Dissertations / Theses on the topic 'Cancer – Surveillance active'

Active Surveillance (AS) for the clinical management of prostate cancer (PC) is a treatment option for men with low-risk PC. Screening procedures have led to the overdetection of PCs that would have never caused problems. Active treatment (e.g., surgery or radiation) for these non-aggressive tumors may not be necessary given the slow-growing nature of PC. AS provides a way to monitor the disease and delay treatment-related compromises on quality of life until clinically indicated (e.g., rising PSA level). However, the intensive monitoring in AS may be a stressful experience and lead to greater anxiety, an emotional state that has been associated with undergoing active treatment despite physician recommendation for AS. The current study aimed to identify psychosocial correlates of anxiety in men undergoing AS. Using Mishel’s Reconceptualized Uncertainty in Illness Model as a framework, the proposed study aimed to examine the relationships between perceived stress management skills, PC psychosocial concerns, and anxiety/arousal. Hierarchical multiple regression analyses were conducted on a sample of 71 men undergoing AS, who were on average 65.40 years old (SD=7.85) and ethnically diverse (52% non-Hispanic White; 31% Hispanic; 17% African American). Results indicated that greater PSMS were significantly associated with less IES-R anxiety (β=-.28, p<.04). PSMS were not significantly associated with PC concerns (β=-.02, p>.05), but greater PC concerns were significantly associated with greater IES-R anxiety (β=.61, p<.01) and PSA anxiety (β=.42, p<.01). These associations held after controlling for relevant covariates. The results suggest a possible role for stress management skills as perceived ability to manage stress was related to less anxiety in the AS experience. Future studies should examine the relationship among these factors in longitudinal designs and whether greater stress is associated with unnecessary active treatment in low-risk PC.

Introduction: Targeted biopsy of tumour-suspicious lesions detected in multiparametric magnetic resonance imaging (mpMRI) plays an increasing role in the active surveillance (AS) of patients with low-risk prostate cancer (PCa). The aim of this study was to compare MRI/ultrasound-fusion biopsy (fusPbx) with systematic biopsy (sysPbx) in patients undergoing biopsy for AS. Methods: Patients undergoing mpMRI and transperineal fusPbx combined with transrectal sysPbx (comPbx) as surveillance biopsy were investigated. The detection of Gleason score upgrading and reclassification according to Prostate Cancer Research International Active Surveillance criteria were evaluated. Results: Eighty-three patients were enrolled. PCa upgrading was detected in 39% by fusPbx and in 37% by sysPbx (p = 1.0). The percentage of patients who were reclassified in fusPbx and sysPbx (p = 0.45) were 64 and 59% respectively. ComPbx detected more frequently tumour upgrading than fusPbx (71 vs. 64%, p = 0.016) and sysPbx (71 vs. 59%, p < 0.001) and more patients had to be reclassified after comPbx than after fusPbx or sysPbx alone. Conclusions: The combination of fusPbx and sysPbx outperforms both modalities alone with regard to the detection of upgrading and reclassification in patients under AS. Because a high missing rate of significant PCa still exists in both biopsy modalities, a combination of fusPbx and sysPbx should be recommended in these patients.

Thesis (Ph.D.)--Case Western Reserve University, 2008
Title from PDF (viewed on 26 May 2009) Includes abstract Department of Epidemiology and Biostatistics Includes bibliographical references [and appendices] Available online via the OhioLINK ETD Center

Le cancer de prostate (CaP) est le plus fréquent chez l’homme de plus de 50 ans. La généralisation du PSA et du dépistage du CaP a permis son diagnostic à des formes localisées (80% des formes diagnostiquées), accessibles à un traitement curatif. De plus, un certain nombre de ces formes localisées sont indolentes, de très faible risque, éligibles à une surveillance active (SA).Cependant, 15 à 25% des patients vont présenter une récidive 10 ans après un traitement curatif, et environ 30% des patients inclus en SA seraient en fait sous-évalués (cancer significatif). Il est donc nécessaire d’identifier de nouveaux biomarqueurs pronostiques capables de distinguer les tumeurs indolentes des tumeurs à haut risque, et capables d’améliorer la prédiction du risque de récidive après traitement curatif. Objectifs : Evaluer la valeur pronostique potentielle du remodelage de la signalisation calcique dans le cancer de prostate : 1) Evaluer le lien entre remodelage de la signalisation calcique et agressivité tumorale 2) Evaluer l’impact pronostique du remodelage de la signalisation calcique sur la récidive systémique après prostatectomie radicale(PR). 3) Evaluer l’apport du remodelage de la signalisation calcique dans la sélection des patients éligibles à la surveillance active. Méthodologie 1) Evaluation de l’expression (immunohistochimie) de TRPC1, TRPC4, Orai1 et STIM1 à différents stades de progression du CaP, et évaluation de l’impact pronostique de cette expression sur la récidive dans le CaP localisé à partir d’une cohorte de 238 patients. 2) Etude cas-témoin à partir d’une cohorte de 112 patients opérés d’un CaP localisé. Evaluation de l’impact pronostique de l’expression (immunohistochimie) de 10 acteurs de la signalisation calcique (Orai1, Orai2, Orai3, STIM1, STIM2, TRPV5 et V6, TRPC1 et C4, TRPM8) sur la récidive systémique après PR. 3). A partir d’une cohorte de patients ayant été opérés pour des cancers de faible risque, ont été inclus les patients potentiellement éligibles à une SA au moment du diagnostic (n=71). Etude de l’apport de la signalisation calcique dans la sélection des patients éligibles à la SA (marquage immunohistochimie sur biopsies et pièce opératoire : TRPC1 et C4, TRPV5 et V6, Orai1, STIM1) Résultats 1) Dans le Cap localisé, une surexpression de TRPC1 était associée à une prolifération plus faible et une meilleure survie sans récidive (indépendant des marqueurs pronostiques usuels). 2) Une surexpression de TRPC4, TRPV5 et TRPV6 est associée à un plus faible risque de récidive systémique après prostatectomie, et ce indépendamment des 5 facteurs pronostiques usuels. 3) Un marquage plus intense de TRPV6 sur les biopsies prostatiques semble associé à un CaP significatif, éligible à un traitement curatif d’emblée chez les patients présentant un CaP de faible risque. Conclusion : Sur pièce de PR, TRPC1, TRPC4, TRPV5 et TRPV6 possèdent une valeur pronostique indépendante et sont associés à un plus faible risque de récidive après PR. Sur biopsie prostatique, TRPV6 permet de distinguer les CaP indolents des significatifs chez les patients présentant un CaP de faible risque
Prostate cancer (PCa) is the most common malignancy in men 50 years and older and the second leading cause of cancerrelated death in men in developed countries. Widespread PSA screening has allowed an increase rate of localised PCa at diagnosis, managed by curative treatment such as radical prostatectomy (RP), or active surveillance (AS) in case of indolent disease. However, 30% of patients experience biochemical relapse during the 10 years following RP. Moreover, 30% of patients in AS are undervalued and present a significant disease. It is therefore necessary to identify new prognostic biomarkers capable of distinguishing indolent from significant tumours, and capable to accurately predict the risk of recurrence after curative treatment. Objectives: To evaluate the potential prognostic value of calcium signalling remodeling in PCa: 1) To assess the impact of calcium signalling remodelling on tumour aggressiveness 2) To assess the prognostic value of calcium signalling remodelling on systemic recurrence after RP. 3) To assess the contribution of calcium signaling remodelling in the selection of patients for active surveillance (AS). Methods 1) Study of the expression (immunohistochemistry) of TRPC1, TRPC4, Orai1 and STIM1 at different stages of PCa, and assessment of the prognostic value of this expression on recurrence in clinically localised PCa (CLC) in a cohort of 238 patients. 2) Case-control study on a cohort of 112 patients who underwent RP for CLC. Evaluation of the prognostic impact of the expression (immunohistochemistry) of 10 actors of calcium signalling (Orai1, Orai2, Orai3, STIM1, STIM2, TRPV5 and V6, TRPC1 and C4, TRPM8) on systemic recurrence after RP. 3) From a cohort of patients who underwent RP for low-risk PCa, were enrolled patients potentially eligible for AS at the time of diagnosis (n = 71). We evaluated the impact of calcium signalling remodelling in patients selection for AS (immunohistochemical staining on biopsies and prostate specimens: TRPC1 and C4, TRPV5 and V6, Orai1, STIM1).Results 1) In CLC, an overexpression of TRPC1 was associated with a decreased proliferation, and with a higher rate of biochemical progression-free survival (independent of usual prognostic markers). 2) Overexpression of TRPC4, TRPV5 and TRPV6 was associated with a lower risk of systemic recurrence after RP, independently of the prognostic factors currently used. 3) More intense staining of TRPV6 on biopsies was associated with a significant PCa, for which a curative treatment is required. Conclusion: On RP specimens, overexpression of TRPC1, TRPC4, TRPV5 and TRPV6 has an independent prognostic value and is associated with a lower risk of recurrence after RP. On prostate biopsies, TRPV6 allows to distinguish indolent from significant disease in patients with low-risk PCa

Le cancer est désormais considéré comme une maladie chronique touchant une population toujours croissante. Une prise en charge et un suivi à long terme, à l’origine d’un bouleversement de la vie des patients et de leur entourage, semblent nécessaires et sont susceptibles d’initier une réorganisation du système de santé. Dans ce travail de thèse interdisciplinaire, nous nous sommes intéressés à l’impact du cancer sur le vécu psychologique et psychosocial des patients en France, en choisissant le modèle du cancer de la prostate. Pour cela, nous avons souhaité combiner deux études. L’une portait sur l’état de santé sexuelle des patients atteints d’un cancer de la prostate via une approche quantitative descriptive basée sur les données représentatives des enquêtes nationales VICAN. L’autre visait à déterminer l’impact du cancer de la prostate sur le couple et sa qualité de vie via une approche compréhensive qualitative complémentaire, focalisée sur une prise en charge en Surveillance Active et basée sur des entretiens semi-directifs de patients et de leurs conjointes. L’analyse des données a permis de montrer une détérioration de la santé sexuelle des patients, selon différents déterminants non nécessairement médicaux, et un endommagement du couple et des relations affectives perçues, avec des stratégies d’ajustements divergentes pour chacun des membres du couple, malgré une prise en charge initialement considérée comme optimale et indemne de conséquences. Une approche pluridisciplinaire pourrait permettre un accompagnement complet des couples pour une amélioration de leurs vécus, de leur bien-être et de leur qualité de vie
Cancer is now considered as a chronic disease affecting an ever-increasing population. Long-term care and follow-up, which are responsible of lives disruptions on patients and their relatives, seem necessary and likely to initiate health system reorganization. In this interdisciplinary thesis work, we focused on the impact of cancer on the psychological and psychosocial experiences of patients in France, by choosing the prostate cancer model. To do this, we decided to combine two studies. One aimed on the sexual health status of prostate cancer patients through a descriptive quantitative approach based on data representative of VICAN national surveys. The other one concentrated on the impact of prostate cancer on the couple and its quality of life through a complementary comprehensive qualitative approach, focused on Active Surveillance management and based on semi-directive interviews of patients and their spouses. The data analysis showed deterioration in patients' sexual health associated to several factors, which are not necessarily medical ones, and damages in the couple and perceived affective relationships, with divergent coping strategies for each member of the couple, despite a care management initially considered as optimal and free of consequences. A multidisciplinary approach could help couples to improve their experiences, well-being and quality of life

Le premier des objectifs du plan cancer 2014-2019 était de guérir plus de malades en favorisant les diagnostics plus précoces. Cet objectif laisse espérer davantage de diagnostic à des stades précoces accessibles à une résection chirurgicale. A l’heure actuelle, la chirurgie exérèse d’un cancer broncho-pulmonaire non à petites cellules (CBNPC) est le traitement offrant le plus d’espoir de guérison. Ce travail de thèse s’intéresse tout particulièrement au devenir des patients opérés.Malgré une intention curatrice, les patients opérés d’un CBNPC sont à risque de récidive du cancer opéré mais ont également un risque de second cancer, et en particulier de second cancer broncho-pulmonaire primitif (SCBP), supérieur à celui de la population générale, de l’ordre de 20% d’incidence cumulée à 10 ans. Lorsque survient une lésion pulmonaire de même diagnostic histologique que le cancer opéré, le diagnostic différentiel entre récidive du cancer opéré ou SCBP est difficile. Plusieurs définitions existent. En se basant sur l’hypothèse que les récidives sont le témoin d’une agressivité de la maladie cancéreuse, et donc le plus souvent de plus mauvais pronostic que les deuxièmes cancers, nous avons conduit dans un premier temps une revue systématique Cochrane de l’ensemble des définitions utilisées dans la littérature afin d’identifier celle qui offre la meilleure distinction pronostique, sur laquelle se baser pour le diagnostic différentiel entre récidive du cancer opéré et SCBP.Il y a quelques années, l'immunothérapie s'est imposée dans l'arsenal thérapeutique du cancer broncho-pulmonaire. D'abord utilisée en situation métastatique, l'immunothérapie est maintenant testée en situation péri-opératoire dans de nombreux essais. Cependant, en raison de la diversité des combinaisons et des stratégies thérapeutiques, qui n'ont pas toutes été comparées entre elles, une incertitude demeure quant à la meilleure thérapie péri-opératoire pour les patients opérés d'un CBNPC de stade précoce. Nous avons initié une revue systématique d’essais interventionnels avec méta-analyse en réseau selon la méthode Cochrane portant sur l'efficacité de ces traitements péri-opératoires chez les patients atteints de cancer du poumon non à petites cellules.L’étude IFCT-0302 est la seule large étude randomisée de surveillance des opérés d’un CBNPC. Elle a inclus 1775 patients. Son objectif était de comparer la survie globale de deux stratégies de surveillance : par clinique et radiographies thoraciques dans le groupe contrôle, et par clinique, radiographies thoraciques et scanners thoraco-abdominaux dans le groupe expérimental. La qualité de vie décrite par le patient (QdV) est une mesure de trois domaines de la santé perçue : physique, social et émotionnel. La QdV est impactée par une condition médicale ou son traitement. L'évidence suggère que la chirurgie du cancer du poumon a un impact significatif sur la QdV. L’objectif de notre travail a été d’évaluer l’influence du type de surveillance sur la QdV dans la population de l’étude IFCT-0302.Lorsqu’une image pulmonaire anormale est détectée, son diagnostic histologique s’obtient fréquemment par ponction transthoracique guidée par le scanner. La principale complication du geste est le pneumothorax. Les contraintes hospitalières ne permettent pas d’hospitaliser tous les patients après une ponction transthoracique. Nous avons dans ce troisième axe, travaillé à la validation d’un score prédictif de survenue d’un pneumothorax retardé après une ponction-biopsie transpariétale pulmonaire scannoguidée, afin de sélectionner les patients qui doivent être surveillés en hospitalisation conventionnelle. Ce travail a été réalisé sur une cohorte de patients du CHU de Besançon, une partie de la cohorte ayant permis d’élaborer le score, l’autre de le valider. Enfin un travail de validation externe sur une cohorte de patients de l’Hôpital Bichat – Claude Bernard a été réalisé
The first objective of the 2014-2019 cancer plan was to cure more patients by promoting earlier diagnosis. This objective gives hope for more diagnosis at early stages accessible to surgical resection. Currently, excisional surgery for non-small cell bronchopulmonary cancer (NSCLC) is the treatment offering the most hope for a cure. This thesis work is particularly interested in the future of operated patients.Despite a curative intention, patients operated on for NSCLC are at risk of recurrence of the operated cancer but also have a higher risk of second cancer, and in particular second primary lung cancer (SPLC), higher than that of the general population. , of the order of 20% cumulative incidence at 10 years.When a lung lesion with the same histological diagnosis as the operated cancer occurs, the differential diagnosis between recurrence of the operated cancer or SPLC is difficult. Several definitions exist. Based on the hypothesis that recurrences indicate an aggressiveness of the cancerous disease, and therefore most often have a worse prognosis than second cancers, we first conducted a Cochrane systematic review of the set of definitions used in the literature in order to identify the one which offers the best prognostic distinction, on which to base the differential diagnosis between recurrence of operated cancer and SCBP.A few years ago, immunotherapy established itself in the therapeutic arsenal for bronchopulmonary cancer. First used in the metastatic situation, immunotherapy is now tested in the perioperative situation in numerous trials. However, due to the diversity of combinations and therapeutic strategies, not all of which have been compared with each other, uncertainty remains regarding the best perioperative therapy for patients undergoing surgery for early-stage NSCLC. We initiated a systematic review of interventional trials with network meta-analysis according to the Cochrane method on the effectiveness of these perioperative treatments in patients with non-small cell lung cancer.The IFCT-0302 study is the only large randomized surveillance study of NSCLC patients. It included 1775 patients. Its objective was to compare the overall survival of two monitoring strategies: by clinic and chest x-rays in the control group, and by clinic, chest x-rays and thoraco-abdominal scans in the experimental group. Patient-described quality of life (HRQoL) is a measure of three domains of perceived health: physical, social, and emotional. QoL is impacted by a medical condition or its treatment. Evidence suggests that lung cancer surgery has a significant impact on QoL. The objective of our work was to evaluate the influence of the type of surveillance on HRQoL in the population of the IFCT-0302 study.When an abnormal lung image is detected, its histological diagnosis is frequently obtained by transthoracic puncture guided by the scanner. The main complication of the procedure is pneumothorax. Hospital constraints do not allow all patients to be hospitalized after a transthoracic puncture. In this third axis, we worked on the validation of a predictive score for the occurrence of delayed pneumothorax after a CT-guided transparietal lung biopsy, in order to select patients who must be monitored in conventional hospitalization. This work was carried out on a cohort of patients from Besançon University Hospital, one part of the cohort having made it possible to develop the score, the other to validate it. Finally, external validation work on a cohort of patients from the Bichat – Claude Bernard Hospital was carried out

Objectives To test upgrading rates in patients on Active Surveillance (AS) for prostate cancer (PCa) after serial multiparametric magnetic resonance imaging (mpMRI) scans. Materials and methods Retrospective analysis of 558 patients. Five different criteria of mpMRI progression were used: 1) PI-RADS score increase; 2) lesion size increase; 3) EPE score increase; 4) overall mpMRI progression; 5) number of criteria for mpMRI progression (0 vs. 1 vs. 2-3). Moreover, two definitions of PCa upgrading were evaluated:1) ISUP GG≥2 with >10% of pattern 4; 2) ISUP GG≥3. The estimated annual percent changes (EAPC) methodology depicted temporal trends of mpMRI progression criteria. Sensitivity, specificity, positive predictive (PPV) and negative predictive value (NPV) of mpMRI progression criteria were analysed. Multivariable logistic regression models tested PCa upgrading rates. Results Lower rates over time of all mpMRI progression criteria were observed. The NPV of serial mpMRIs spans from 90.5 to 93.5% (ISUP GG≥2 with >10% of pattern 4 PCa upgrading) and from 98 to 99% (ISUP GG≥3 PCa upgrading), according to the different mpMRI progression criteria. A PSA-D cut-off of 0.15 ng/ml/ml sub stratified those patients who could skip a prostate biopsy. In multivariable logistic regression models testing PCa upgrading rates, all five mentioned mpMRI progression criteria achieved independent predictor status. Conclusions: During AS, approximately 27% of patients experience mpMRI progression at first repeated scan. However, the rates of mpMRI progression decrease over time at subsequent mpMRIs. Patients with stable mpMRI findings and with PSA-D<0.15 ng/ml/ml could safely skip surveillance biopsies. Conversely, patients who experience mpMRI progression should undergo a prostate biopsy.

Part 1: Occult high-risk disease in clinically low-risk prostate cancer patients: Incidence and clinical predictors from SEER data Objective: First, to determine the incidence of pathologic upgrading and upstaging for contemporary, clinically low-risk patients and identify predictors of having occult, advanced disease to inform selection of patients for active surveillance. We will further consider the differing risk of upgrading at prostatectomy between clinically low-risk patients with ≥50% biopsy cores positive and other prostate cancer patients. Methods: For the first portion of the study, we identified 10,273 patients in the Surveillance, Epidemiology, and End Results (SEER) database diagnosed with clinically low-risk disease (cT1c/T2a, Prostate specific antigen (PSA)<10ng/mL, Gleason 3+3=6) in 2010-2011 who received a prostatectomy. The primary outcome was the incidence of upgrading to pathologic Gleason score 7-10 or upstaging to pathologic T3-T4/N1 disease. Multivariable logistic regression (MVA) of men with complete biopsy data (n=5,581) identified significant predictors of upgrading or upstaging. As a second analysis, we identified 14,902 patients with prostate cancer of any risk-group diagnosed 2010-2011 with prostatectomy who also had percent positive biopsy cores (PBC) available. Patients were categorized by NCCN clinical risk-groups, separating low-risk patients by percent PBC. We measured incidence of pathologic high-risk disease, defined as pT3a-T4 or Gleason 8-10, and used MVA to consider differing risk of advanced disease in patients with clinical low-risk disease and ≥50% PBC. Results: Of the first cohort, 44% of patients were upgraded and 9.7% were upstaged at prostatectomy. MVA showed age, PSA, and percent positive cores (all p<0.001), but not race, were associated with occult, more aggressive disease. With these variables dichotomized at the median, age >60 (Adjusted Odds Ratio [AOR] 1.39), PSA>5.0 (AOR 1.28), and >25% positive cores (AOR 1.76) were significantly associated with upgrading (all p<0.001). Similarly, age>60 (AOR 1.42), PSA>5.0 (AOR 1.44), and >25% positive cores (AOR 2.26) were associated with upstaging (all p<0.001). In the second cohort, 9.2% of clinically low-risk and <50%PBC, 18.6% of clinically low-risk and ≥50%PBC, and 27.6% of clinically intermediate-risk patients had occult, high-risk disease at prostatectomy (p<0.001). On MVA, low-risk with ≥50%PBC were more likely than low-risk with <50%PBC to have pathologic high-risk disease (AOR 2.28, 95%CI 1.90-2.73, p<0.001), had similar risk to favorable-intermediate disease overall (AOR 1.09, 0.91-1.31, p=0.33), and had higher risk than favorable-intermediate among men over 60 (AOR 1.28, 1.00-1.64, p=0.04). Conclusion: Nearly half of clinically low-risk patients harbor Gleason ≥7 or ≥pT3 disease. Percent PBC demonstrates utility for identifying a subset of NCCN low-risk patients who should have further testing before deciding on active surveillance as nearly one in five clinically low-risk prostate cancer patients with ≥50% positive biopsy cores harbored occult pT3a-T4 or Gleason 8-10. This suggests that such patients should not be classified by national guidelines as “low-risk” and these patients should be made aware of this excess risk if considering active surveillance. Part 2: Association of Androgen Deprivation Therapy with Depression in Localized Prostate Cancer Using SEER-Medicare Objective: Androgen deprivation therapy (ADT) may contribute to depression, yet several studies have not demonstrated a link. We aimed to determine if receipt of any ADT or longer duration of ADT for prostate cancer is associated with increasing risk of depression. Methods: We identified 78,552 men over 65 with stage I-III prostate cancer using the Surveillance, Epidemiology, and End Results-Medicare linked database from 1992-2006, excluding patients with psychiatric diagnoses within the prior year. Our primary analysis was the association of pharmacologic ADT with the diagnosis of depression, or receipt of inpatient- or outpatient-psychiatric treatment, using Cox-proportional hazard regression. Drug-data for treatment of depression was not available. Our secondary analysis was association of duration of ADT with each endpoint. Results: Overall, 43% (33,882) of patients received ADT and had higher 3-year cumulative incidence of depression (7.1% vs. 5.2%), inpatient- (2.8% vs. 1.9%), and outpatient-psychiatric treatment (3.4% vs. 2.5%) than patients without ADT (all p<0.001). Adjusted cox-analyses demonstrated patients with ADT had a 23% increased risk of depression (adjusted hazard ratio [AHR]=1.23,95%CI=[1.15-1.31]), 29% increased risk of inpatient-psychiatric treatment (AHR=1.29,95%CI=[1.17-1.41]), and a non-significant 7% increased risk of outpatient-psychiatric treatment (AHR=1.07,95%CI=[0.97-1.17]) compared to patients without ADT. The risk of depression increased with duration of ADT, from 12% with ≤6, 26% with 7-11, to 37% with ≥12 months (p-trend<0.0001). Similar duration-effect was seen for inpatient- (p-trend<0.0001) and outpatient-psychiatric treatment (p-trend<0.0001). Conclusion: Pharmacologic ADT increased the risk of depression and inpatient-psychiatric treatment in this large study of elderly men with localized prostate cancer. This risk increased with longer duration of ADT. The possible psychiatric effects of ADT should be recognized by physicians and discussed with patients prior to initiating treatment.

Le neutrophile est la cellule immunitaire la plus représentée dans le sang chez l’Homme, dont la migration au site inflammatoire est rapide. Le rôle du neutrophile a largement été décrit dans des contextes infectieux, auto-immunitaires et allergiques mais reste controversé dans le cancer, notamment dans les mécanismes d’immunosurveillance précoce. Le neutrophile se révèle être une population hétérogène tant phénotypiquement que fonctionnellement. L’origine et la compréhension de l’hétérogénéité des neutrophiles est un sujet émergent et croissant, mais aucune étude à ce jour ne décrit l’évolution de l’hétérogénéité des neutrophiles à différents stades. L’objectif de ma thèse est de caractériser cette hétérogénéité au sein des tissus au cours de la tumorigenèse, à partir de deux modèles d’études. Mon premier projet s’est intéressé au cancer colorectal (CCR) chez l’Homme de par l’accès privilégié à des échantillons de tissus adjacents colorectaux (AT), de tissus prénéoplasiques (polypes, P) et d'adénocarcinomes (ADK), frais, synchrones et pairés à partir de patients subissant des colectomies partielles ou totales. Des quantifications protéomiques démontrent que les neutrophiles représentent la principale augmentation de cellules immunitaires innées au sein de l'ADK. Pour la première fois, les profils transcriptomiques de neutrophiles triés et de leurs partenaires cellulaires par RNA-seq et single cell RNA-seq (scRNA-seq) au cours de la tumorigenèse ont été établis et intégrées pour déchiffrer l'hétérogénéité, l’évolution et les interactions cellulaires clés des neutrophiles, au cours du CCR. Alors que le microenvironnement du P et de l’ADK sont similaires et distinct de l’AT, le transcriptome des neutrophiles de P et d’AT sont corrélés mais différents de ceux de l’ADK. Ces résultats suggèrent une niche pré-inflammatoire dans le P favorable aux modifications des neutrophiles, précédant l'inflammation cancéreuse, favorisant la migration et l’activation des cellules myéloïdes. Les neutrophiles du P présentent des propriétés fonctionnelles (e.g. dégranulation, activation, production de cytokines) tandis que les neutrophiles de l'ADK présentent un état “d’épuisement” associé à un profil plutôt pro-tumoral (i.e. perte de fonctions canoniques et profil pro-tumoral). Le scRNA-seq de neutrophiles triés identifie 8 clusters distincts, dont deux sont spécifiquement enrichis dans l’AT et l’ADK. Le cluster enrichi dans l’AT est associé à des signatures anti-tumorales tandis que le cluster associé à l'ADK démontre des caractéristiques pro-tumorales, basées sur des analyses d’enrichissement de signatures issues de données publiques. Les analyses de trajectoire démontrent un continuum de l’AT, à P et ADK avec 3 trajectoires distinctes, où un cluster unique de neutrophiles exprimant des gènes induits par les interférons et enrichi dans l’ADK se distingue des autres. Le second projet s’est basé sur un modèle murin de carcinogenèse mammaire spontanée MMTV-NeuT pour lequel, à la différence du modèle chez l’Homme, nous avons accès aux différents stades tumoraux mais également au sang et aux organes lymphoïdes primaire (moelle osseuse) et secondaire (rate). Les analyses transcriptomiques de neutrophiles triés révèlent des états phénotypiques et fonctionnels distincts selon l’organe et le stade tumoral analysé. De manière originale, nous avons mis en évidence l’existence de neutrophiles EpCAM+ uniques aux tissus tumoraux et constituant 60 à 90% des neutrophiles totaux au cours de la tumorigenèse. L’expression d’EpCAM n’est pas endogène mais semblerait provenir de fragments membranaires exogènes à la surface du neutrophile, suggérant un mécanisme de trogocytose voire de trogoptose des cellules prénéoplasiques et tumorales. De futures études fonctionnelles permettront d’élucider le mécanisme et le rôle des neutrophiles EpCAM+
The neutrophil is the most abundant immune cell in the human blood that migrates rapidly to the inflammatory site. The role of neutrophils has been extensively described in infectious, autoimmune, and allergic contexts, but it remains controversial in cancer, particularly in early immune surveillance mechanisms. Neutrophils are a heterogeneous population, both phenotypically and functionally. The origin and understanding of neutrophil heterogeneity are emerging and increasingly studied, albeit to date, no study has described the evolution of neutrophil heterogeneity at different stages. The aim of my thesis is to characterize this heterogeneity within tissues during tumorigenesis, using two models. My first project focused on colorectal cancer (CRC) in humans, taking advantage of a privileged access to fresh, synchronous, and paired adjacent colorectal tissue samples (AT), preneoplastic tissues (polyps, P), and adenocarcinomas (ADK), from patients undergoing partial or total colectomies. Proteomic quantification demonstrated that neutrophils represent the main increase in the innate immune compartment within ADK. For the first time, transcriptomic profiles of FACS-sorted neutrophils and their cellular partners using RNA-seq and single-cell RNA-seq (scRNA-seq) throughout tumorigenesis were established and integrated to decipher the heterogeneity, evolution, and key cellular interactions of neutrophils in CRC. While the microenvironment of P and ADK were similar and distinct from AT, the transcriptome of P and AT neutrophils were correlated but different from ADK-associated neutrophils. These results suggest a pre-inflammatory niche in P that favors neutrophil modifications, preceding cancer-related inflammation, promoting migration and activation of myeloid cells. P-associated neutrophils exhibited functional properties (e.g. degranulation, activation, cytokine production), while ADK-associated neutrophils showed an "exhausted" state associated with a more pro-tumoral profile (i.e. loss of canonical functions and pro-tumoral profile). scRNA-seq of FACS-sorted neutrophils identified 8 distinct clusters, two of which were specifically enriched in AT and ADK. The AT-enriched cluster was associated with anti-tumoral signatures, while the ADK-enriched cluster demonstrated pro-tumoral characteristics, based on enrichment analyses of publicly available data signatures. Trajectory analyses showed a continuum from AT to P and ADK with three distinct trajectories, where a unique ADK-enriched cluster of neutrophils expressing interferon-stimulated genes stood out from the others. The second project was based on a mouse model of spontaneous mammary carcinogenesis, MMTV-NeuT, for which, unlike the human model, we have access to breast tissues at different stages as well as blood and primary (bone marrow) and secondary (spleen) lymphoid organs. Transcriptomic analysis of FACS-sorted neutrophils revealed distinct phenotypic and functional states depending on the organ and tumor stage. Interestingly, we unveiled the existence of a unique EpCAM+ neutrophil population in tumor tissues, representing 60 to 90% of total neutrophils throughout tumorigenesis. EpCAM expression was not endogenous but seemed to originate from exogenous membrane fragments on the surface of neutrophils, suggesting a mechanism of trogocytosis or even trogoptosis of preneoplastic and tumor cells. Further functional studies will elucidate the mechanism and the role of EpCAM+ neutrophils

L’IRM représente une modalité d’imagerie du cancer de la prostate qui occupe une place de plus en plus importante pour le diagnostic positif. D’autres indications sont en cours de validation pour établir le pronostique, pour guider le traitement et pour assurer le suivi après traitement notamment partiel. La première partie de ce travail a porté sur les études cliniques de l’IRM dans la sélection des candidats à une surveillance active. Les performances de l’IRM particulièrement dans la détection des cancers antérieurs permettront de réduire le risque de sous-estimation initiale des tumeurs et par conséquent le risque de la reclassification au cours des protocoles de surveillance active. La seconde partie de ce travail a porté sur la corrélation entre les anomalies de signal à l’IRM et les zones tumorales et non tumorales intra-prostatiques. La validation d’une technique simple et reproductible de recalage a permis ensuite une corrélation des anomalies de signal enregistrées sur l’IRM et des paramètres histo-pathologiques quantitatifs des pièces opératoires de prostatectomie
MRI is an increasingly important imaging modality for prostate cancer diagnosis. Further indications are being validated in prostate cancer to establish the prognostic, to guide treatment and to follow up patients especially after partial treatment. The first part of this work has focused on clinical studies of MRI in patient selection for active surveillance. The performance of MRI particularly in the detection of anterior cancers would reduce the risk of initial underestimation of tumor burden and therefore reduce the risk of reclassification during active surveillance protocols. The second part of this work has focused on the correlation between the signal abnormalities on MRI and intra-prostatic areas. We used a simple and reproducible technique for MRI and histopathology registration and we correlated signal abnormalities recorded on MRI with quantitative histopathological parameters at prostatectomy surgical specimens

Varje år diagnostiseras 10 000 män med sjukdomen prostatacancer i Sverige. Att drabbas av sjukdomen prostatacancer är emotionellt ansträngande. Väntetiden vad gäller behandling för patienter med prostatacancer är lång. Detta gör att patienter med prostatacancer lever med sjukdomen prostata-cancer och känslorna kopplade till diagnosen prostatacancer under en lång tid. Syftet med den aktuella studien var att beskriva copingprocessen för patienter med prostatacancer innan medicinsk behandling. Metoden som använts till studien var en litteraturstudie baserad på 15 vetenskapliga artiklar. Resultatet visade att den kognitiva bedömningen av sjukdomen prostatacancer präglades av den information som patienter med prostata-cancer fick. Den kognitiva bedömningen av sjukdomen prostatacancer påverkades också av ålder och tid efter diagnos. Copingresurser som hade betydelse för patienter med prostatacancer var socialt stöd, personlighet och psykisk hälsa. De copingstrategier som användes av patienter med prostatacancer var främst emotionellt fokuserade. Patienter med prostatacancer är under stor emotionell belastning. Information och socialt stöd från vårdpersonal hjälper patienter med prostatacancer att hantera den emotionella belastningen. Ytterligare forskning krävs för att identifiera effektiva copingstrategier i ett tidigt stadium av diagnosen prostatacancer.
Every year 10 000 men are diagnosed with prostate cancer in Sweden. Affection of the disease is emotionally strenuous. The wait for treatment among patients diagnosed for prostate cancer is long. This result in patients diagnosed with prostate cancer living with the disease and the emotions associated with the diagnosis of prostate cancer for an extended time. The aim of the current study was to describe the coping process used by patients diagnosed with prostate cancer prior to treatment. The method of the current study was a literature study based on 15 scientific articles. The results indicated that appraisal of prostate cancer was influenced by the information that patients diagnosed with prostate cancer received. Furthermore appraisal of prostate cancer was affected by age and time since diagnosis. Social support, personality and mental health were coping resources that were of significance to patients diagnosed with prostate cancer. Emotion focused coping strategies were primarily used by patients diagnosed with prostate cancer. Patients with prostate cancer are emotionally distressed. Information and social support from healthcare personnel reduces the emotional distress. Further research should investigate what coping strategies are effective in an early stage of prostate cancer diagnosis.

Les cellules tumorales circulantes (CTCs) sont la principale voie de dissémination du cancer dans le corps humain au travers de la circulation sanguine. Ces cellules ont la capacité de se détacher de la tumeur primaire, de rejoindre la circulation sanguine et de survivre dans cet environnement. Une sous-population spécifique de ces cellules a la capacité de coloniser de nouveaux tissus et de former des métastases. L'importance de ces cellules rares dans la circulation sanguine a été intensément étudiée au cours des dernières décennies, et il a été constaté que les informations phénotypiques et génomiques qu'elles contiennent pourraient être corrélées avec celles obtenues à partir d'une biopsie tissulaire. De plus, le nombre et l'incidence des CTC chez les patients métastatiques pourraient être utilisés comme indicateurs pronostics. Ainsi, leur isolement à partir d'échantillons sanguins et leur analyse a été proposé en remplacement des biopsies conventionnelles, comme une alternative moins invasive et permettant un échantillonnage plus répété. In fine, la détection et l'analyse des CTC en routine clinique pourraient être utilisées pour le suivi en temps réel des thérapies et de leur efficacité pour améliorer la prise en charge des patients, un pas de plus vers une médecine de précision. Dans ce projet de thèse, nous avons développé de nouveaux micro-dispositifs pour la capture, sous flux, de cellules cancéreuses à partir de sang complet humain. Nous avons exploité les propriétés physiques des CTC, plus grandes et moins déformables que les cellules sanguines normales, pour discriminer ces cellules rares (<1 cellule par mL aux premiers stades de la maladie). Des micro-dispositifs ont été conçus tels des tamis à trois dimensions pour filtrer sélectivement les cellules cancéreuses tout en préservant l'intégrité et la viabilité des cellules. De plus, les dispositifs ont été conçus pour permettre l'accès au matériel biologique isolé et effectuer ainsi une identification des cellules in situ, e.g. par immunocytochimie, mais aussi potentiellement pour servir de plateforme pour une analyse fonctionnelle de ces cellules. Nous avons proposé deux approches totalement compatibles avec la routine clinique. La première consiste en un guide équipé de microdispositifs, conçu pour être introduit directement dans la circulation sanguine au travers d'un cathéter médical et effectuer la capture des cellules cancéreuses in vivo. La deuxième approche vise à réaliser l'isolement des CTCs en utilisant des microdispositifs intégrés à des plateformes ex vivo compatibles avec les consommables médicaux de prélèvement sanguin.[...]
Circulating tumor cells (CTCs) are believed to represent the main pathway of cancer dissemination in the human body through the circulatory system. These cells have the ability to detach from the primary tumor, enter into the bloodstream, and survive in this environment. A specific subpopulation of these cells possesses the capacity of colonizing new tissues and forming metastases. The relevance of these rare cells in the bloodstream has been intensively investigated during the last decades, finding that phenotypic and genomic information they carry could be correlated with that of solid biopsies. Moreover, the number and incidence of CTCs in metastatic patients could be used as an indicator for prognosis. Thus, their isolation from blood samples and analysis has been proposed as a surrogate to solid biopsies, having the added value of being a less invasive procedure and allow a more repeated measure. In fine, the routine analysis of CTCs in clinical practice could be used for the real-time monitoring of therapies and the adaptation of treatment in order to improve the outcome of patients, a step forward towards so-called precision medicine. In this PhD project, we have developed novel micro- devices for the capture, in flow conditions, of tumor-derived cells from human whole blood. CTCs being larger and less deformable than normal blood cells, we exploited theses physical traits to discriminate them. Sieve-like micro-devices were engineered to selectively sort out tumor-derived cells having as a priority the preservation of cell integrity and viability. In addition, devices were designed to allow direct access to the isolated biological material and thus perform in situ cell identification, such as immunocytochemistry, but also to potentially serve as a platform for functional analysis. We proposed two approaches compatible with clinical routine. The first approach consists in a customized guiding-strip equipped with integrated microfilters, designed to be introduced directly within the bloodstream through a conventional medical catheter to perform the capture of tumor-derived cells in vivo. The second approach aims to perform CTC isolation ex vivo through the integration of microfilters into a platform compatible with blood collection medical sets. [...]

Purpose Lower serum vitamin D levels have been associated with an increased risk of aggressive prostate cancer. Among men with localized prostate cancer, especially with low-or intermediate-risk disease, vitamin D may serve as an important biomarker of disease aggression. The aim of this study was to assess the relationship between adverse pathology at the time of radical prostatectomy and serum 25-hydroxyvitamin D (25-OH D) levels. Methods This cross-sectional study was carried out from 2009 to 2014, nested within a large epidemiologic study of 1,760 healthy controls and men undergoing prostate cancer screening. In total, 190 men underwent radical prostatectomy in the cohort. Adverse pathology was defined as the presence of primary Gleason 4 or any Gleason 5 disease, or extraprostatic extension. Descriptive and multivariate analyses were performed to assess the relationship between 25-OH D and adverse pathology at the time of prostatectomy. Results Eighty-seven men (45.8%) in this cohort demonstrated adverse pathology at radical prostatectomy. The median age in the cohort was 64.0 years (interquartile range, 59.0 to 67.0). On univariate analysis, men with adverse pathology at radical prostatectomy demonstrated lower median serum 25-OH D (22.7 v 27.0 ng/mL, P = .007) compared with their counterparts. On multivariate analysis, controlling for age, serum prostate specific antigen, and abnormal digital rectal examination, serum 25-OH D less than 30 ng/mL was associated with increased odds of adverse pathology (odds ratio, 2.64; 95% CI, 1.25 to 5.59; P = .01). Conclusion Insufficiency/deficiency of serum 25-OH D is associated with increased odds of adverse pathology in men with localized disease undergoing radical prostatectomy. Serum 25-OH D may serve as a useful biomarker in prostate cancer aggressiveness, which deserves continued study. (C) 2016 by American Society of Clinical Oncology

Over 1.4 million men were diagnosed with prostate cancer worldwide in 2020. Due to increased early testing and detection, higher numbers are being diagnosed with low risk, localised prostate cancer. Active surveillance is the recommended treatment option for patients with low risk, localised prostate cancer, as it provides patients the opportunity to delay definitive treatments until clinically necessary whilst actively monitoring progression. However, there is no global consensus on eligibility criteria, best practice for management, or triggers for discontinuation, and therefore uptake, practice, and patient experiences may vary greatly across clinics and countries. In order to (a) understand patient experiences during active surveillance, (b) inform changes to active surveillance management that align with the needs of patients, and (c) identify critical research areas, consideration of the individual, social and ecological factors that influence patient experiences is required. To reach this aim, this thesis includes four studies using a range of methodologies to investigate patient experiences from diagnosis to active surveillance discontinuation. A fifth study focusing on enhancing methodology in this research domain is also included. Study One used qualitative methods to explore patient and partner experiences after low risk localised prostate cancer diagnosis as they navigated the treatment decision between active surveillance and definitive treatment. Study Two systematically reviewed the literature on patients’ unmet supportive care needs during active surveillance. Data for studies Three and Four were collected together using a mix of methodologies (quantitative survey and qualitative interviews). Given the outcomes of the systematic review (Study Two), in Study Three we investigated the unmet supportive care needs and psychological wellbeing of patients during active surveillance. In Study Four, we explored the personal and/or medical reasons patients discontinue active surveillance and move to definitive treatment. Finally, Study Five was a randomised trial embedded within Studies Three and Four to examine the influence of different unconditional monetary incentives on survey response rates. This body of research demonstrated that whilst patients on active surveillance generally report positive experiences and outcomes, a significant proportion report unmet supportive care needs across informational, sexual, physical, psychological, and patient care domains. Patients on active surveillance frequently report experiencing fear of cancer progression, appear to be greatly influenced by a variety of factors when navigating treatment decision (both at diagnosis and prior to discontinuation), and report uncertainty about active surveillance and their future. In addition, we observed that prostate cancer patients are no more likely to respond to long surveys when provided a larger unconditional monetary incentive ($20AUD) than a smaller unconditional monetary incentive ($10AUD). Further research to inform the development of supportive care interventions which directly address patient needs, align with their preferences, and consider their perspectives, is essential for improving active surveillance uptake, adherence, and overall experience for both patients and their partners/close allies. Doing so will require a strong engagement in research, which may be improved by using a variety of engagement strategies such as unconditional incentives, though further research is required.
Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2022

PURPOSE: To determine the accuracy of prostate biopsy Gleason score (GS) compared to prostatectomy GS. To determine whether a biopsy is a satisfactory diagnostic procedure to offer active surveillance for patients with low-grade prostate cancer. METHODS: This study was conducted in Tuft Medical Center as retrospective cohort study over the period from 2007-2010. The study included 83 patients for whom biopsy and prostatectomy GS were available. MEASUREMENTS: Gleason scores of 6, 7, and 8-10 were assigned to low, moderate, and high-grades, respectively. The kappa statistic was calculated to assess the degree of agreement between biopsy and prostatectomy. The ROC curve was used to evaluate the sensitivity and specificity of prostate biopsy for different Gleason grades. Also, compared whether the use of specific criteria for active surveillance (Johns Hopkins and UCSF) may decrease the level of up-grading in patient with low-grade prostate cancer using Chi-square test. RESULTS: The distribution of low, moderate, and high-grade cancer in biopsy (52%, 32%, 16%) and prostatectomy specimen (33%, 55%, 12%) showed fair agreement with weighted kappa 0.35. The prostate biopsy accurately predicted GS in 46%, up-graded in 38%, and down-graded in 16%. The patients with low-grade cancer and potentially eligible for active surveillance showed up-grading in 50% of cases. This up-grading reduced to 40% with the use of Johns Hopkins criteria and to 41% with the use of UCSF criteria. CONCLUSIONS: The accuracy of biopsy GS in predicting prostatectomy GS is severely limited and therefore biopsy is not enough diagnostic procedure to offer active surveillance.