The purpose of this work is to investigate the influence of possible patient movement and anatomy alteration on the quality of delivered prostate US based HDR-brachytherapy. The effect of patient movement and anatomy change (after the needle implantation and 3D image set acquisition) on catheter and organ dislocation and the consequences that this generated on the DVHs, conformity index and on radiobiological parameters. Materials and methods: This work is based on 3D image sets and treatment plans of 48 patients obtained right after the needle implantation (clinical plan is based on this 3D image set) and before and after the irradiation. In our institution the 3D-US based pre-planning, the transperineal implantation of needles using template and the intraoperative planning and irradiation is realized using the real-time dynamic planning system Oncentra Prostate. All pre-plans and all the inverse optimization of clinical plans were based on HIPO using the modulation restriction option. The patient body/OARs/catheters movement are generated from the clinical, pre- and post- irradiation plans and its influence on DVH-, COIN and radiobiological parameters of PTV and OARs are calculated and presented. Results: It is observed a slight decrease of treatment plan quality with increase of time between the clinical image set acquisition and the patient irradiation. Also, we show that the patient body movement/anatomy alteration and/or catheters dislocation results in decreased plan quality; change of values of the COIN, DVH- and radiobiological parameters. Conclusion: The measured mean shift of anatomy and needles (beams) is as low as 1.0mm that is lower by an order of magnitude to values known from external beam irradiation. For high modulated plans as those in HDR Brachytherapy such small shifts result in dosimetric changes which are in general lower than 5%. Our results demonstrate that quality assurance procedures have to be clinically implemented to guarantee anatomy and implant stability of the order of 1mm. This can only be realized without any manipulation of the implant and anatomy as done, for instance in the case of removing the US-probe before treatment delivery or moving the patient from one bed to another for the irradiation purposes / Σκοπός της εργασίας αυτής είναι να διερευνήσει την επιδραση που έχει η πιθανή μετακίνηση του ασθενούς και η αλλαγή της ανατομίας στην ποιότητα της Βραχυθεραπείας. Η μετακίνηση του ασθενούς, οι αλλαγές της ανατομίας ( μετά την εμφύτευση των βελονών και την συλλογή των τρισδιάστατων 3D εικόνων), η μετακίνηση των καθετήρων και των οργάνων επιφέρουν αλλαγές που παρουσιάζονται μέσα από τα ιστογράμματα δόσης - όγκου (DVH), δείκτη συμμορφίας (conformity index) και των ραδιοβιολογικών παραμέτρων. Υλικά και Μέθοδοι: Η μελέτη αυτή βασίζεται στην συλλογή τρισδιάστατων εικόνων υπερήχων (3D set) και στους σχεδιασμούς θεραπείας (treatment plans) από 48 ασθενείς που συλλέχθηκαν σε τρείς φάσεις: μετά την εμφύτευση των καθετήρων (κλινικός σχεδιασμός θεραπείας (clinical plan) βασίζεται σε αυτή την συλλογή 3D εικόνων), πριν την ακτινοβόληση και μετά την ακτινοβόληση.Στην κλινική μας ο προσχεδιασμός της θεραπείας (pre-planing) που βασίζεται στο τρισδιάστατο υπερηχογράφημα (3D-US), η διαπερινεϊκή εμφύτευση των καθετήρων με την βοήθεια του οδηγού template, ο διεγχειρητικός σχεδιασμός της θεραπείας (intraoperative planning) και η ακτινοβόληση πραγματοποιούνται με την χρήση του Real-time dynamic planning system Oncentra Prostate. Όλα τα pre-plans και όλα τα inverse optimization clinical plans βασίζονται στο HIPO χρησιμοποιώντας την επιλογή του modulation restriction. Οι μετακινήσεις του σώματος του ασθενούς/ των ευαίσθητων σε κίνδυνο οργάνων (OARs)/ και των καθετήρων αναπαράγονται από τα clinical, pre και post- irradiation plans. Κατόπιν υπολογίζεται και παρουσιάζεται η επίδρασή τους στο DVH, COIN και στις ραδιοβιολογικές παραμέτρους του όγκου στόχου σχεδιασμού (PTV) και των (OARs). Αποτελέσματα: Παρατηρείται μια ελαφρά μείωση της ποιότητας του σχεδιασμού θεραπείας με την αύξηση του χρόνου μεταξύ του κλινικού σχεδιασμού και της ακτινοβόλησης του ασθενούς. Επίσης παρουσιάζουμε ότι η μετακίνηση του ασθενούς/ η αλλαγή στην ανατομία ή/ και η μετακίνηση των καθετήρων έχει ως αποτέλεσμα στην μείωση της ποιότητας του σχεδιασμού. Έχουμε αλλαγή στις αλλαγές στις τιμές του COIN, του DVH και των ραδιοβιολογικών παραμέτρων. Συμπέρασματα: Η μέση τιμή των μετρούμενων μετακινήσεων της ανατομίας και των βελονών είναι ιδιαίτερα μικρή περίπου 1.0mm σε σύγκριση με τις γνωστές τιμές από την εξωτερική ακτινοθεραπεία. Για τους υψηλής διαμόρφωσης σχεδιασμούς, όπως αυτοί της HDR βραχυθεραπείας, μικρές μετακινήσεις οδηγούν σε δοσιμετρικές αλλαγές γενικά μικρότερες από 5%. Τα αποτελέσματα μας παρουσιάζουν ότι λαμβάνοντας υπόψη τις διαδικασίες εξασφάλισης ποιότητας επιτυγχάνεται η ακινητοποίηση του εμφυτεύματος της τάξης του 1mm. Αυτό μπορεί να επιτευχθεί μόνο με ακινητοποίηση του εμφυτεύματος και της ανατομίας, για παράδειγμα στην περίπτωση όπου μετακινούμε την κεφαλή της συσκευής υπερήχων (US- probe) πριν την ακτινοβόληση ή μετακινώντας τον ασθενή από ένα κρεβάτι σε ένα άλλο για τις ανάγκες τις ακτινοβόλησης.

Τhe purpose of this study is to investigate and analyze the influence of the possible errors eventually occurring in a 3D-US based HDR Brachytherapy of prostate cancer on the quality of dose delivery. The influence of modulation restriction tool on the plan quality and sensitivity is also investigated. Materials: Twelve clinical implants for HDR Brachytherapy of prostate cancer have been selected out of the clinical routine. The range of the prostate volumes was 26-101 cm3. Due to the fact that the implanted needles are fixed on the template, the most probable error should be a systematic shift of the implanted catheters on the cranial-caudal direction caused by the movement of the patient relative to the template. The planning was done using HIPO which is implemented in the real time intraoperative planning system Oncentra Prostate (OcP). HIPO offers a unique modulation restriction option that limits the free modulation of dwell times. Firstly the reference plans, where no catheter shift has been simulated, the clinical with MR >0 and the theoretical with MR=0, for all 12 implants have been compared. Then for each of the 12 clinical implants, 10 systematic shifts of the implanted catheters in the range of [-5, +5] mm in step of 1mm were simulated. The influence of this systematic shift on DVH-, COIN, EI and radiobiological parameters of PTV and OARs is calculated and recorded. The analysis of the observed changes has been done firstly by addressing the quality of the implant. For this purpose the range of shift was estimated that the resulted 3D dose distributions keep fulfilling the clinical dosimetric protocol. Secondly, the focus was placed to the stability of the dose distribution. Here the range for the shift has been estimated which enables that the dosimetric, conformity and radiobiological parameters of the implant remain within ±5% or ±10% of the originally planned values. Results: The use of modulation restriction (MR>0) results in plans with more conformal dose distribution (COIN, EI) but slightly lower D90 and V100 , gEUD, EUD2,v and EUD2,s values. The quality analysis demonstrate that for the DVH based parameters values of prostate a maximal shift of ±1.0 mm can be tolerated, although in case of using the modulation restriction the sensitivity from the influence of the systematic shift is greater. Similar were the results for the DVH parameters for urethra, rectum and bladder. For the stability analysis in order to keep the dosimetric parameters within ±5% of the originally planned value for the prostate and OARs, a maximum shift of around ±0.5 mm can be tolerated and for the ±10% criterion this is -1.0/+0.5 mm. The same behavior applies for the radiobiological parameters. The analysis based on COIN considering only the target and also the OARs have shown a maximum shift range of ±1.5 mm. For the EI analysis this range is ±0.0 mm. For ±10% criterion this is ±2.5 mm and ±0.5 mm respectively. Conclusion: Our study has demonstrated that high modulated, high conformal Brachytherapy dose distributions for prostate HDR implants are sensitive to systematic catheter shift. The consequence of shift changes is not clear. We can generally speak about a required geometrical stability of the implant as high as ±1.0mm. Modulation restriction without improving this reduces significantly the total dwell time keeping the plan quality and increasing conformity (COIN, EI). / Ο σκοπός αυτής της μελέτης είναι να ερευνήσουμε και να αναλύσουμε την επιρροή που μπορεί να έχουν τα πιθανά λάθη που συμβαίνουν στην Υψηλού Ρυθμού Δόσης (HDR) Βραχυθεραπεία του καρκίνου του προστάτη, η οποία βασίζεται σε τρισδιάστατες εικόνες (3D) υπερήχου, στη ποιότητα εναπόθεσης δόσης. Επίσης διερευνάται η επίδραση του Modulation Restriction (MR) στην ποιότητα και ευαισθησία του πλάνου θεραπείας. Υλικά και Μέθοδοι: Επιλέχθηκαν 12 κλινικά εμφυτεύματα για την HDR Βραχυθεραπεία του καρκίνου του προστάτη από την κλινική ρουτίνα μας. Το εύρος του όγκου του προστάτη είναι 26-101 cm3. Επειδή οι βελόνες που εμφυτεύθηκαν στον προστάτη είναι σταθεροποιημένες πάνω στο template, το πιο πιθανό λάθος που μπορεί να συμβεί είναι η συστηματική μετατόπιση των εμφυτευμένων καθετήρων σε cranial – caudal (κρανιακή – ουραία ) διεύθυνση η οποία έχει προκληθεί από την κίνηση του ασθενούς σε σχέση με το template. Το πλάνο θεραπείας έγινε χρησιμοποιώντας την επιλογή HIPO του προγράμματος real time intraoperative planning system Oncentra Prostate (OcP). Το HIPO προσφέρει την δυνατότητα επιλογής του Modulation Restriction (MR) το οποίο περιορίζει την ελεύθερη διαμόρφωση των χρόνων παραμονής της πηγής στους καθετήρες. Στα αρχικά μας πλάνα θεραπείας (reference plans) δεν έχει γίνει προσομοίωση μετακίνησης του καθετήρα. Συγκρίνουμε τα κλινικά μας πλάνα (MR>0) και τα θεωρητικά μας (MR=0) και για τα 12 εμφυτεύματα. Στην συνέχεια για κάθε ένα από τα 12 εμφυτεύματα γίνεται η προσομοίωση 10 συστηματικών μετακινήσεων των εμφυτευμένων καθετήρων με εύρος [-5,+5]mm και με βήμα 1mm. Υπολογίζεται και καταγράφεται η επίδραση της συστηματικής μετακίνησης στα ιστογράμματα δόσης - όγκου (DVH), δείκτη συμμορφίας (conformity index- COIN), External Index (EI) και στις ραδιοβιολογικές παραμέτρους για τον όγκο στόχου (PTV) και των ευαίσθητων σε κίνδυνο οργάνων (OARs). Αρχικά η ανάλυση των παρατηρούμενων αλλαγών έχει γίνει σύμφωνα με την ποιότητα του εμφυτεύματος (quality analysis). Για αυτό τον λόγο το εύρος της μετακίνησης έχει υπολογιστεί έτσι ώστε τα αποτελέσματα από τις 3D κατανομές δόσεις να πληρούν το κλινικό δοσιμετρικό μας πρωτόκολλο. Στην συνέχεια εστιάσαμε στην σταθερότητα της κατανομής της δόσης (stability analysis). Σε αυτή την περίπτωση το εύρος μετακίνησης των καθετήρων έχει υπολογιστεί έτσι ώστε οι τιμές των DVH, COIN και ραδιοβιολογικών παραμέτρων των εμφυτευμάτων να παραμένουν μέσα στο ±5% ή στο ±10% των αρχικών πλάνων (reference). Αποτελέσματα: Χρησιμοποιώντας την επιλογή του Modulation Restriction (MR>0) προκύπτουν πλάνα με πιο ομοιόμορφη κατανομή της δόσης (COIN, EI) αλλά με ελαφρώς μικρότερες τιμές των D90, V100, gEUD, EUD2,v και EUD2,s. H “quality analysis” έδειξε ότι για τις δοσιμετρικές παραμέτρους του προστάτη η μέγιστη μετατόπιση που μπορούμε να έχουμε είναι ±1mm. Χρησιμοποιώντας την επιλογή του MR η μετατόπιση αυτή γίνεται ακόμα πιο ευαίσθητη. Παρόμοια ήταν τα αποτελέσματα μας για τις δοσιμετρικές παραμέτρους των OARs (ουρήθρα, κύστη και ορθό). Σύμφωνα με την “stability analysis” η μέγιστη μετατόπιση που μας επιτρέπεται έτσι ώστε να διατηρήσουμε τις τιμές των δοσιμετρικών παραμέτρων του προστάτη και των OARs μέσα στο ±5% της τιμής του αρχικού μας πλάνου είναι ±0.5mm ενώ για το ±10% το όριο αυτό είναι -1.0/+0.5 mm. Την ίδια συμπεριφορά παρατηρούμε και για τις ραδιοβιολογικές παραμέτρους. Η ανάλυση που βασίζεται στο COIN, συμπεριλαμβάνοντας αρχικά μόνο τον στόχο μας και στην συνέχεια και τα OARs έδειξε ότι η μέγιστη μετακίνηση μας έχει εύρος ±1.5mm . Για την ανάλυση που βασίζεται στο EI αυτό το εύρος είναι ±0.0 mm . Για το ±10% τα όρια είναι ±2.5mm και 0.5mm αντίστοιχα. Συμπεράσματα: Η μελέτη μας έδειξε ότι οι υψηλά διαμορφωμένες και οι υψηλά ομοιόμορφες κατανομές δόσης των εμφυτευμάτων της HDR βραχυθεραπείας του προστάτη είναι ευαίσθητες στις συστηματικές μετακινήσεις των καθετήρων. Οι συνέπειες από τις αλλαγές αυτών των μετακινήσεων δεν είναι ξεκάθαρες. Μπορούμε γενικά να μιλήσουμε για μια απαιτούμενη γεωμετρική σταθερότητα του εμφυτεύματος τόσο υψηλή όσο ±1.0mm. Η δυνατότητα επιλογής του MR χωρίς να βελτιώνει αυτό, μειώνει σημαντικά τον ολικό χρόνο παραμονής της πηγής στους καθετήρες διατηρώντας την ποιότητα του πλάνου θεραπείας και αυξάνοντας την ομοιομορφία στην κατανομή της δόσης (COIN, EI).

Η αντιμετώπιση του καρκίνου του προστάτη (αλλά και των υπόλοιπων νεοπλασματικών νοσημάτων) δεν περιλαμβάνει απλώς την ανεύρεση νέων χημειοθεραπευτικών φαρμάκων. Αφορά και την κατοχύρωση ορισμένων δεικτών που μπορούν να μας δώσουν περισσότερες πληροφορίες για την ύπαρξη της νόσου, αλλά και του σταδίου εξέλιξης που βρίσκεται έτσι ώστε να παίρνονται οι πλέον σωστές αποφάσεις για την διαχείριση του ασθενούς. Η βιβλιογραφική αναφορά που ακολουθεί θα ασχοληθεί εκτενώς με αυτά τα ζητήματα (δηλ. τους δείκτες νόσου/σταδίου νόσου του καρκίνου του προστάτη) και ιδιαίτερα με μια υποομάδα αυτών: των μοριακών δεικτών της σταδιοποίησης της λεμφαδενικής νόσου στον καρκίνο του προστάτη. Αφορά μια πολλά υποσχόμενη μερίδα μοριακών δεικτών στην αντιμετώπιση της συγκεκριμένης νόσου που ενδέχεται να επηρεάσει και την προσέγγιση άλλων συμπαγών όγκων. / Use of new molecular markers for staging of lymph node disease in the prostate cancer.

Τα ρετινοειδή αποτελούν μια μεγάλη οικογένεια οργανικών μορίων που μοιάζουν δομικά με τη βιταμίνη Α. Το all-trans ρετινοϊκό οξύ (atRA) συμμετέχει σε μεγάλο εύρος βιολογικών διεργασιών μέσω της πρόσδεσής του και της ενεργοποίησης των υποδοχέων του, τους υποδοχείς ρετινοϊκού οξέος (RAR) και τους υποδοχείς ρειτινοειδών Χ (RXR). Κάθε κατηγορία υποδοχέων περιλαμβάνει τρία μέλη, α, β και γ. Τα ρετινοειδή χρησιμοποιούνται για τη θεραπεία πολλών ασθενειών, από την κοινή ακμή ως την οξεία προμυελωτική λευχαιμία. Λόγω των σοβαρών ανεπιθύμητων ενεργειών τους, γίνεται προσπάθεια να συντεθούν ανάλογα με λιγότερες ανεπιθύμητες δράσεις ή/και καλύτερη αποτελεσματικότητα. Προς αυτήν την κατεύθυνση έχουν συντεθεί πολλά ανάλογα, ανάμεσα τους και αυτά που χρησιμοποιήθηκαν στην παρούσα εργασία: RA2SPM (ένα σύζευγμα δύο μορίων atRA με σπερμίνη), ACI2SPM (ένα σύζευγμα δύο μορίων ασιτρετίνης με σπερμίνη), TRX2SPM (ένα σύζευγμα δύο μορίων τριοξαλενίου με σπερμίνη), ACI-SPM-TRX (σύζευγμα ασιτρετίνης και τριοξαλενίου με σπερμίνη), RA-SPM-ACI (σύζευγμα atRA και τριοξαλενίου με σπερμίνη). Τα ανάλογα αυτά συντέθηκαν από την ερευνητική ομάδα του καθηγητή Δ. Παπαϊωάννου, στο Τμήμα Χημείας του Πανεπιστημίου Πατρών. Στην παρούσα εργασία μελετήθηκε η δράση των αναλόγων αυτών στην ανάπτυξη καρκινικών κυττάρων προστάτη PC3 in vitro και έγινε μια αρχική διερεύνηση του μηχανισμού δράσης και της πιθανής εμπλοκής των υποδοχέων ρετινοειδών. Ως πρότυπη ένωση με την οποία συγκρίθηκαν όλες οι άλλες ενώσεις χρησιμοποιήθηκε το ανάλογο RA2SPM, Το ανάλογο ACI2SPM έχει την καλύτερη δράση σε σύγκριση με τα άλλα ανάλογα, αφού προκάλεσε δοσο-εξαρτώμενη μείωση του αριθμού των κυττάρων PC3 σε ποσοστό παρόμοιο με τη δράση του RA2SPM και είναι πιο δραστικό στη συγκέντρωση 10-6Μ σε σχέση με τα άλλα ανάλογα. Αυτή η δράση φαίνεται να σχετίζεται με αύξηση των επιπέδων του mRNA του ογκοκατασταλτικού γονιδίου RARβ, που όμως είναι μικρότερη από αυτήν που προκαλεί το ανάλογο RA2SPM. Ο εκλεκτικός ανταγωνιστής του RARα, Ro-41-5253, βρέθηκε ότι επίσης προκαλεί αύξηση των επιπέδων του mRNA του RARβ, ενώ δεν επηρεάζει τη δράση του ACI2SPM. Επιπλέον, το ανάλογο ACI2SPM μείωσε τα επίπεδα της πρωτεΐνης πλειοτροπίνης (PTN), η οποία είναι γνωστό πως παίζει σημαντικό ρόλο στην ανάπτυξη των καρκινικών κυττάρων προστάτη PC3. Η μείωση είναι μικρότερη από αυτήν που προκαλεί το ανάλογο RA2SPM και δεν επηρεάζεται από τον ανταγωνιστή Ro 41-5253, ο οποίος έχει από μόνος του ανασταλτική δράση. Συμπερασματικά, τα αποτελέσματα της παρούσας εργασίας υποδεικνύουν ότι το ανάλογο ACI2SPM είναι αποτελεσματικό στη μείωση του αριθμού των καρκινικών κυττάρων προστάτη PC3 και στη μείωση των επιπέδων της (PTN), αλλά η δράση του είναι μικρότερη από αυτήν του RA2SPM. Επίσης, καταδεικνύουν ότι ο εκλεκτικός αναστολέας του RARα Ro-41-5253, όπως έχει αναφερθεί ξανά στη διεθνή βιβλιογραφία, παρουσιάζει προβλήματα εκλεκτικότητας και πρέπει να χρησιμοποιείται με προσοχή. / Retinoids constitute a large family of organic compounds structurally related to the naturally occurring vitamin A. All-trans-retinoic acid (atRA) is known to modulate a wide range of cellular biological processes through binding to and activation of its specific receptors, retinoic acid receptors (RAR) and retinoid X receptors α, β and γ. Retinoids are being used for the treatment of various diseases, ranging from acne vulgaris to acute promyelocytic leukemia. However, due to serious adverse effects, there has been a great effort to synthesize analogues with better efficacy or/and minimized adverse effects. Towards this direction, many analogues have been synthesized, among which those that have been used in the present work: RA2SPM (a conjugate of all-trans retinoic acid with spermine), ACI2SPM (a conjugate of 2 molecules of acitretin with spermine), TRX2SPM (a conjugate of 2 molecules of trioxalen with spermine), ACI-SPM-TRX (a conjugate of trioxalen and acitretin with spermine), RA-SPM-ACI (a conjugate of all-trans retinoic acid and acitretin with spermine). These analogues have been synthesized by the research group of Prof. D. Papaioannou at the Department of Chemistry of the University of Patras. The present work represents an initial investigation of the in vitro effects of these analogues on prostate cancer cell growth (PC3), as well as of their mechanism of action and the possible involvement of retinoid receptors. The analogue RA2SPM was used as a reference control. The analogue ACI2SPM decreased the number of prostate cancer PC3 cells in a concentration-dependent manner, being as effective as RA2SPM and more effective compared with the rest of the tested analogues. This effect seems to correlate with an increase of the mRNA levels of the RARβ tumour repressor gene; however, the RARβ tumour repressor mRNA levels decrease is smaller than that observed with RA2SPM. The RARa selective antagonist Ro 41-5253 also increases the RARβ mRNA levels, while it does not affect the ACI2SP-induced increase. Furthermore, the ACI2SPM analogue was found to decrease the protein levels of the growth factor pleiotrophin (PTN), which is known to play an important role in the growth of the prostate cancer cell line PC3. Similarly to the effect on RARβ, the decrease of the PTN levels achieved by ACI2SPM is smaller than the one achieved by RA2SPM and is unaffected by the antagonist Ro 41-5253. Ro 41-5253 decreased PTN levels by itself, supporting the increasing notion that it should be used with caution as a RARα antagonist. In conclusion, the results of this work suggest that the ACI2SPM analogue is efficient in decreasing the prostate cancer PC3 cell numbers and PTN protein levels but seems to be less effective than RA2SPM action. More work is required in order to define the mechanism(s) of action of the tested analogues, as well as to better specify their effectiveness and toxicity.

Introduction: Prostate cancer is the most diagnosed cancer in males in Brazil. As it has a relatively indolent evolution and effective screening, patients with localized disease should be referred to the referral centers to perform treatment with curative intent. This study aimed to determine at what stage of the disease patients with prostate cancer are referred to tertiary care and regional referral public hospital for cancer treatment and how these cases were conducted. Methodology: This study included patients diagnosed with prostate cancer from the year 2000 to 2006. They were referred to the University Hospital of Santa Maria (HUSM). The data were described in prevalence percent, being used the Chi Square and Fisher tests, according to application; logistic regression was used to describe potential risk factors, the prevalence ratio was calculated by a non-parametric generalized regression model, using the Poisson distribution, significant statistical difference was considered when p <0.05. Excel 2007 was used to tabulate the data and the analysis was performed using version 18.0 IBM statistical program SPSS for Windows. Results (Article 1): 240 patients with prostate cancer were referred to HUSM during the years 2000 and 2006, of which 59.6% had localized disease, 25% had metastatic disease, and 15.4% had biochemical recurrence. Considering the 143 patients with localized disease, 34.3% were treated with radical prostatectomy, 33.6% with radiotherapy, 20.2% underwent palliative treatments, and 11.9% were under observation. The causes associated with not performing curative treatment of patients with localized disease were: undetermined in 32.6% of the cases, problems due to delay in hospital care in 30.4% of the cases, locally advanced disease in 21.7% of the cases, high surgical risk in 13.1% of the cases, and other reasons in 2.2% of the cases. Of the patients who were referred with localized disease, 20.2% underwent palliative treatments and 11.9% were under observation; in this situation, approximately, one third of the patients with localized disease did not undergo curative treatment due to delay in the waiting list for surgery and, in one third of the cases, the cause was not defined in the medical charts, showing that medical reports were not adequately filled in. Results (Article 2): In patients with localized prostate cancer treated with radical prostatectomy, biochemical recurrence occurred in 34 of 47 patients (72.3%). In this sample, unlike what is described in the literature, there was no correlation between risk ratings and possible risk factors (age, Gleason score, PSA level at diagnosis, T stage) with biochemical recurrence. Conclusions: In comparison with the Medical Literature, there were a greater number of patients referred to a referral hospital with metastatic disease, a lower proportion of patients undergoing curative treatment and less use of radical prostatectomy as a curative treatment. Regarding patients who were treated with radical prostatectomy, there was a higher prevalence of biochemical recurrence. / Introdução: O câncer de próstata é o mais diagnosticado em homens no Brasil. Como tem evolução relativamente indolente e rastreamento efetivo, os pacientes deveriam ser encaminhados, aos centros de referência, com doença localizada para realização de tratamento com intenção curativa. Este estudo objetivou determinar em que estágio da doença os pacientes com câncer de próstata são encaminhados a um hospital público, de atenção terciária e referência regional para tratamento oncológico e como estes casos foram conduzidos. Metodologia: Foram incluídos pacientes com diagnóstico de câncer de próstata confirmados histologicamente entre os anos 2000 e 2006 e que foram encaminhados ao Hospital Universitário de Santa Maria (HUSM). Os dados foram descritos em prevalência por cento, sendo utilizados os testes de Chi Quadrado e Fisher, conforme aplicabilidade; regressão de logística foi utilizada para descrever possíveis fatores de risco; a razão de prevalências foi calculada por um modelo de regressão generalizado não paramétrico, utilizando-se a distribuição de Poisson; foi considerada diferença estatisticamente significativa quando valor de p <0,05. O Excel 2007 foi usado para tabelar os dados e a análise foi realizada utilizando-se a versão 18.0 do programa estatístico IBM SPSS para Windows. Resultados (artigo 1): Foram encaminhados 240 pacientes com câncer de próstata ao HUSM entre os anos 2000 e 2006, sendo que 59,6% com doença localizada, 25% com doença metastática e 15,4% com recorrência bioquímica. Dos 143 pacientes com doença localizada, 34,3% foram tratados com prostatectomia radical; 33,6%, com radioterapia; 20,2% foram submetidos a tratamentos paliativos, e 11,9% ficaram em observação. As causas associadas a não realização de tratamento curativo em pacientes encaminhados com doença localizada foram em: 32,6% dos casos indeterminada, 30,4% por problemas relacionados ao atraso na assistência hospitalar, 21,7% doença localmente avançada, 13,1% alto risco cirúrgico e 2,2% outros motivos. Dos pacientes que foram encaminhados com doença localizada, 20,2% foram submetidos a tratamentos paliativos e 11,9% ficaram em observação; nesta situação, aproximadamente 1/3 dos pacientes com doença localizada não foram submetidos a tratamento curativo por atraso em lista de espera para cirurgia e em 1/3 dos casos a causa não estava definida nos prontuários, mostrando um preenchimento inadequado destes. Resultados (artigo 2): Nos pacientes com câncer de próstata localizado tratados com prostatectomia radical, a recorrência bioquímica ocorreu em 34 dos 47 pacientes (72,3%). Nessa amostra, ao contrário do que descrito na Literatura, não houve correlação entre classificação de risco e dos possíveis fatores de risco (idade, Escore de Gleason, valor do PSA ao diagnóstico, estadiamento T) com recorrência bioquímica. Conclusões: Comparado com a Literatura Médica, obteve-se um maior número de pacientes encaminhados ao hospital de referência com doença metastática, uma menor proporção de pacientes tratados de forma curativa e uma menor utilização de prostatectomia radical como tratamento curativo. E, em relação aos pacientes que foram tratados com prostatectomia radical, houve uma maior prevalência de recorrência bioquímica.

Orientador: Valber de Albuquerque Pedrosa / Resumo: O desenvolvimento de novos dispositivos para monitorar o metabolismo celular e o diagnóstico de doenças expandiu as pesquisas com biossensores, que aliados à nanotecnologia possibilitaram a criação de novos elementos com alta sensibilidade de detecção, especificidade e capacidade de multiplexação, mostrando grande potencial para sua aplicabilidade no diagnóstico clínico. O trabalho foi desenvolvido em duas etapas. A primeira, referiu-se no desenvolvimento de uma metodologia para acoplar o aptâmero conjugado com as nanopartículas de ouro sobre o sensor da Ressonância Plasmônica de Superfície (SPR). Foi utilizado MUA para formação das monocamadas auto-organizadas; ativação dos grupos carboxílicos utilizando solução de EDC/NHS e a imobilização do aptâmero conjugado. Após este processo, foram realizadas as injeções de Mucina Epitelial Polimórfica tipo 1 (MUC1). A segunda etapa, consistiu na mesma metodologia de acoplamento do aptâmero, porém substituindo a MUC1 por sobrenadante da linhagem celular LNCaP (células prostáticas tumorais). Desse modo, foi desenvolvida uma metodologia analítica utilizando aptâmeros e biomarcadores para diagnosticar o Câncer de Próstata (PCa) através da SPR. / Mestre

Prostate cancer is the most common type of cancer in men in Europe and the USA. Some prostate tumours are regarded as stiffer than the surrounding normal tissue, and therefore it is of interest to be able to reliably measure prostate tissue stiffness. The methods presently used to detect prostate cancer are inexact, and new techniques are needed. In this licentiate thesis resonance sensor technology, with its ability to measure tissue stiffness, was applied to normal and cancerous prostate tissue. A piezoelectric transducer element in a feedback system can be set to vibrate at its resonance frequency. When the sensor element contacts an object a change in the resonance frequency is observed, and this feature has been utilized in sensor systems to describe physical properties of different objects. For medical applications it has been used to measure stiffness variations due to various pathophysiological conditions. An impression-controlled resonance sensor system was used to quantify stiffness in human prostate tissue in vitro using a combination of frequency change and force measurements. Measurements on prostate tissue showed statistically significant (p &lt; 0.001) and reproducible differences between normal healthy tissue and tumour tissue when using a multivariate parameter analysis. Measured stiffness varied in both the normal tissue and tumour tissue group. One source of variation was assumed to be related to differences in tissue composition. Other sources of error could be uneven surfaces, different levels of dehydration of the prostates, and actual differences between patients. The prostate specimens were also subjected to morphometric measurements, and the sensor parameter was compared with the morphology of the tissue with linear regression. In the probe impression interval 0.5–1.7 mm, the maximum coefficient of determination was R2 ≥ 0.60 (p &lt; 0.05, n = 75). An increase in the proportion of prostate stones (corpora amylacea), stroma, or cancer in relation to healthy glandular tissue increased the measured stiffness. Cancer and stroma had the greatest effect on the measured stiffness. The deeper the sensor was pressed, the greater, i.e., deeper, volume it sensed. It is concluded that prostate cancer increases the measured stiffness as compared with healthy glandular tissue, but areas with predominantly stroma or many stones could be more difficult to differentiate from cancer. Furthermore, the results of this study indicated that the resonance sensor could be used to detect stiffness variations in human prostate tissue in vitro, and especially due to prostate cancer. This is promising for the development of a future diagnostic tool for prostate cancer.

Cancer is one of the greatest causes of death in modern societies, affecting over 350,000 new cases every year in the UK. Although there are currently more than 100 different cancer types, breast and prostate cancer remain the most common types for women and men respectively. A number of different cancer types follow, with bladder cancer being the ninth most significant type, accounting for 3% of the total new cases. The currently employed techniques aim to diagnose the cancer at an early stage, where the symptoms are easier to be treated and the disease more likely to be cured. A further issue is that many cancers diagnosed will not affect a patient in their lifetime. The current gold standard for cancer diagnosis, biopsy followed by histopathology, is an invasive, restrictive technique and the screening tests suffer from low specificity, the need for a novel diagnostic concept is vital. Furthermore, the current clinical approach does not identify those patients most at risk of advancing disease. A promising approach consists of molecular vibrational spectroscopy techniques, which are based on the interactions of light with matter. One of these is Raman spectroscopy, a technique with wide applications in research and industry, which has the advantage of being non-invasive and chemically highly specific. In this thesis we explore the potential of a group of minimally invasive diagnostic techniques, based on Raman scattering, for prostate, breast and bladder cancer. In the case of the two most prevalent types of cancer, prostate and breast cancer, deep Raman spectroscopy has been employed to study the origin of Raman scattering (Chapters 5 and 6) in animal tissue and tissue phantoms, containing highly scattering materials resembling suspicious features found in tissues (calcifications). The spatial distribution of the Raman signal through the sample volume has been studied in relation to the optical properties and the composition of the sample, showing that a couple of transmission measurements would potentially cover the measuring volume of prostate of typical dimensions. Deep Raman measurements were also extended to animal and human tissue samples, in order to investigate the feasibility of collecting Raman scattering from human prostate tissue and its major tissue components (Chapter 6). Further improvements on these measurements were attempted by introducing the ‘’photon diode’’ element (Chapter 7) in order to achieve signal enhancement, which proved to be in the range of ×1-2.4, depending on the optical properties of the tissue and the depth of the probing element. The same ‘’photon diode’’ concept was utilised to attempt depth prediction of a calcification feature in sample volume (Chapter 8). Regarding bladder cancer, the minimally invasive approach adopted was Raman spectroscopy on urine samples, rather than deep Raman spectroscopy. Raman microscopy was employed in order to discriminate pathological features of bladder cancer between healthy and malignant urine samples. For that reason, the potential differences in urea’s distribution and interactions in urine from healthy and patients with bladder cancer were studied, resulting in promising diagnostic values (73% sensitivity, 80% specificity). The results presented in this thesis are expected to lead to a better understanding of the Raman scattering signals collection through biological tissues and help in this way the future design of Raman instruments aiming to target disease specific signals. This study shows promise for future application of Raman spectroscopy and paves the way towards the future integration of Raman spectroscopy in a non-invasive cancer diagnosis.

The aryl hydrocarbon receptor (AhR) has been reported to interact with multiple signaling pathways during prostate development including the androgen receptor. AhR was overexpressed in LNCaP using PLNCX2 retrovirus vector containing AhR cDNA to determine if ectopic overexpression induces castrate resistant phenotype. The highly overexpressed AhR clone illustrated further increase in transcriptional and promotor activity for AhR and AR compared to the moderately overexpressed AhR clone and control. Western blot analysis showed more AhR, AR, cSrc, and pSrc protein expression in clones. AhR overexpression was found to induce several biological properties such as migration, invasion, proliferation, and promotion of G1 to S phase during the cell cycle. Bicalutamide treatment had no effect on AR transcriptional activity in either clone, proving resistance to anti-androgen therapy. Our results confirm that overexpression of AhR induces constitutive activity and stimulates androgen receptor signaling. This suggests a role for AhR in the development of CRPC.

Bakgrund: Prostatacancer är den vanligaste cancerdiagnosen för män i västvärlden. Det finns flera biverkningar av de olika behandlingsalternativen varav sexuell dysfunktion är en vanlig sådan. Sjuksköterskans ansvar går ut på att vårda patienten som en helhet och främja delaktighet. Det har visats att sjuksköterskor upplevde det som svårt att samtala med patienter om sexualitet eftersom ämnet anses vara tabubelagt. Syfte: Syftet var att belysa mäns upplevelser av sexualitet vid prostatacancer. Metod: En allmän litteraturöversikt enligt Friberg (2017) gjordes och baserades på elva vetenskapliga artiklar. Åtta var av kvalitativ metod och tre av mixad. De inhämtades från databaserna CINAHL Complete, PubMed samt PsycINFO. Sökorden som användes var: experience, experienc*, lived experience, prostate cancer, prostatic neoplasms, sexuality och sexual health. Resultat: Resultatet presenterades genom två huvudteman. Det första huvudtemat var: Behandlingarnas inverkan på sexualiteten, vilket visade olika känsloyttringar kopplat till att få en förändrad sexuell funktion, intimitet och maskulinitet samt minskad sexuell lust. Det andra huvudtemat var: Yttre och inre resurser för att kunna hantera behandlingarnas biverkningar som visade att vårdpersonal, partners och stödgrupper hjälpte männen att hantera förändringarna. Diskussion: Författarna diskuterade mäns behov av adekvat information gällande olika behandlingars biverkningar, sjukdomens påverkan på maskuliniteten, hur kommunikation i parrelationer kunde påverkas samt sjuksköterskans stödjande roll. Diskussionen belystes utifrån Katie Erikssons hälsokors, tidigare forskning samt författarnas reflektioner. / Background: Prostate cancer is the most common cancer disease for men in the western world. There are several common side effects from different treatments and sexual dysfunction is one of them. It is the nurse’s responsibility to care for the patient as a whole and to promote participation. However, it has been shown that nurses found it difficult to talk about sexuality with patients since the subject is considered to be taboo. Aim: The aim was to explore experiences of sexuality for men with prostate cancer.   Method: A general literature review according to Friberg (2017) was made and based on eleven scientific articles. Eight were of qualitative method and three of mixed. They were obtained from the databases CINAHL Complete, PubMed and PsycINFO. The following key words were used: experience, experienc*, lived experience, prostate cancer, prostatic neoplasms, sexuality and sexual health. Results: The result was presented by two main themes. The first one was: The treatments impact on the sexuality which showed different emotions associated with having a changed sexual function, intimacy and masculinity and a reduced sexual desire. The second main theme was: The external and internal resources to be able to handle the side effects of the treatments which showed that care staff, partners and support groups helped the men to handle the changes. Discussion: The authors discussed men’s need of adequate information about the side effects of different treatments and how the disease could affect the masculinity, the communication in relationships and the nurse’s supporting role. The discussion was highlighted in relation to Katie Eriksson´s “health cross”, previous research and the authors’ reflections.