[The place of radiation therapy following radical prostatectomy in 2024]. / La place de la radiothérapie après une prostatectomie dans les cancers de la prostate en 2024.

Radiation therapy after prostatectomy for a prostate cancer is a recommended treatment in case of biochemical relapse (rising PSA) following surgery. Controversies regarding its optimal use, delivery, and toxicities are often discussed, not only within scientific congresses but also during multidisciplinary oncological boards. This article aims at making an assessment of up-to-date knowledge and recommendations to guide decision making regarding the treatments of patients with prostate cancer.

La radiothérapie après prostatectomie pour un cancer de prostate est un traitement recommandé en cas de «récidive biochimique¼ (ré-élévation du PSA) après l'opération. Des controverses quant à son utilisation optimale, sa réalisation, et ses toxicités font régulièrement l'objet de discussio, que ce soit au sein des sociétés scientifiques ou lors des concertations oncologiques multidisciplinaires. Cet article a pour but de faire l'état des lieux des connaissances actuelles et des recommandations existantes afin de guider nos réflexions et prises de décision concernant les traitements des patients présentant un cancer de la prostate.

[Urinary cytology for the detection of urothelial lesions]. / Rôle de la cytologie urinaire dans le dépistage des lésions urothéliales.

Urine cytology is a long-used technique for the detection of high grade neoplastic urothelial lesions. Since 2016, «The Paris System¼ classification has revolutionized this field by introducing a standardized terminology widely adopted by cytopathologists and urologists. In this article, we explain this classification and discuss its impact on the clinical management of patients with urothelial lesions, as well as its role in the secondary prevention of these lesions.

La cytologie urinaire est une technique utilisée depuis longtemps dans la détection des lésions urothéliales tumorales de haut grade. Depuis 2016, la classification «The Paris System¼ a révolutionné ce domaine en introduisant une terminologie standardisée largement adoptée par les cytopathologistes et les urologues. Dans cet article, nous expliquons cette classification et discutons de son impact sur la prise en charge clinique des lésions urothéliales, ainsi que son rôle dans la prévention secondaire de ces lésions.

[Ulcerative Zoon's balanitis]. / Balanite de Zoon ulcérée.

Zoon's balanitis is a rare genital dermatosis of unknown etiology, usually presenting as a red-orange macule or plaque with a «cayenne pepper¼ appearance on the glans and/or foreskin. Unfortunately, atypical presentations are not uncommon, including vegetating or ulcerative lesions. Usually, it affects middle-age to older uncircumcised men. Although it is a benign pathology, Zoon's balanitis may be superimposed on another inflammatory or neoplastic dermatosis. As topical treatments are generally non satisfactory and relapses are usual on treatment with-drawal, circumcision remains an interesting option with usually a rapid and complete remission of the symptoms.

La balanite de Zoon est une dermatose génitale peu fréquente d'étiologie inconnue, se présentant habituellement par une macule ou une plaque de couleur rouge- orange avec un aspect en «poivre de cayenne¼, sur le gland et/ou le prépuce. Néanmoins, des formes atypiques, végétantes ou ulcérées, sont possibles. Elle touche plus souvent l'homme d'âge moyen à avancé et non circoncis. Il s'agit d'une pathologie bénigne, mais qui peut se surajouter à d'autres dermatoses inflammatoires ou néoplasiques. Les traitements topiques ne sont pas très efficaces et entraînent généralement une récidive à l'arrêt, tandis que la circoncision permet souvent une disparition rapide et complète des symptômes.

[The overactive bladder syndrome]. / Le syndrome d'hyperactivité vésicale.

The overactive bladder (OAB) syndrome is defined as urinary urgency, usually with urinary frequency and nocturia, with or without urgency urinary incontinence. It significantly impacts patients' quality of life and represents a significant public health issue. Treatment options include conservative and hygienic measures, pharmacological treatments and surgery.

Le syndrome d'hyperactivité vésicale (SHV) est défini par la survenue d'urgenturie avec ou sans incontinence urinaire, habituellement associée à une pollakiurie ou à une nycturie. Il impacte significativement la qualité de vie des patients et représente un réel problème de santé publique. Les options thérapeutiques incluent des mesures conservatrices et hygiéno-diététiques, des traitements médicamenteux et chirurgicaux.

Parastomal hernia after radical cystectomy with ileal conduit diversion: a narrative review.

Radical cystectomy (RC) with ileal conduit urinary diversion has become a common surgical procedure. Stomal complications and particularly parastomal hernia (PH) are the most frequent complications and causes of reintervention after RC with ileal conduit urinary diversion. PH is usually asymptomatic. When PH increases in size and becomes symptomatic, it clearly impairs patients' quality of life in terms of physical limitation, mental distress and social interaction. The aim of this article was to review the current knowledge on PH after RC with ileal conduit urinary diversion, regarding its natural history, risk factors, prevention and surgical management. There is no strong recommendation on the ideal surgical technique for repair of PH after RC, but laparoscopic Sugarbaker or Sandwich techniques with non-absorbable meshes are emerging as the preferred modern means of PH repair. Techniques for prevention and repair of PH after RC need to be specifically evaluated in future prospective studies.

Outcomes after salvage radical prostatectomy and first-line radiation therapy or HIFU for recurrent localized prostate cancer: results from a multicenter study.

INTRODUCTION: Despite no consensus on the optimal management of recurrent prostate cancer after primary radiation or HIFU therapy, salvage prostatectomy (sRP) is reserved for only 3% of patients because of technical challenges and frequent post-operative complications. We assessed outcomes after sRP in a series of patients with localized PCa and that had received radiation therapy or HIFU as a first-line treatment. MATERIALS AND METHODS: Data from nine French referral centers on patients treated with sRP between 2005 and 2017 were collected. Pre- and post-operative data, including oncological and functional outcomes after first treatment and sRP, were analyzed to determine the predictors for biochemical recurrence (BCR) and cancer-specific survival (CSS) after sRP. RESULTS: First-line treatments were external beam-radiation therapy (EBRT) for 30 (55%), brachytherapy (BT) for 10 (18%), and high-intensity focused ultrasound (HIFU) for 15 (27%). Median (IQR) PSA at diagnosis was 6.4 (4.9-9.5) ng/mL, median PSA at nadir was 1.9 (0.7-3.0) ng/mL, and median (IQR) to first BCR was 13 (6-20) months. Of the 55 patients, 44 (80%) received robot-assisted salvage radical prostatectomy and 11 (20%) received salvage retropubic radical prostatectomy. Restoration of continence was achieved in 90% of preoperatively continent patients; 24% that had received nerve-sparing (NS) procedures were potent after surgery. Prolonged catheterization due to anastomotic leakage was the most common complication. Age, preoperative clinical stage, NS procedure, and a pathological Gleason score were predictors for BCR. CONCLUSIONS: sRP was safe, feasible, and effective using either an open or robot-assisted approach, in experienced hands. Age, preoperative clinical stage, NS procedure, and pathological GS were linked with BCR after sRP.

AMS-800 Artificial urinary sphincter in female patients with stress urinary incontinence: A systematic review.

AIMS: To perform a systematic review of studies reporting the outcomes of AMS-800 artificial urinary sphincter (AUS) implantation in female patients with stress urinary incontinence (SUI) resulting from intrinsic sphincter deficiency (ISD). METHODS: A systematic literature search of the Medline and Embase databases was performed in June 2018 in accordance with the PRISMA statement. No time limit was used. The protocol was registered in PROSPERO (CRD42018099612). Study selection and data extraction were performed by two independent reviewers. RESULTS: Of 886 records screened, 17 were included. All were retrospective or prospective non-comparative case series. One study reported on vaginal AUS implantation, 11 on open AUS implantation, two on laparoscopic AUS implantation, two on robot-assisted AUS implantation and one compared open and robot-assisted implantations. The vast majority of patients had undergone at least one anti-incontinence surgical procedure prior to AUS implantation (69.1-100%). The intraoperative bladder neck injury rates ranged from 0% to 43.8% and the intraoperative vaginal injury rates ranged from 0 to 25%. After mean follow-up periods ranging from 5 to 204 months, the complete continence rates ranged from 61.1% to 100%. The rates of explantation, erosion and mechanical failure varied from 0% to 45.3%, 0% to 22.2% and 0% to 44.1%, respectively. CONCLUSIONS: AMS-800 AUS can provide excellent functional outcomes in female patients with SUI resulting from ISD but at the cost of a relatively high morbidity. High level of evidence studies are needed to help better define the role of AUS in the female SUI armamentarium.

Incidence and risk factors of postoperative stress urinary incontinence following laparoscopic sacrocolpopexy in patients with negative preoperative prolapse reduction stress testing.

INTRODUCTION AND HYPOTHESIS: The objectives of this study were to evaluate the incidence of postoperative stress urinary incontinence (SUI) after laparoscopic sacrocolpopexy (LSCP) in women with negative preoperative prolapse reduction stress testing (PPRST) and to identify associated risk factors. METHODS: This was a retrospective cohort study comprising women who consecutively underwent double-mesh LSCP without concomitant SUI surgery after a negative PPRST at a tertiary referral center. Negative PPRST was defined by the absence of SUI during cough testing and urodynamic studies with prolapse reduction. RESULTS: Fifty-five patients were assessed in the final analysis. No significant complication was encountered during and after LSCP. Mean follow-up was 25 ± 11 (range 12-48) months. No patient developed recurrent pelvic organ prolapse (POP) or mesh erosion at last follow-up. Thirty (54.5 %) patients reported the symptom of SUI (subjective SUI) postoperatively, 13 (23.6 %) had a positive cough test (objective SUI) at last visit, and nine (16.4 %) underwent a sling procedure. In univariate analyses, advanced cystocele (stage 3-4) and a history of patient-reported SUI before surgery were associated with a higher risk of postoperative subjective and objective SUI after LSCP. Multivariate analyses identified preoperative SUI as the sole independent predictor of subjective SUI [risk ratio (RR = 4.03; 95% confidence interval (CI) = 1.16-14.09), objective SUI, (RR = 4.67; 95% CI = 1.14-19.23), and subsequent anti-SUI surgery after LSCP (RR = 6.17; 95% CI = 1.30-29.41). CONCLUSIONS: SUI is far from uncommon in women after LSCP despite negative PPRST, especially in those with advanced cystocele and a history of SUI preoperatively; after at least 1 year of follow-up, approximately one in six women eventually underwent a sling surgery. These data are useful for counseling patients.

New surgical technique for treatment of stress urinary incontinence TVT-ABBREVO from development to clinical experience.

Tension-free suburethral tapes have revolutionized the surgical treatment of female stress urinary incontinence (SUI). These tapes are inserted by way of a retropubic or transobturator route. The inside-out tension-free vaginal tape transobturator approach, or TVT-Obturator system (TVT-O, Ethicon Women's Health and Urology, Somerville, NJ), was developed ten years ago with the aim of minimizing the risk of urinary tract injuries associated with retropubic and outside-in transobturator tapes while reproducibly ensuring minimal tissue dissection. Cadaveric studies have shown that the anatomical trajectory of the TVT-O tape is strictly perineal and courses away from neighboring obturator and pudendal neurovascular structures. Several meta-analyses have shown similar SUI cure rates after retropubic and transobturator tape procedures. Yet, the transobturator route may be associated with less voiding dysfunction, blood loss, bladder perforation, and shorter operating time. The original TVT-O procedure was modified with the aim of reducing the incidence of postoperative groin pain as well as the rather theoretical risk of obturator nerve injury. This modified procedure, named TVT-ABBREVO (Ethicon Women's Health and Urology, Somerville, NJ), utilizes a shortened, 12-cm-long polypropylene tape. In addition, perforation of the obturator membrane with the scissors and guide is avoided in order to reduce the depth of lateral dissection, and consequently, to maximize securing of the tape within the obturator muscular/aponeurotic structures. In a comparative anatomical study, it was indeed observed that the shorter tape traversed less muscular structures (with no or only a minimal amount of tape lying in the adductor muscles) than its original counterpart, while still consistently anchoring in the obturator membrane at a similarly safe distance from the obturator canal. In a single-center randomized clinical trial, after a 3-year minimum follow-up, the modified TVT-O procedure with a shorter tape and reduced dissection was found to be as safe and efficient as the primal procedure for treating female SUI, with less severe and frequent groin pain in the immediate postoperative period.

Identification of stromal proteins overexpressed in nodular sclerosis Hodgkin lymphoma.

Hodgkin lymphoma (HL) represents a category of lymphoid neoplasms with unique features, notably the usual scarcity of tumour cells in involved tissues. The most common subtype of classical HL, nodular sclerosis HL, characteristically comprises abundant fibrous tissue stroma. Little information is available about the protein composition of the stromal environment from HL. Moreover, the identification of valid protein targets, specifically and abundantly expressed in HL, would be of utmost importance for targeted therapies and imaging, yet the biomarkers must necessarily be accessible from the bloodstream. To characterize HL stroma and to identify potentially accessible proteins, we used a chemical proteomic approach, consisting in the labelling of accessible proteins and their subsequent purification and identification by mass spectrometry. We performed an analysis of potentially accessible proteins in lymph node biopsies from HL and reactive lymphoid tissues, and in total, more than 1400 proteins were identified in 7 samples. We have identified several extracellular matrix proteins overexpressed in HL, such as versican, fibulin-1, periostin, and other proteins such as S100-A8. These proteins were validated by immunohistochemistry on a larger series of biopsy samples, and bear the potential to become targets for antibody-based anti-cancer therapies.

The original versus a modified inside-out transobturator procedure: 1-year results of a prospective randomized trial.

INTRODUCTION AND HYPOTHESIS: The aim of this study is to compare a modified inside-out transobturator procedure with its original counterpart [inside-out transobturator (TVT-O)] for the treatment of female stress urinary incontinence (SUI). METHODS: A prospective, randomized trial in women suffering from SUI was used. The modified procedure consisted of a shorter tape whilst the scissors or guide no longer perforated the obturator membrane. The primary outcome was the resolution of subjective and objective SUI at 1 year. Secondary outcome measures included adverse events, quality of life measures, and groin pain. RESULTS: One hundred seventy-five patients were randomized. No intraoperative complications were recorded. The SUI cure rate was 91.7% versus 90.7% (original versus modified, respectively; p = 0.824). Incidence and intensity of groin pain was higher in the original TVT-O group on day 0 and 1 (p < 0.05), requiring more analgesics (p = 0.015) but not thereafter. CONCLUSIONS: At 1 year follow-up, the modified inside-out transobturator tape procedure was as efficient and safe as the original technique but associated with less immediate postoperative groin pain.

An anatomic comparison of the original versus a modified inside-out transobturator procedure.

INTRODUCTION AND HYPOTHESIS: The objective of this study was to evaluate the modification of a shortened tape and reduced dissection of the inside-out transobturator procedure on the tape's relationship to the relevant anatomical structures. METHODS: In ten fresh frozen cadavers, relevant distances between the two different tapes and anatomical structures were recorded. RESULTS: The shorter tape traversed less muscular structures, but consistently traversed the obturator membrane. The median distance from the tape to the obturator canal measured 2.0 versus 1.9 cm, to the anterior obturator nerve 3.0 versus 2.7 cm, and to the posterior obturator nerve 2.2 versus 2.0 cm [modified versus original procedure, respectively (p > 0.05)]. Significantly, less mesh was inserted in the modified procedure on each side of the body (6.1 versus 9.9 cm, p < 0.05). CONCLUSIONS: The shorter, inside-out transobturator tape traverses less muscular structures than its original counterpart, while still consistently anchoring in the obturator membrane at a similarly safe distance from the obturator canal.

Open and Laparoscopic Partial Nephrectomy: Comparison and Validation of Preoperative Scoring Systems, Including PADUA, RENAL, ABC Nephrometric Scores and Perinephric Fat Evaluation with Mayo Adhesive Probability Score.

PURPOSE: To evaluate potential associations between 4 nephrometric scoring systems, namely the PADUA (preoperative aspects and dimensions used for anatomical classification), RENAL (radius endophytic/exophytic nearness anterior posterior location), ABC (arterial-based complexity), and MAP (Mayo adhesive probability) scores and their individual components, with surgical and oncological outcomes of patients undergoing a partial nephrectomy. MATERIALS AND METHODS: A consecutive, monocentric cohort of partial nephrectomy patients was retrospectively analyzed. PADUA, RENAL, ABC and MAP nephrometry scores were determined from preoperative axial images. Unadjusted and adjusted associations between overall scores, individual components, surgical approach, complications and oncological outcomes were determined using univariate and multivariate logistic regressions. RESULTS: A total of 189 partial nephrectomies were performed in 181 patients, via an open or a laparoscopic approach. Among scoring systems, only the MAP classification, which assesses adherent perinephric fat, was associated with severe surgical complications as well as with operative time (p<0.05). Among all components of the PADUA and RENAL scores, only proximity of the tumor to the collecting system was associated with overall surgical complication rates, while the diameter of the tumor influenced the operative time (p<0.05). The ABC score was not relevant. Male gender, antiplatelet therapy, and a laparoscopic approach were associated with higher overall surgical complication rates (p<0.05). The number of oncologic recurrences during follow-up was too low to run statistical analyses. CONCLUSION: Nephrometry scores could be simplified to predict surgical complications after partial nephrectomy. In this framework, adherent perinephric fat seemed to be strongly associated with an increased risk of surgical complications.

Lipidomic Profiling of Clinical Prostate Cancer Reveals Targetable Alterations in Membrane Lipid Composition.

Dysregulated lipid metabolism is a prominent feature of prostate cancer that is driven by androgen receptor (AR) signaling. Here we used quantitative mass spectrometry to define the "lipidome" in prostate tumors with matched benign tissues (n = 21), independent unmatched tissues (n = 47), and primary prostate explants cultured with the clinical AR antagonist enzalutamide (n = 43). Significant differences in lipid composition were detected and spatially visualized in tumors compared with matched benign samples. Notably, tumors featured higher proportions of monounsaturated lipids overall and elongated fatty acid chains in phosphatidylinositol and phosphatidylserine lipids. Significant associations between lipid profile and malignancy were validated in unmatched samples, and phospholipid composition was characteristically altered in patient tissues that responded to AR inhibition. Importantly, targeting tumor-related lipid features via inhibition of acetyl-CoA carboxylase 1 significantly reduced cellular proliferation and induced apoptosis in tissue explants. This characterization of the prostate cancer lipidome in clinical tissues reveals enhanced fatty acid synthesis, elongation, and desaturation as tumor-defining features, with potential for therapeutic targeting. SIGNIFICANCE: This study identifies malignancy and treatment-associated changes in lipid composition of clinical prostate cancer tissues, suggesting that mediators of these lipidomic changes could be targeted using existing metabolic agents.

Versican overexpression in human breast cancer lesions: known and new isoforms for stromal tumor targeting.

Proteoglycans play a key role in cancer development and progression by participating in the constitution of a specific fertile tumor microenvironment. As they are largely overexpressed in the malignant stroma, proteoglycans provide a reservoir of potential new targets for anticancer therapies, because they can serve to convey toxic payloads in the close proximity of cancer cells and subsequently destroy them. In this context, versican, a proteoglycan largely overexpressed in several solid cancers, bears the potential to be such an ideal target. As 4 main versican isoforms have been characterized, we sought to determine which isoform could represent the best target in human breast cancer. We used a series of 10 primary breast cancer lesions that were characterized as overexpressing the versican protein, when compared with matched normal breast tissues, using shotgun mass spectrometry and immunohistochemistry experiments. Quantitative polymerase chain reaction and western-blotting experiments were used to evaluate versican isoform expression in breast cancer/normal tissue pairs for which ARN quality was excellent. All known isoforms were significantly overexpressed in the malignant lesions, both at the mRNA and at the protein levels. In the course of this study, we also identified and cloned a new alternatively spliced versican isoform, referred to as V4, which was also found to be upregulated in human breast cancer. This study provides for the first time a comprehensive mRNA and protein analysis of versican isoforms expression in human breast tissues, and offers insights into which therapeutic strategy would be best suited to target versican in human breast cancer lesions.

Interobserver agreement of [68Ga]Ga-PSMA-11 PET/CT images interpretation in men with newly diagnosed prostate cancer.

BACKGROUND: Prostate-specific membrane antigen (PSMA) ligand PET/CT has already provided promising results in prostate cancer (PC) imaging, yet simple and reproductible reporting criteria are still lacking. This study aimed at retrospectively evaluating interobserver agreement of [68Ga]Ga-PSMA-11 PET/CT images interpretation according to PC molecular imaging standardized evaluation (PROMISE) criteria and reproducibility of PSMA reporting and data systems (RADS). METHODS: Forty-three patients with newly diagnosed, histologically proven intermediate- or high-risk PC, eligible for radical prostatectomy and who underwent [68Ga]Ga-PSMA-11 PET/CT before surgery were retrospectively included. Three nuclear medicine physicians (2 experienced and 1 resident) independently reviewed PET/CT images. Interpretation of [68Ga]Ga-PSMA-11 PET/CT images was based on PROMISE criteria including miTNM staging and lesions miPSMA expression score visual estimation and PSMA-RADS version 1.0 for a given scan. Readers' agreement was measured using Krippendorff's coefficients RESULTS: Agreement between observers was almost perfect (coefficient ≥ 0.81) for miM; it was substantial (coefficient ≥ 0.61) for the following criteria: miT, miN, PSMA-RADS, and miPSMA expression score of primary PC lesion and metastases. However, agreement was moderate (coefficient = 0.41-0.60) for miPSMA score of positive lymph nodes and for detection of PC primary lesion. CONCLUSION: Visual interpretation of [68Ga]Ga-PSMA-11 PET/CT images in patients with newly diagnosed PC in a clinical setting leads to at least substantial agreement for PROMISE criteria and PSMA-RADS classification except for PC primary lesion detection and for miPSMA expression scoring of positive lymph nodes that might have been hampered by the interindividual variability of reference organs PSMA expression.

A noninvasive urine-based methylation biomarker panel to detect bladder cancer and discriminate cancer grade.

BACKGROUND: Highly sensitive and specific urinary biomarkers for the early detection of bladder cancer (BC) to improve the performance of urinary cytology are needed. OBJECTIVE: To investigate the usefulness of methylation markers in voided urine to identify BC presence and grade. DESIGN, SETTINGS, AND PARTICIPANTS: Using genome-wide methylation strategies in Toronto, Canada and Liège, Belgium, we have identified differentially methylated genes (TWIST1, RUNX3, GATA4, NID2, and FOXE1) in low-grade vs. high-grade BC tissue and urine. We accrued urine samples from 313 patients using a 2:1 ratio in a case-control setting from Toronto, Canada, Halifax, Canada, and Zurich, Switzerland. We studied the usefulness of these 5 methylated genes to identify BC and discriminate cancer grade in voided urine specimens. Urinary cell sediment DNA was evaluated using qPCR-based MethyLight assay. Multivariable logistic regression prediction models were created. RESULTS AND LIMITATIONS: We included 211 BC patients (180 nonmuscle invasive) and 102 controls. In univariate analyses, all methylated genes significantly predicted BC vs. no BC, and high grade vs. low grade (all P < 0.05). In multivariable analysis, NID2, TWIST1, and age were independent predictors of BC (all P < 0.05). Sensitivity of NID2 and TWIST1 to predict BC and BC grade was 76.2% and 77.6%, respectively, whereas specificity was 83.3% and 61.1%, respectively. Multivariable models predicting BC overall and discriminating between high-grade and low-grade BC reached area under the receiver operating characteristics curves of 0.89 and 0.78, respectively. CONCLUSIONS: This multi-centric study in a real life scenario (different countries, techniques, and pathologists) supports the promise of epigenetic urinary markers in noninvasively detecting BC. With sensitivities and specificities in the range of 80%, the overall performance characteristics of this panel of methylated genes probably does not allow such signature to significantly alter clinical care at this stage but is worth further studying for instance in BC surveillance or screening in high-risk populations.

Histone deacetylase 7 silencing alters endothelial cell migration, a key step in angiogenesis.

Global inhibition of class I and II histone deacetylases (HDACs) impairs angiogenesis. Herein, we have undertaken the identification of the specific HDAC(s) with activity that is necessary for the development of blood vessels. Using small interfering RNAs, we observed that HDAC7 silencing in endothelial cells altered their morphology, their migration, and their capacity to form capillary tube-like structures in vitro but did not affect cell adhesion, proliferation, or apoptosis. Among several factors known to be involved in angiogenesis, platelet-derived growth factor-B (PDGF-B) and its receptor (PDGFR-beta) were the most upregulated genes following HDAC7 silencing. We demonstrated that their increased expression induced by HDAC7 silencing was partially responsible for the inhibition of endothelial cell migration. In addition, we have also shown that treatment of endothelial cells with phorbol 12-myristate 13-acetate resulted in the exportation of HDAC7 out of the nucleus through a protein kinase C/protein kinase D activation pathway and induced, similarly to HDAC7 silencing, an increase in PDGF-B expression, as well as a partial inhibition of endothelial cell migration. Collectively, these data identified HDAC7 as a key modulator of endothelial cell migration and hence angiogenesis, at least in part, by regulating PDGF-B/PDGFR-beta gene expression. Because angiogenesis is required for tumor progression, HDAC7 may represent a rational target for therapeutic intervention against cancer.

Histone deacetylase 4 is required for TGFbeta1-induced myofibroblastic differentiation.

Transforming Growth Factor beta1 (TGFbeta1) is a crucial cytokine triggering myofibroblastic (MF) differentiation, a process involved in tissue healing as well as in pathologic conditions such as fibrosis and cancer. Together with cell shape modifications, TGFbeta1-mediated differentiation of fibroblasts into myofibroblasts is characteristically associated with the neo-expression of smooth muscle alpha-actin (alpha-SMA), a cytoskeletal protein that enhances their contractile activity. Several cellular differentiation programs have been linked to epigenetic regulation of gene expression, including gene methylation and histone acetylation. Herein, we sought to investigate the role of histone deacetylases (HDAC) in TGFbeta1-induced MF differentiation. We found that TSA, a global inhibitor of class I and class II HDACs, prevented alpha-SMA transcript and protein expression and morphological changes mediated by TGFbeta1 in cultured human skin fibroblasts. In order to identify the HDAC(s) participating in MF differentiation, the impact of specific HDAC silencing (HDAC1 through HDAC8) using RNA interference was investigated in fibroblasts exposed to TGFbeta1. Among the eight HDACs tested, silencing of HDAC4, HDAC6, and HDAC8 expression impaired TGFbeta1-induced alpha-SMA expression. HDAC4 silencing most efficiently abrogated alpha-SMA expression and also prevented TGFss1-mediated morphological changes. Forced down-regulation of HDAC4 stimulated the expression of 5'-TG-3'-Interacting Factor (TGIF) and TGIF2 homeoproteins, two known endogenous repressors of the TGFbeta signaling pathway, but not of the inhibitory Smad7. Collectively, these data suggest that HDAC4 is an essential epigenetic regulator of MF differentiation and unveil HDAC4 as a potential target for treating MF-related disorders.

Identification of new accessible tumor antigens in human colon cancer by ex vivo protein biotinylation and comparative mass spectrometry analysis.

One of the most promising new strategies for the development of efficacious cancer therapies relies on the targeted delivery of biopharmaceutical to the tumor environment by the use of selective and specific antibodies. The identification of accessible perivascular proteins selectively overexpressed in cancer tissue may facilitate the development of antibody-based biopharmaceutical administration. This approach is potentially highly selective and specific, combining the presence of tumor biomarkers readily accessible from the blood vessels and the high rate of angiogenesis characteristic of cancer tissues. We performed ex vivo perfusions of surgically resected human colon cancer using a reactive ester derivative of biotin, thus achieving a selective covalent modification of accessible proteins in vascular structures and stroma. After extraction and purification, biotinylated proteins were digested and the resulting peptides submitted to a comparative mass spectrometry-based proteomic analysis, revealing quantitative differences between normal and cancer colon. Sixty-seven of the total 367 proteins identified were found to be preferentially expressed at the tumor site. We generated human monoclonal antibodies against 2 potential tumor targets, NGAL and GW112, and we proved their selective expression in cancer colon and not or barely in healthy tissues. This article presents the first proteomic analysis of human colorectal cancer structures readily accessible from the tumor vasculature, revealing the overexpression of novel tumor antigens which may serve as selective targets for antibody-based imaging and therapeutic biomolecular strategies.