Reconstruction of the Meatus Urethrae After Oncologic Vulvectomy: Outcome of 42 Vaginal Flap Advancements in 41 Women.

BACKGROUND AND AIM: Resection of the distal part of the urethra is performed in 15% to 55% of women with vulvar cancer to achieve radicality of vulvectomy. Urinary reconstruction in these women may be complicated by urethral stenosis resulting from circular inset of the meatus. We report on our experience with 2 surgical techniques of noncircular inset to prevent such stenosis. METHODS: From January 2005 to January 2020, 42 urethral meatus reconstructions were performed in 41 women after vulvectomy for (pre)malignant skin disorders by a "limited" (n = 17) or "extended" (n = 25) anterior vaginal wall advancement technique, including V-Y insertion of part of the vaginal flap in a posterior longitudinal urethrotomy. Preoperative characteristics, procedural details, and surgical outcomes were reviewed. RESULTS: We observed 1 neomeatal stenosis and 1 case of partial vaginal wall flap necrosis as major complications following the "limited" technique and 1 circumferential neomeatal dehiscence and occlusion as major complication after the "extended" technique. Both the neomeatal stenosis and the dehiscence/occlusion are felt to have been preventable and not caused by a flaw of design of the advancement technique. CONCLUSIONS: We advocate applying these vaginal wall advancement techniques to prevent circular inset of the neomeatus. The "extended" technique offers a solution in cases where the periurethral vulvar defect cannot be closed by transpositioning of labial skin.

HPV16 E7 DNA tattooing: safety, immunogenicity, and clinical response in patients with HPV-positive vulvar intraepithelial neoplasia.

BACKGROUND: Usual type vulvar intraepithelial neoplasia (uVIN) is caused by HPV, predominantly type 16. Several forms of HPV immunotherapy have been studied, however, clinical results could be improved. A novel intradermal administration route, termed DNA tattooing, is superior in animal models, and was tested for the first time in humans with a HPV16 E7 DNA vaccine (TTFC-E7SH). METHODS: The trial was designed to test safety, immunogenicity, and clinical response of TTFC-E7SH in twelve HPV16+ uVIN patients. Patients received six vaccinations via DNA tattooing. The first six patients received 0.2 mg TTFC-E7SH and the next six 2 mg TTFC-E7SH. Vaccine-specific T-cell immunity was evaluated by IFNγ-ELISPOT and multiparametric flow cytometry. RESULTS: Only grade I-II adverse events were observed upon TTFC-E7SH vaccination. The ELISPOT analysis showed in 4/12 patients a response to the peptide pool containing shuffled E7 peptides. Multiparametric flow cytometry showed low CD4+ and/or CD8+ T-cell responses as measured by increased expression of PD-1 (4/12 in both), CTLA-4 (2/12 and 3/12), CD107a (5/12 and 4/12), or the production of IFNγ (2/12 and 1/12), IL-2 (3/12 and 4/12), TNFα (2/12 and 1/12), and MIP1ß (3/12 and 6/12). At 3 months follow-up, no clinical response was observed in any of the twelve vaccinated patients. CONCLUSION: DNA tattoo vaccination was shown to be safe. A low vaccine-induced immune response and no clinical response were observed in uVIN patients after TTFC-E7SH DNA tattoo vaccination. Therefore, a new phase I/II trial with an improved DNA vaccine format is currently in development for patients with uVIN.

[Frequent visitors to psychiatric emergency service: Demographical and clinical analysis]. / Patients récurrents aux urgences psychiatriques : analyse démographique et clinique.

INTRODUCTION: Frequent visitors of psychiatric emergency wards are an important health care problem. Previous studies underlined that 2 % to 9 % of patients induce 15 % to 33 % of total clinical activity. Those patients have chronic and severe mental illness such as schizophrenia, associated with social and financial difficulties. OBJECTIVE: The aim of this study was to describe demographic and clinical characteristics of frequent visitors to a psychiatric emergency ward in a French Academic hospital over 6years in comparison to non-frequent visitors. METHODS: The study is based on a retrospective review of the psychiatric emergency wards' administrative and medical computer databases; data that included demographic, financial, clinical, and management information. During this 6-year study, the psychiatric ward recorded 16,754 care episodes for 8800 different patients. We compared frequent visitors with other visitors using univariate and multivariate analyses. Frequent visitors were defined by a number of visits greater than 2 of the mean standard deviation. RESULTS: Two percent of patients (n=192) had nine or more visits during the period. These patients caused 21 % of the total number of the visits. In the univariate analysis, the most significant reasons for referral in frequent visitors versus others (P<0.001) were: more frequent anxiety (37.6 % vs. 32.1 %), less frequent disruptive behavior (8.4 % vs. 12.9 %), depression (7.8 % vs. 17.2 %) and suicide attempt (4.5 % vs. 11.1 %). Factors associated with frequent visitors (P<0.001), after including all significant or confounding variables (multivariate analysis), were: schizophrenia and schizophrenia spectrum disorders (OR=29.5, IC: 11.4-76), DSM-IV cluster B personality disorders (OR=5.5, IC: 3.6-8.4), mental and behavioral disorders due to psychoactive substance use (OR=4.6, IC: 3.1-7), financial assistance through social government programs (OR range: 9.1-2.4, all significant) and being homeless (OR=2.7, IC: 1.8-4). Factors associated with non-frequent visitors were mood disorders (OR=0.07, IC: 0.03-0.19) and neurotic, stress-related, and somatoform disorders (OR=0.14, IC: 0.05-0.4). Sex and age were not significant in multivariate analysis. DISCUSSION: This study identifies significant demographic and clinical factors associated with frequent visits in psychiatric emergency ward in accordance with the large majority of previous studies. We found that psychotic disorders or schizophrenia were the main diagnosis of these patients. Moreover, precariousness (homeless, financial assistance) is an important demographic factor associated with recurrence. However, contrary to numerous studies, we found no effect of sex or age. Due to this important economical and clinical burden, more specific care and alternative solutions to emergency care have to be proposed to this population of patients.

[Suicidal ideas in psychiatric emergency departments: prospective study comparing self- and hetero-assessment]. / Idées suicidaires aux urgences psychiatriques : étude prospective comparant auto- et hétéro-évaluation.

OBJECTIVE: Many suicide victims had contacts with an emergency department before their attempt. We aimed to determine whether patients coming to a psychiatric emergency department were well assessed concerning their suicidal risk, and to test an easy to fill in scale rapidly assessing suicidal risk. METHOD: We conducted a descriptive epidemiological survey in Marseille. The source population was all patients admitted to the psychiatric emergency department. We used a booklet containing three questionnaires for "nurse", "psychiatrist" and "patient". We estimated the suicidal risk using both a visual analogue scale (similar for patients and caregivers), and validated scales on self-assessment (scale of suicidality SBQ-R and the Beck Hopelessness Scale). RESULTS AND DISCUSSION: The questionnaire results have shown that people who visited a psychiatric emergency department presented a significant suicidal risk on several criteria: socio-demographic criteria (social isolation, low level of education, low number of people with a job), psychiatric history (rate of pre-existing psychiatric disorders significantly higher than in the general population, high proportions of family and personal history of suicide attempts, psychiatric hospitalizations, and people with a psychiatrist). Six percent of patients claimed to have come to an emergency unit for suicidal ideas but they were ten times more with a suicidal risk, according to the SBQ-R score. The suicidal risk self-assessed by patients on our visual analogue scale was well correlated with SBQ-R scale and Beck Hopelessness scale, but was not well correlated with the evaluation of caregivers. CONCLUSION: Hence, the analog scale we created is easy to use and seems to be a good tool for suicidal risk estimation when it is self-assessed by patients in our study population.

Carotid endarterectomy benefits patients with CKD and symptomatic high-grade stenosis.

Endarterectomy is generally recommended for symptomatic high-grade (70 to 99%) stenosis of the internal carotid artery, but whether this procedure is beneficial among patients with chronic kidney disease (CKD) is unknown. In this re-analysis of data from the North American Symptomatic Carotid Endarterectomy Trial, we included patients with symptomatic stenosis and either stage 3 CKD (n = 524) or preserved kidney function (n = 966; estimated GFR > or = 60). For medically treated patients with high-grade stenosis, risk for ipsilateral stroke at 2 yr was significantly higher in patients with CKD than in those with preserved renal function (31.6 versus 19.3%; P = 0.042); carotid endarterectomy significantly reduced this risk by 82 and 51%, respectively. To prevent one ipsilateral stroke, the number needed to treat by endarterectomy was four for patients with CKD and 10 for patients with preserved renal function. Compared with patients with preserved renal function, those with CKD had similar rates of perioperative stroke and death but higher rates of cardiac events. In conclusion, patients with stage 3 CKD and symptomatic high-grade carotid stenosis gain a large benefit in stroke risk reduction after endarterectomy.

Immune landscape in vulvar cancer-draining lymph nodes indicates distinct immune escape mechanisms in support of metastatic spread and growth.

BACKGROUND: Therapeutic immune intervention is highly dependent on the T-cell priming and boosting capacity of tumor-draining lymph nodes (TDLN). In vulvar cancer, in-depth studies on the immune status of (pre)metastatic TDLN is lacking. METHODS: We have phenotyped and enumerated various T-cell and myeloid subsets in tumor-free (LN-, n=27) and metastatic TDLN (LN+, n=11) using flow cytometry. Additionally, we studied chemokine and cytokine release profiles and assessed expression of indoleamine 2,3-dioxygenase (IDO) in relation to plasmacytoid dendritic cell (pDC) or myeloid subsets. RESULTS: Metastatic involvement of TDLN was accompanied by an inflamed microenvironment with immune suppressive features, marked by hampered activation of migratory DC, increased cytokine/chemokine release, and closely correlated elevations of pDC and LN-resident conventional DC (LNR-cDC) activation state and frequencies, as well as of terminal CD8+ effector-memory T-cell (TemRA) differentiation, regulatory T-cell (Treg) rates, T-cell activation, and expression of cytotoxic T-lymphocyte protein-4 (CTLA-4) and programmed cell death protein-1 (PD-1) immune checkpoints. In addition, high indoleamine 2,3-dioxygenase (IDO) expression and increased frequencies of monocytic myeloid-derived suppressor cells (mMDSC) were observed. Correlation analyses with primary and metastatic tumor burden suggested respective roles for Tregs and suppression of inducible T cell costimulator (ICOS)+ T helper cells in early metastatic niche formation and for CD14+ LNR-cDC and terminal T-cell differentiation in later stages of metastatic growth. CONCLUSIONS: Metastatic spread in vulvar TDLN is marked by an inflamed microenvironment with activated effector T cells, which are likely kept in check by an interplay of suppressive feedback mechanisms. Our data support (neoadjuvant) TDLN-targeted therapeutic interventions based on CTLA-4 and PD-1 blockade, to reinvigorate memory T cells and curb early metastatic spread and growth.

Adenocarcinoma of the Uterine Cervix Shows Impaired Recruitment of cDC1 and CD8+ T Cells and Elevated ß-Catenin Activation Compared with Squamous Cell Carcinoma.

PURPOSE: Adenocarcinoma of the uterine cervix is the second most common type of cervical cancer after squamous cell carcinoma (SCC). Although both subtypes are treated similarly, patients with adenocarcinoma have a worse prognosis. In this study, immunologic features of the tumor microenvironment in these two subsets were pursued with potential therapeutic implications. EXPERIMENTAL DESIGN: The immune microenvironment of primary tumors and nonmetastatic tumor-draining lymph nodes (TDLN) was compared between patients with cervical adenocarcinoma (n = 16) and SCC (n = 20) by polychromatic flow cytometry and by transcriptional profiling of the primary tumors (n = 299) using publicly available data from The Cancer Genome Atlas (TCGA). RESULTS: Flow cytometric analyses revealed intact T-cell differentiation in TDLNs, but hampered effector T-cell trafficking to the primary tumors in adenocarcinoma, as compared with SCC. TCGA analysis demonstrated higher expression of chemokines involved in effector T-cell homing (CXCL9/10/11) in SCC primary tumors as compared with adenocarcinoma primary tumors, which was highly correlated to a transcriptional signature for type I conventional dendritic cells (cDC1). This was consistent with elevated frequencies of CD141/BDCA3+cDC1 in primary tumor SCC samples relative to adenocarcinoma and correspondingly elevated levels of CXCL9 and CXCL10 in 24-hour ex vivo cultures. Hampered cDC1 recruitment in adenocarcinoma was in turn related to lower transcript levels of cDC1-recruiting chemokines and an elevated ß-catenin activation score and was associated with poor overall survival. CONCLUSIONS: Our data have identified an opportunity for the investigation of potentially novel therapeutic interventions in adenocarcinoma of the cervix, that is, ß-catenin inhibition and cDC1 mobilization.

PD-L1 and PD-L2 Expression in Cervical Cancer: Regulation and Biomarker Potential.

PD-1/PD-L1 immune checkpoint inhibitors show potential for cervical cancer treatment. However, low response rates suggest that patient selection based on PD-L1 protein expression is not optimal. Here, we evaluated different PD-L1 detection methods and studied transcriptional regulation of PD-L1/PD-L2 expression by The Cancer Genome Atlas (TCGA) mRNAseq analysis. First, we determined the copy number of the PD-L1/PD-L2 locus by fluorescence in situ hybridization (FISH), PD-L1 mRNA expression by RNA in situ hybridization (RNAish), and PD-L1/PD-L2 protein expression by immunohistochemistry (IHC) on tissue microarrays containing a cohort of 60 patients. Additionally, distribution of PD-L1/PD-L2 was visualized based on flow cytometry analysis of single-cell suspensions (n = 10). PD-L1/PD-L2 locus amplification was rare (2%). PD-L1 mRNA expression in tumor cells was detected in 56% of cases, while 41% expressed PD-L1 protein. Discordant scores for PD-L1 protein expression on tumor cells between cores from one patient were observed in 27% of cases. Interestingly, with RNAish, PD-L1 heterogeneity was observed in only 11% of the cases. PD-L2 protein expression was found in 53%. PD-L1 mRNA and protein expression on tumor cells were strongly correlated (p < 0.001). PD-L1 and PD-L2 protein expression showed no correlation on tumor cells (p = 0.837), but a strong correlation on cells in stromal fields (p < 0.001). Co-expression of PD-L1 and PD-L2 on macrophage-like populations was also observed with flow cytometry analysis. Both PD-L1 and PD-L2 TCGA transcript levels strongly correlated in the TCGA data, and both PD-L1 and PD-L2 strongly correlated with interferon gamma (IFNG) expression/transcript levels (p < 0.0001). Importantly, patients with high PD-L1/PD-L2/IFNG transcript levels had a survival advantage over patients with high PD-L1/PD-L2 and low IFNG expression. Based on these findings, we conclude that PD-L1/PD-L2 expression in cervical cancer is mainly associated with interferon induction and not gene amplification, which makes FISH unsuitable as biomarker. The heterogeneous PD-L1 and PD-L2 expression patterns suggest IHC unreliable for patient selection. RNAish, in conjunction with interferon signaling evaluation, seems a promising technique for immune checkpoint detection. These results warrant further investigation into their prognostic and predictive potential.

[Perception and use of an electronic medical record system by professionals of a public psychiatric hospital]. / Perception et utilisation d'un dossier patient informatisé par les professionnels d'un établissement public de psychiatrie.

OBJECTIVES: The aim of this study was to evaluate the interest taken by the health care providers in the electronic medical file and its use within the quality improvement process. SETTING: Our institution is a 204-bed psychiatric hospital, employing 328 professionals and comprising three sectors: six units of complete hospitalisation (102 beds), one unit of week hospitalisation (15 beds), one unit of emergency (7 beds) and one unit of night hospitalisation (15 beds). Three extrahospital structures include the day hospitalisation (65 places), the medicopsychological centers (CMP) and the part-time therapeutic reception centers (CATTP) of the three sectors. METHODS: We conducted face-to-face, semi-structured interviews with health care providers of a public psychiatric hospital. All the solicited people agreed to answer the investigation. The interviews were conducted until no new ideas emerged in the content analysis performed in real time, comprising 60 care providers: 10 psychiatrists, 42 nurses and eight paramedical professionals. Content analysis was performed by two members of the steering committee who were skilled in textual analysis. A descriptive analysis was also performed. The variables were described by proportions and means. The proportions were compared using the Chi-squared test or Fisher exact test where appropriate. A two-tailed P-value of greater than 0.05 was considered to indicate statistical significance. Statistical analyses were carried out using SPSS version 13.0. RESULTS: Ninety-six percent of the interviewed subjects used the electronic medical file. The average number of daily use was seven (S.D.=5). Sixty-seven percent had a favorable opinion of the electronic medical file. Physicians had more frequent favorable opinions than nurses who considered that electronic medical files cannot capture real nursing activity. Health care providers considered that electronic medical file could be associated with improved quality of care, but two points should be taken into account: the increased documentation time (slow system response, multiple screens, the lack of computer knowledge, the absence of bedside documentation technology...) and dysfunctions in the information processing system. This could have an impact on documentation completeness, and quality and could also lead to a reduction of time devoted to care. CONCLUSION: This study proposes tracks of improvement in the use of the DPIP. In spite of this, a true debate must be initiated on these new information systems in psychiatry since their real objectives can be perceived as ambiguous, so that programs of clarification, education and reinsurance can be set-up.

Endothelium specific matrilysin (MMP-7) expression in human cancers.

Over-expression of matrilysin (MMP-7) is predominantly associated with epithelial (pre)malignant cells. In the present study MMP-7 expression is also found in endothelial cells in various human cancer types. Endothelial MMP-7 was associated with CD34 and/or CD105 expression. These immunohistochemical data were confirmed by RT-PCR on VEGF-stimulated endothelial cells. In addition, MMP-7 was also identified in sprouting endothelial cells in vitro. The potential clinical relevance of endothelial MMP-7 was assessed for cervical cancer patients by evaluating the association with overall survival. In contrast to MMP-7 in malignant epithelial cells, MMP-7 expression in endothelial cells showed a significant association with poor survival (LR 5.12, P=0.02, n=30). Our data suggest that MMP-7 is involved in tumor angiogenesis, thereby contributing to malignant growth and hence associated with decreased survival.

Glutamate dependent NMDA receptor 2D is a novel angiogenic tumour endothelial marker in colorectal cancer.

Current vascular-targeted therapies in colorectal cancer (CRC) have shown limited benefit. The lack of novel, specific treatment in CRC has been hampered by a dearth of specific endothelial markers. Microarray comparison of endothelial gene expression in patient-matched CRC and normal colon identified a panel of putative colorectal tumour endothelial markers. Of these the glutamate dependent NMDA receptor GRIN2D emerged as the most interesting target. GRIN2D expression was shown to be specific to colorectal cancer vessels by RTqPCR and IHC analysis. Its expression was additionally shown be predictive of improved survival in CRC. Targeted knockdown studies in vitro demonstrated a role for GRIN2D in endothelial function and angiogenesis. This effect was also shown in vivo as vaccination against the extracellular region of GRIN2D resulted in reduced vascularisation in the subcutaneous sponge angiogenesis assay. The utility of immunologically targeting GRIN2D in CRC was demonstrated by the vaccination approach inhibiting murine CRC tumour growth and vascularisation. GRIN2D represents a promising target for the future treatment of CRC.

The future of surgical training in the context of the 'Shape of Training' Review: Consensus recommendations by the Association of Surgeons in Training.

ASiT has long maintained that in order to provide the best quality care to patients in the UK and Republic of Ireland, it is critical that surgeons are trained to the highest standards. In addition, it is imperative that surgery remains an attractive career choice, with opportunities for career progression and job satisfaction to attract and retain the best candidates. In 2013, the Shape of Training review report set out recommendations for the structure and delivery of postgraduate training in light of an ever increasingly poly-morbid and ageing population. This consensus statement outlines ASIT's position regarding recommendations for improving surgical training and aims to help guide discussions with regard to future proposed changes to surgical training.

MCAM and LAMA4 Are Highly Enriched in Tumor Blood Vessels of Renal Cell Carcinoma and Predict Patient Outcome.

The structure and molecular signature of tumor-associated vasculature are distinct from those of the host tissue, offering an opportunity to selectively target the tumor blood vessels. To identify tumor-specific endothelial markers, we performed a microarray on tumor-associated and nonmalignant endothelium collected from patients with renal cell carcinoma (RCC), colorectal carcinoma, or colorectal liver metastasis. We identified a panel of genes consistently upregulated by tumor blood vessels, of which melanoma cell adhesion molecule (MCAM) and its extracellular matrix interaction partner laminin alpha 4 (LAMA4) emerged as the most consistently expressed genes. This result was subsequently confirmed by immunohistochemical analysis of MCAM and LAMA4 expression in RCC and colorectal carcinoma blood vessels. Strong MCAM and LAMA4 expression was also shown to predict poor survival in RCC, but not in colorectal carcinoma. Notably, MCAM and LAMA4 were enhanced in locally advanced tumors as well as both the primary tumor and secondary metastases. Expression analysis in 18 different cancers and matched healthy tissues revealed vascular MCAM as highly specific in RCC, where it was induced strongly by VEGF, which is highly abundant in this disease. Lastly, MCAM monoclonal antibodies specifically localized to vessels in a murine model of RCC, offering an opportunity for endothelial-specific targeting of anticancer agents. Overall, our findings highlight MCAM and LAMA4 as prime candidates for RCC prognosis and therapeutic targeting. Cancer Res; 76(8); 2314-26. ©2016 AACR.

The risk and benefit of endarterectomy in women with symptomatic internal carotid artery disease.

BACKGROUND AND PURPOSE: Perioperative risk and long-term benefit of carotid endarterectomy (CE) are not detailed in women with symptomatic internal carotid artery (ICA) stenosis. Our aim was to compare the efficacy of CE versus medical therapy in women and men with symptomatic ICA stenosis. METHODS: Data were taken from the North American Symptomatic Carotid Endarterectomy Trial (873 women, 2012 men) and the ASA and Carotid Endarterectomy trial (335 women, 813 men). RESULTS: The 30-day perioperative risk of death was higher in women than in men (2.3% versus 0.8%, P=0.002). Higher perioperative risk of stroke and death was also observed (7.6% versus 5.9%) but not statistically significant. With > or =70% stenosis, the 5-year absolute risk reduction (ARR) in stroke from CE was similar between women (15.1%) and men (17.3%). With 50% to 69% stenosis, CE was not beneficial in women (ARR=3.0%, P=0.94), contrary to men (ARR=10.0%, P=0.02). Medically treated women had low risk for stroke. A stroke prognosis instrument (SPI-II) assigned points to 7 factors that identified higher risk for medically treated women: 3 points for hemispheric (not retinal) event, history of diabetes, previous stroke; 2 for age older than 70 years, stroke (not transient ischemic attack); 1 for severe hypertension, history of myocardial infarction. CE was beneficial only for 29.0% of women with 50% to 69% stenosis who had the highest total score of 8 to 15 (ARR=8.9%). CONCLUSIONS: Women and men with > or =70% symptomatic stenosis had similar long-term benefit from CE, although the perioperative risks were higher for women. CE was not beneficial for women with 50% to 69% stenosis without other risk factors for stroke.