stromal modifications occurring during antiangiogenic therapy.
The reported findings, if confirmed in clinical studies, could be applied in diagnosis,
treatment planning and therapy assessment of human carcinomas. In any case they are relevant in
experimental studies considering the emerging role of cancer-associated stroma to understand
cancer progression and eventually to develop new targeted therapies
Interstitial fluid pressure as a function of DCE-MRI derived parameters.
No full textComment on:
Radiother Oncol. 2009 Apr;91(1):107-13
Combining low-dose radiation therapy and magnetic resonance guided focused ultrasound to reduce Amyloid-β deposition in Alzheimer's Disease
No full textAmyloid-β deposition is one of the neuropathological hallmarks of Alzheimer's disease (AD), but pharmacological strategies toward its reduction are poorly effective.Preclinical studies indicate that low-dose radiation therapy (LD-RT) may reduce brain amyloid-β. Animal models and proof-of-concept preliminary data in humans have shown that magnetic resonance guided focused ultrasound (MRgFUS) can reversibly open the blood-brain-barrier and facilitate the delivery of targeted therapeutics to the hippocampus, to reduce amyloid-β and promote neurogenesis in AD. Ongoing clinical trials on AD are exploring whole-brain LD-RT, which may damage radio-sensitive structures, i.e., hippocampus and white matter, thus contributing to reduced neurogenesis and radiation-induced cognitive decline. However, selective irradiation of cortical amyloid-β plaques through advanced LD-RT techniques might spare the hippocampus and white matter. We propose combined use of advanced LD-RT and targeted drug delivery through MRgFUS for future clinical trials to reduce amyloid-β deposition in AD since its preclinical stages
Baseline preadjuvant magnetic resonance imaging for response assessment and for planning radiotherapy in glioblastoma.
No full textNo abstract availabl
Reproducibility of BOLD signal change induced by breath holding.
No full textBlood oxygen level dependent (BOLD) contrast is influenced by some physiological factors such as blood flow and blood volume that can be a source of variability in fMRI analysis. Previous studies proposed to use the cerebrovascular response data to normalize or calibrate BOLD maps in order to reduce variability of fMRI data both among brain areas in single subject analysis and across subjects. Breath holding is one of the most widely used methods to investigate the vascular reactivity. However, little is known about the robustness and reproducibility of this procedure. In this study we investigated three different breath holding periods. Subjects were asked to hold their breath for 9, 15 or 21 s in three separate runs and the fMRI protocol was repeated after 15 to 20 days. Our data show that the BOLD response to breath holding after inspiration results in a complex shape due to physiological factors that influence the signal variation with a timing that is highly reproducible. Nevertheless, the reproducibility of the magnitude of the cerebrovascular response to CO2, expressed as amplitude of BOLD signal and number of responding voxels, strongly depends on duration of breath holding periods. Breath holding period of 9 s results in high variability of the magnitude of the response while longer breath holding durations produce more robust and reproducible BOLD responses
Washout of small molecular contrast agent in carcinoma-derived experimental tumors.
No full textThe use of contrast-enhanced magnetic resonance imaging (MRI) for the assessment of breast carcinomas reveals satisfactory sensitivity, but due to low specificity, it does not obviate the need for subsequent tissue sampling. Its capability to differentiate benign from malignant lesion is under continuous investigation. Dynamic contrast-enhanced MRI (DCE-MRI) could improve specificity of MRI through the analysis of the kinetic of contrast enhancement. In particular, the study of the washout pattern is considered a promising tool to improve in vivo diagnosis and even to evaluate the response under chemotherapy. To provide a comprehensive characterization of this parameter in malignant tumor models, in vivo mapping of the washout of small molecular contrast agent (Gd-DTPA, molecular weight 0.57 kDa) was carried out in three transplanted/spontaneous mammary tumors, which differed in their histopathological and microvascular features. It resulted that in all models around 40% of tumor volume lacks efficient washout; washout areas are frequently, but not always, restricted to the tumor periphery and that non-washout areas are not restricted to necrotic regions. Difference in the distribution of lymphatic vessels characterized spontaneous vs. transplanted tumors but did not produce a corresponding different washout pattern, confirming that Gd-DTPA drainage does not mainly depend on lymphatic architecture. Finally, the efficiency of washout is correlated with parameters obtainable during the earlier phases of the enhancement curve and in malignant tumors it could be indirectly estimated from them
Polyunsaturated fatty acids mapping by H-1 MR-chemical shift imaging
No full textParametric mapping of polyunsaturated fatty acids (PUFA) distribution in adipose
tissues was obtained by (1)H chemical shift imaging (CSI). A matrix of spectra,
acquired with a CSI sequence having two spatial and one spectroscopic dimension,
was processed with ad hoc algorithms. The protocol was applied to phantoms
containing different lipids in which the degree of polyunsaturation was
determined by high-resolution nuclear magnetic resonance (NMR). High correlation
(R(2) = 0.998) between degrees of polyunsaturation given by our protocol and that
measured by high-resolution NMR was found. The thoracic region of rats was also
examined. Parametric maps of the polyunsaturation degree were obtained for the
brown adipose tissue and the white axillary fat: the first deposit was found more
polyunsaturated than the second. Finally, in vivo mapping of the inguinal region
of the rat was produced that allowed us to individuate PUFA-rich areas in adipose
tissue. This work demonstrates the feasibility of PUFA imaging in vivo
Heterogeneous enhancement pattern in DCE-MRI reveals the morphology of normal lymph nodes: an experimental study
Full text linkPurpose: To investigate the heterogeneous enhancement pattern in normal lymph nodes of healthy mice by different albumin-binding contrast agents. Methods: The enhancement of normal lymph nodes was assessed in mice by dynamic contrast-enhanced MRI (DCE-MRI) after the administration of two contrast agents characterized by different albumin-binding properties: gadopentetate dimeglumine (Gd-DTPA) and gadobenate dimeglumine (Gd-BOPTA). To take into account potential heterogeneities of the contrast uptake in the lymph nodes, k-means cluster analysis was performed on DCE-MRI data. Cluster spatial distribution was visually assessed. Statistical comparison among clusters and contrast agents was performed on semiquantitative parameters (AUC, wash-in rate, and wash-out rate) and on the relative size of the segmented clusters. Results: Cluster analysis of DCE-MRI data revealed at least two main clusters, localized in the outer portion and in the inner portion of each lymph node. With both contrast agents, AUC (p < 0.01) and wash-in (p < 0.05) rates were greater in the inner cluster, which also showed a steeper wash-out rate than the outer cluster (Gd-BOPTA, p < 0.01; Gd-DTPA, p=0.056). The size of the outer cluster was greater than that of the inner cluster by Gd-DTPA (p < 0.05) and Gd-BOPTA (p < 0.01). The enhancement pattern of Gd-DTPA was not significantly different from the enhancement pattern of Gd-BOPTA. Conclusion: DCE-MRI in normal lymph nodes shows a characteristic heterogeneous pattern, discriminating the periphery and the central portion of the lymph nodes. Such a pattern deserves to be investigated as a diagnostic marker for lymph node staging
DCE-MRI data analysis for cancer area classification
No full textOBJECTIVES: The paper aims at improving the support of medical researchers in the context of in-vivo cancer imaging. Morphological and functional parameters obtained by dynamic contrast-enhanced MRI (DCE-MRI) techniques are analyzed, which aim at investigating the development of tumor microvessels. The main contribution consists in proposing a machine learning methodology to segment automatically these MRI data, by isolating tumor areas with different meaning, in a histological sense. METHODS: The proposed approach is based on a three-step procedure: i) robust feature extraction from raw time-intensity curves, ii) voxel segmentation, and iii) voxel classification based on a learning-by-example approach. In the first step, few robust features that compactly represent the response of the tissue to the DCE-MRI analysis are computed. The second step provides a segmentation based on the mean shift (MS) paradigm, which has recently shown to be robust and useful for different and heterogeneous clustering tasks. Finally, in the third step, a support vector machine (SVM) is trained to classify voxels according to the labels obtained by the clustering phase (i.e., each class corresponds to a cluster). Indeed, the SVM is able to classify new unseen subjects with the same kind of tumor. RESULTS: Experiments on different subjects affected by the same kind of tumor evidence that the extracted regions by both the MS clustering and the SVM classifier exhibit a precise medical meaning, as carefully validated by the medical researchers. Moreover, our approach is more stable and robust than methods based on quantification of DCE-MRI data by means of pharmacokinetic models. CONCLUSIONS: The proposed method allows to analyze the DCE-MRI data more precisely and faster than previous automated or manual approaches.IE
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