Tissue cholesterol metabolism and prostate cancer aggressiveness: Ethno-geographic variations.

BACKGROUND: Prostate cancer (PCa) is more frequent and more aggressive in populations of African descent than in Caucasians. Since the fatty acid composition of peri-prostatic adipose tissue (PPAT) has been shown to differ according to the ethno-geographic origin and is involved in PCa aggressiveness, we aimed to analyze the cholesterol content of PPAT from Caucasian and African-Caribbean patients, in correlation with markers of disease aggressiveness and cholesterol metabolism in cancer tissues. METHODS: The quantification of cholesterol in PPAT was analyzed in 52 Caucasian and 52 African-Caribbean PCa patients, with in each group 26 indolent tumors (ISUP Group1 and pT2) and 26 potentially aggressive tumors (ISUP Group 3-5 and/or pT3). The expression of proteins involved in cholesterol metabolism was analyzed by immunohistochemistry on cancer tissue samples included in tissue microarrays. RESULTS: The amount of cholesterol esters was lower in PPAT from African-Caribbean patients compared with Caucasians, without any correlation with markers of disease aggressiveness. In cancer tissues from African-Caribbean patients, the expression of ABCA1 (involved in cholesterol efflux) was decreased, and that of SREBP-2 (involved in cholesterol uptake) was increased. In both groups of patients, SREBP-2 expression was strongly associated with that of Zeb1, a key player in the epithelial-to-mesenchymal transition (EMT) process. CONCLUSION: These results suggest that cholesterol metabolism differs according to the ethno-geographic origin, in both PPAT and cancer tissues. In African-Caribbeans, the orientation towards accumulation of cholesterol in cancer cells is associated with a more frequent state of EMT, which may promote PCa aggressiveness in this population.

[High-intensity focused ultrasound for locally prostate cancer: An Afro-Caribbean single-center study]. / Ultrasons focalisés de haute intensité pour le traitement du cancer localisé de la prostate : étude mono-centrique caribéenne.

INTRODUCTION: High-intensity focused ultrasound (HIFU) has proved to be effective in the treatment of localized prostate cancer. The aim of this prospective study is to assess their first oncological and functional results in an Afro-Caribbean population. METHODS: From May 2018 to January 2020, 77 patients issued from French West Indies were included. Several treatments were carried out: whole-gland treatment hemi or focal ablation; in a primary setting (group I) or a salvage therapy (group II). PSA level was assessed at 2, 6, 9 and 12 months. MpMRI and post HIFU biopsy were performed between 6 and 9 months postoperatively. Continence, urinary end erectile functions were assessed by ICS, IPSS and IIEF scores. RESULTS: Groupe I included 71.2% patients, group II, 28.8%. The median age was 75.4 years [IQR 69.6-79.4]. The median follow-up was 8.3 months [IQR 3.5-12.25]. At inclusion, PSA was 7.7ng/ml [IQR 5.5-11.2] in group I, and 5.9ng/ml [IQR 4.4-7.9] in group II. In the whole population, there was 73.5% negative biopsies; 14.7% of the biopsies were positive in treated zone and 11.8% in non-treated zone. Regarding morbidities, urinary incontinence appeared in 7.5% and erectile dysfunction rate was 13.2%. CONCLUSION: Our study reveals the first experience of HIFU by Focal One® device in an Afro-Caribbean population. It seems to be a safe and reproducible treatment with acceptable oncological results and low genitourinary morbidity. Long term follow-up and a higher number of patients are necessary to validate these results.

Active surveillance in prostate cancer is possible for Afro-Caribbean population: Comparison of oncological outcomes with a Caucasian cohort.

BACKGROUND: Prostate cancer is supposedly more aggressive among Afro-Caribbean men. There is a lack of data in this population for active surveillance. Published series are retrospective or have small samples and results are discordant. The objective was to determinate whether actual active surveillance modalities can be applied for Afro-Caribbean men by comparing their oncological outcomes with Caucasian men. METHODS: A total of 449 consecutive patients who underwent active surveillance for favorable-risk prostate cancer in two French University-Medical-Centers between 2005 and 2018: 261 in Guadeloupe, French West Indies, and 188 in Bordeaux, metropolitan France. Median follow-up was 56 months, (95% CI [32-81]) and 52 months (95% CI [30-75]), respectively (P=0.07). Curative treatment was given in case of histological, biological, or imaging progression, or upon patient demand. Primary endpoints were treatment-free, overall and specific survival. Secondary outcomes were reasons of discontinuating active surveillance, histological poor prognosis factors after prostatectomy, CAPRA-S score, biochemical-recurrence-free after treatment and metastasis-free survival. Kaplan-Meier method was used. RESULTS: Median treatment free survival was 58.4 months (CI 95% [48.6-83.1]) for ACM and not reached at 120 months for CM (P=0.002). Overall survival (P=0.53), and specific survival (P=0.21) were similar in the two groups. CM were likely to have poor prognosis factor on prostatecomy piece (57 vs 30%, P=0.01). No difference for repartition of the CAPRA-S score (P=0.86), biochemical-recurrence-free (P=0.92) and metastasis-free (P=0.44) survival. CONCLUSIONS: Oncological outcomes for active surveillance of Afro-Caribbean and Caucasian men were similar in terms of mortality, recurrence and metastasis in our bicentric study, showing usability of current criteria for Afro-Caribbean. The higher rate of disease progression in the Afro-Caribbean population requires close monitoring. LEVEL OF EVIDENCE: 3.

Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation.

BACKGROUND: Data on dermatological manifestations of Noonan syndrome (NS) remain heterogeneous and are based on limited dermatological expertise. OBJECTIVES: To describe the dermatological manifestations of NS, compare them with the literature findings, and test for dermatological phenotype-genotype correlations with or without the presence of PTPN11 mutations. METHODS: We performed a large 4-year, prospective, multicentric, collaborative dermatological and genetic study. RESULTS: Overall, 129 patients with NS were enrolled, including 65 patients with PTPN11-NS, 34 patients with PTPN11-NS with multiple lentigines (NSML), and 30 patients with NS who had a mutation other than PTPN11. Easy bruising was the most frequent dermatological finding in PTPN11-NS, present in 53·8% of patients. Multiple lentigines and café-au-lait macules (n ≥ 3) were present in 94% and 80% of cases of NSML linked to specific mutations of PTPN11, respectively. Atypical forms of NSML could be associated with NS with RAF1 or NRAS mutations. In univariate analysis, patients without a PTPN11 mutation showed (i) a significantly higher frequency of keratinization disorders (P = 0·001), including keratosis pilaris (P = 0·005), ulerythema ophryogenes (P = 0·0001) and palmar and/or plantar hyperkeratosis (P = 0·06, trend association), and (ii) a significantly higher frequency of scarce scalp hair (P = 0·035) and scarce or absent eyelashes (P = 0·06, trend association) than those with PTPN11 mutations. CONCLUSIONS: The cutaneous phenotype of NS with a PTPN11 mutation is generally mild and nonspecific, whereas the absence of a PTPN11 mutation is associated with a high frequency of keratinization disorders and hair abnormalities.

[Pelvimetrics measures as predictives factors of positives surgical margins after robot-assisted laparoscopic prostatectomy]. / Mesures pelvimétriques prédictives de marges chirurgicales au décours d'une prostatectomie totale robot-assitée pour cancer prostatique.

INTRODUCTION: Anthropometric data report that pelvic bone of African subjects are narrower and the pelvic cavity is deeper. The aim of the study was to evaluate the influence of pelvic dimensions (PD) on Positive surgical margins (PSM) rate in Afro-Caribbean population after robot-assisted laparoscopic prostatectomy (RALP). PATIENTS AND METHODS: Preoperative pelvic MRI of all patients who have had RALP at the University Hospital Center of Guadeloupe between January 2013 and December 2015 was retrospectively analyzed. PD, including the Height of the upper edge of the prostate (HP), the Apical Depth (AD) and Ischial Spines Distance (ISD), and indexes (prostate volumetric index [ISD/VP], apical depth index [ISD/AD] and prostate depth index [ISD/(AD/HP)]) were compared according to the presence or absence of PSM with uni and multivariate analysis. RESULTS: One hundred and seventy-eight patients were included in the study, of whom 60 (33.7%) presented PSM. In univariate analysis, significant differences between the presence or absence of PSM were observed on the AD (30.3±8.7mm versus 24.8±8.0mm, P<0.001), the HP (9.5±8.5mm versus 16.8±11.9mm, P<0.001) and the ISD (89.6±8.8mm versus 96.1±8.4mm) as well as the indexes of apical depth and prostatic depth. In multivariate logistic regression, the ISD (P<0.001) and HP (P=0.02) were associated with increased likelihood of PSM, but not AD or indexes. CONCLUSION: This study suggests that interspinous distance is the best predictor of PSM during RALP in Afro-Caribbean patients. This measure may be useful to define the therapeutic pattern of patients with prostate cancer. A prospective study with a larger population, comparing RALP in Afro-Caribbean and in caucasians patients, would be needed.

Comprehensive molecular classification of localized prostate adenocarcinoma reveals a tumour subtype predictive of non-aggressive disease.

Background: Management of localized prostate cancer (PCa) is a major clinical challenge since most of these cancers would not evolve but a majority of patients will still undergo a life-changing radical surgery. Molecular studies have shown that PCa can be classified according to their genomic alterations but none of the published PCa molecular classifications could identify a subtype corresponding to non-evolutive tumours. Materials and methods: Multi-omics molecular profiling was carried out on post-radical prostatectomy material from a cohort of 130 patients with localized PCa. We used unsupervised classification techniques to build a comprehensive classification of prostate tumours based on three molecular levels: DNA copy number, DNA methylation, and mRNA expression. Merged data from our cohort and The Cancer Genome Atlas cohort were used to characterize the resulting tumour subtypes. We measured subtype-associated risks of biochemical relapse using Cox regression models and survival data from five cohorts including the two aforementioned. Results: We describe three PCa molecular subtypes associated with specific molecular characteristics and different clinical outcomes. Particularly, one subtype was strongly associated with the absence of biochemical recurrence. We validated this finding on 746 samples from 5 distinct cohorts (P = 3.41 × 10-8, N = 746 tumour samples), and showed that our subtyping approach outperformed the most popular prognostic molecular signatures to accurately identify a subset of patients with a non-evolutive disease. We provide a set of 36 transcriptomic biomarkers to robustly identify this subtype of non-evolutive cases whose prevalence was estimated to 22% of all localized PCa tumours. Conclusion: At least 20% of patients with localized PCa can be accurately predicted to have a non-evolutive disease on the basis of their molecular subtype. Those patients should not undergo immediate surgery and rather be placed under active surveillance.

Predictors of biochemical recurrence after radical prostatectomy in an Afro-Caribbean population in Guadeloupe (French West Indies).

PURPOSE: Few studies have investigated predictive risk factors of biochemical recurrence (BCR) after radical prostatectomy (RP) in other than Caucasian and Asian populations. We aimed to identify pre- and post-operative predictors of BCR after RP in an Afro-Caribbean population in Guadeloupe (French West Indies). PATIENTS AND METHODS: The study included 964 patients who underwent RP for clinically localized prostate cancer between April 1, 2000 and December 31, 2010 in the University Hospital of Guadeloupe. The hazard ratio (HR) and corresponding 95% confidence interval (CI) for single variable associations with BCR were calculated using the Cox proportional hazards regression. Multiple variable analyses for association with BCR were performed, including all variables that reached statistical significance (P value<0.05) in univariate analysis. A backward selection model was then applied with a P value ≥0.1 for retention in the final model. Sensitivity analysis was performed and restricted to patients with known values for all variables (complete case analysis). RESULTS: With a median follow-up of 4.8 years, the BCR rate was 26.7%. In multivariable analysis, predictors of BCR before surgery were diabetes mellitus type 2 (DT2) (HR: 1.37, 95% CI: 1.02-1.85; P=0.038), pre-operative PSA>7.5ng/ml (1.49, 1.15-1.92; P=0.002), clinical stage T2 (1.55, 1.21-1.98; P=0.0006), Gleason score>7 or 4+3 (2.12, 1.54-2.91; P<0.0001), and percentage of length of biopsy positive scores (1.66, 1.24-2.20; P=0.0006). Predictors of BCR after surgery were DT2 (HR: 1.37, 95% CI: 1.01-1.85; P=0.045), pre-operative PSA>7.5ng/ml (1.37, 1.06-1.79; P=0.018), pathological Gleason score>7 or 4+3 (2.36, 1.74-3.19; P<0.0001), pathological stage pT3b (1.68, 1.15-2.45; P=0.007), positive surgical margins (1.72, 1.32-2.45; P=0.0001), and perioperative blood loss>2000ml (3.74, 1.37-10.2; P=0.01). The results were virtually the same by sensitivity analysis (complete cases), except for DT2, which was associated with BCR with borderline statistical significance in the pre-operative model and not retained in the post-operative model. CONCLUSIONS: Afro-Caribbean populations in French West Indies share the same major clinical and pathological risk factors of BCR after RP identified in other ethnic groups. Perioperative blood loss appears to be an additional and independent predictive factor of BCR. LEVEL OF PROOF: 4.

[Epidemiology of urolithiasis in French West Indies: A retrospective study]. / Épidémiologie de la lithiase urinaire aux Antilles françaises : étude rétrospective monocentrique.

INTRODUCTION: The incidence of urolithiasis is increasing with dietary changes especially in developed countries. Guadeloupe is a French department overseas where western diet meets traditional local food. The objective was to describe and analyze the epidemiology of urolithiasis in Guadeloupe. MATERIAL AND METHODS: We conducted a retrospective single-center study throughout the year 2015 on patients hospitalized for urolithiasis at University Hospital of Pointe-à-Pitre. Data of the patients, treatments performed and the types of stones were recorded. According to their mineral content, groups were composed. RESULTS: In total, 165 patients were included. The sex ratio was 1.61. The median body mass index (BMI) was 26.5kg/m2. The most common stone was oxalocalcic (64.7%). Mixed stones (24.7%) were in second place. There were only 3.5% of uric acid urolithiasis. Calcium oxalate stones were predominantly monohydrate. The oxalocalcic stones were significantly more frequent in men (80% versus 47.5%, P=0.01) and in the age group over 50 years old (72.2% versus 51.6%, P=0.04). There was no association between the type of stone and the BMI. CONCLUSION: Epidemiology of urolithiasis in our French Caribbean island is, therefore, similar to continental France. However, our population is distinguished by the proportion of women affected and by the different proportions among each type of stone. Other studies on larger samples are needed to study these specificities. LEVEL OF EVIDENCE: 4.

Prostate cancer clinical presentation, incidence, mortality and survival in Guadeloupe over the period 2008-2013 from a population-based cancer registry.

PURPOSE: The Caribbean population of Guadeloupe has one of the highest incidence rates of prostate cancer worldwide. In 2008, a population-based cancer registry was set up for the monitoring of cancer incidence in the aftermath of the environmental pollution with chlordecone, a persistent organochlorine insecticide formerly used in banana plantations. We describe the clinical presentation, incidence, mortality and survival of prostate cancer for the period 2008-2013. METHODS: The Guadeloupe cancer registry has been routinely collecting all incident cases of cancer since 2008. We compared age-specific incidence rates between different populations, and calculated incidence and mortality rates standardized to the world population. Kaplan-Meier observed survival and estimated age-standardized net survival were calculated by category for age, PSA level, and Gleason score using the Pohar-Perme method. RESULTS: Overall, 3,295 cases of prostate cancer were recorded. World-standardized incidence and mortality were respectively 184.1 [177.8-190.4] and 23.9 [21.9-25.7] per 100,000 person-years. At diagnosis, the mean age of patients was 68 ± 9.6 years old and 22% were aged over 75. Median PSA level was 8.9 [IQR: 6.0-16.0] and 13.6% of the patients had a Gleason ≥ 8. Five-year observed and net survivals were, respectively, 79.6% [77.9-81.2] and 90.7% [88.6-92.8]. CONCLUSION: The incidence of prostate cancer in Guadeloupe is among the highest in the world, along with those of the neighboring Caribbean countries and US African-Americans. We observed no decrease in incidence rates, and a decreasing but non-significant trend in mortality rates, which nonetheless remain higher than in high-income countries. Many Genome-Wide Association Studies are conducted to identify genetic markers involved in prostate cancer risk. In the Caribbean, complementary studies on both lifestyle and behavioral factors should highlight potential common risks among populations who share both genetic and environmental characteristics.

[Impact of Gleason score on biochemical recurrence free survival after radical prostatectomy with positive surgical margins]. / Impact du score de Gleason sur la survie sans récidive biologique après prostatectomie totale pour cancer avec marges chirurgicales positives.

PURPOSE: Research of predictive factors of biochemical recurrence to guide the establishment of an adjuvant treatment after radical prostatectomy for cancer with positive surgical margins. METHODOLOGY: A retrospective cohort of 1577 afro-caribbean patients undergoing radical prostatectomy operated between 1st January 2000 and 1st July 2013 was analyzed. In this cohort, 406 patients had positive surgical margin, we excluded 11 patients who received adjuvant therapy (radiotherapy, hormonotherapy, radio-hormonotherapy) and 2 patients for whom histological analysis of the surgical specimen was for a pT4 pathological stage. After a descriptive analysis, we used a Cox model to look for predictors of survival without biochemical recurrence then, depending on the significant variables, we separated our population into six groups: stage pT2 with Gleason score≤3+4 (group 1), stage pT2 with a score of Gleason≥4+3 (group 2), stage pT3a with a Gleason core≤3+4 (group 3), pT3a stage with a score of Gleason≥4+3 (group 4), stage pT3b with a Gleason score≤3+4 (group 5) and stage pT3b Gleason≥with a score of 4+3 (group 6) and compared survival without biochemical recurrence using a log rank test. After radical prostatectomy with surgical margins with an anatomopathological stage≤pT3b, a Gleason score≥4+3 had a pejorative survival without biochemical recurrence than pathological stage (P<0.001). RESULTS: In multivariate analysis, predictors of survival without biochemical recurrence after radical prostatectomy with positive surgical margins were the majority Gleason postoperative (P<0.0001), pathological stage (P=0.049) adjusted preoperative PSA (P=0.826), with the body mass index (BMI) (P=0.59) and tumor volume (P=0.95). CONCLUSION: A high postoperatively Gleason score (≥4+3) has a better predictive value of biochemical recurrence than pathological stage pT2 or pT3 at the patients having been treated for prostate cancer by radical prostatectomy with positive surgical margins. LEVEL OF EVIDENCE: 4.

[Incidence of skin and non-skin cancers in Afro-Caribbean renal transplant recipients: Guadeloupe data from 2004 to 2011]. / Incidence des cancers cutanés et non cutanés chez les transplantés rénaux afro-caribéens : données guadeloupéennes de 2004 à 2011.

BACKGROUND: Cancer is the main complication of transplantation surgery. The literature concerning renal transplant recipients among the Afro-Caribbean population is scant. The aim of this study was to determine the incidence of cancer in these patients, with the secondary objective being to identify predisposing factors for cancer. PATIENTS AND METHODS: This was an epidemiological and retrospective study that included all Guadeloupians of phototype V-VI undergoing renal transplantation from 01/01/2004 to 31/12/2011. Skin cancer screening was performed before transplantation and during an annual dermatological consultation following transplantation. Screening for non-cutaneous cancers was guided by clinical symptoms or by the results of the screening examinations recommended in the current guidelines. At the study time-point (31/12/2011), all patients were examined by a dermatologist. RESULTS: One hundred and two patients were included : 42 women and 60 men (mean age: 52.1±11.6 years at transplantation). Eight cancers were diagnosed. The cumulative incidence of cancer was 7.8% at 3 years. Three factors were associated with more rapid onset of cancer: personal history or familial history of cancer, and genital lesion induced by HPV. CONCLUSION: Our results suggest a low incidence of cancer in Afro-Caribbean renal transplant patients. Personal or family history of cancer and HPV-induced genital lesions would appear to accelerate the onset of cancer in this population.

[The significance of PSA density as predictive factor in Afro-Caribbean patients eligible for active surveillance by the French protocol criteria]. / Intérêt de la densité du PSA comme facteur prédictif chez les patients afro-caribéens éligibles à la surveillance active du cancer de prostate selon les critères du protocole français.

OBJECTIVES: Study the interest of addition of PSA density (PSAD), to the selection criteria of the French protocol for inclusion patients Afro-Caribbean on active surveillance prostate cancer. METHODS: A retrospective analysis of 1505 patients who had, in turn, a radical prostatectomy for cancer between 2000 and 2012, in a single reference center. One hundred and forty-one patients was eligible, at the time of their diagnosis, for active surveillance by the criteria of the French protocol. This population was divided into 2 groups according to the histological analysis of the prostatectomy specimen confirmed indolent cancer or overturned. The median PSAD of each group was calculated to be compared. Secondarily, the most discriminating PSAD was investigated by the method of ROC after constitution tables intrinsic validity in this population. This threshold has secondary conducting a comparative analysis of the underestimation of cancer in terms of aggressiveness and/or extension between patients selected according to the criteria of the French protocol and "on-selected" patients according to these criteria and their PSAD. RESULTS: Of the 141 patients identified for analysis, histological examination of the prostatectomy specimen has to show that 42 patients (29.7 %) were actually more aggressive cancer (20.6 % of Gleason ≥ 7), wider (4.2 % ≥ pT3) or larger and more aggressive (4.9 %) than foreshadowed criteria French protocol. The median PSAD these 42 patients were significantly higher than the median PSAD patients correctly estimated (0.18 vs. 0.14, p-value=0.046). The application of the most discriminating threshold: 0.15 ng/ml/cm(3) in this population allowed to significantly improve the selection of candidates of the 79 "on-selected" patients, six (20.2 %) were actually more aggressive cancer (13.9 % of Gleason ≥ 7), wider (2.5 % ≥ pT3) or larger and more aggressive (3.8 %). CONCLUSION: The criteria for the French protocol for active surveillance, applied to the Caribbean population underestimate 29 % of non-latent cancers. Adjuvants criteria that must be inexpensive, sensitive and specific seem necessary in this population. A PSAD<0.15 ng/ml/cm(3) could be one of these criteria.

[Stage IV prostate cancer in Guadeloupe, a French Caribbean archipelago]. / Cancer de prostate non localisé au diagnostic en Guadeloupe.

OBJECTIVES: To study clinical characteristics, in terms of survival and response to treatment, of patients with non-localized prostate cancer at diagnosis in an Afro-Caribbean population from Guadeloupe. METHODS: Cases of stage IV prostate cancer (T4N0M0, TxN1M0 and TxNxM1) at diagnosis in the Pointe à Pitre Hospital were selected from 1995 to 2012 and studied. RESULTS: One hundred and eighty-three patients were included. Median age at diagnosis was 70.3 years old (79.2% were more than 65 years). A total of 81.5% of them was TxNxM1 and 11.5% was TxN1M0. Median disease free survival was 18.5 months. Median overall survival was 49.0 months. CONCLUSION: This study about non-localized prostate cancer at diagnosis in an Afro-Caribbean population from a French Caribbean archipelago seemed to show no difference with general population suffering from the same disease, although prostate cancer incidence in this area is one of the highest in the world.