Feasibility of vaginal mesh for anterior vaginal wall prolapse in an ambulatory setting: A retrospective case series.

INTRODUCTION: Vaginal mesh has been proven to be an effective aid in the treatment of cystocele. Could an ambulatory approach be feasible for the Uphold Lite®-mesh? HYPOTHESIS: We investigate the feasibility of an ambulatory approach of Uphold Lite® insertion in a well-selected population. Risk factors for a non-successful ambulatory approach are identified. METHODOLOGY: We conducted a retrospective case series of 236 women who underwent Uphold Lite® vaginal mesh insertion for the treatment of pelvic organ prolapse at our center. Indications for surgery were symptomatic anterior and/or apical prolapse, stages POPQ≥2. We compared women having an ambulatory approach, to those having a one day hospitalization planned but needed to stay. Comparisons between percentages were calculated using the chi-square or Fisher's exact test, depending on the number of women in each group. The mean comparisons were performed using the Student t-test, and the median test comparisons by the Kruskal-Wallis test. A difference was considered significant if p<0.05. RESULTS: The most common reason for staying (85.7% of all ambulatory failures) after Uphold® surgery is the presence of an elevated post void residual. This complication was more found in the following: surgery in the afternoon, use of high-dose morphinics in general anesthesia, and in women with a higher parity. CONCLUSIONS: Our study shows that Uphold® surgery in a one-day setting is feasible and safe. Women desiring this approach should be counselled on the 42.6% risk of one-day failure though, mostly due to non-validation of a post void residual. General anesthesia with high-dose morphinics, a higher parity, and surgery in the afternoon are risk factors for failure of an ambulatory protocol.

Hepatocellular carcinoma with distant double bile duct tumoral thrombus: a case report.

The authors report a case of a 3 cm hepatocellular carcinoma at the junction of segments VI and VII with double bile duct tumoral thrombi (Types I and III). The type I thrombus was suspected during the pre-operative workup, but the type III bile duct tumoral thrombus (BDTT) was an intra-operative additional finding on cholangiography. The patient underwent a bisegmental posterolateral resection to remove the primary tumour and the first tumoral thrombus located in the posterolateral intrahepatic duct. A choledocotomy was also performed to remove, by balloon catheter, the floating thrombus located in the common bile duct just over the papilla. The authors discuss their diagnostic and therapeutic approach and review the literature.

Heart rate responses during a breath-holding competition in well-trained divers.

The diving response elicited by breath-holding (BH) and immersion mainly consists of bradycardia, decreased cardiac output, and peripheral vasoconstriction. These responses reduce oxygen consumption and thereby prolong the duration of the dive. They may also lead to cardiac arrhythmias or hypoxia, however, which in turn may play a role in the occurrence of syncope during BH. The aim of the present study was to analyze the cardiac responses to prolonged breath-holding in elite divers during a competition. Heart rate behaviour and the incidence of arrhythmia were recorded in 16 well-trained breath-hold divers (BHD) using a cardio-frequency meter (for 15 divers) and a Holter (for one diver) during maximal static breath-holding. Anthropometric, spirometric, and training characteristics such as percentage of body fat, pulmonary volumes and years of BH training were also determined. Forced vital capacity (FVC) and forced expiratory volume in one second (FEV (1)) were higher than the predicted values (+7.7%, p<0.05 and+6.6%, p<0.05, respectively). During the static BH, divers presented apneic bradycardia (-44%) correlated with static BH times (p<0.05); this was associated with cardiac arrhythmias (supraventricular extrasystoles and ventricular extrasystoles) in the Holter-equipped subject. These results are in agreement with those obtained in laboratory conditions and confirm the existence of cardiac arrhythmias in well-trained BHD.

Apocrine adenocarcinoma of the nipple: a case report.

Apocrine adenocarcinoma of the skin is a rare and, most of the time, clinically misdiagnosed malignant adnexal tumour. A 66-year-old female patient presented with an asymptomatic swelling of the left nipple that on pathological evaluation was confirmed as an apocrine adenocarcinoma. Surgery is to be considered as the mean treatment for such a lesion and the diagnosis is always difficult to establish. To our best knowledge, this is only the second reported apocrine adenocarcinoma arising from a nipple and the first presenting with Paget's phenomenon.

Correlation between complete response to anthracycline-based chemotherapy and topoisomerase II-alpha gene amplification and protein overexpression in locally advanced/metastatic breast cancer.

UNLABELLED: Anthracycline-based regimens are among the most active but also with greater risk of both acute and long-term side effects, namely cardiotoxicity. Predictive markers of response to anthracyclines are therefore essential. Topoisomerase-IIalpha (topo-II) is the target of anthracyclines and preliminary data suggest its promising role as a predictive marker of sensitivity to these drugs. After screening a population of about 350 patients with locally advanced or metastatic breast cancer, two subgroups were selected for the present analysis: a study group (31 patients), composed of 14 complete responders (CR-a) and 17 true non-responders (PD-a) to anthracycline-based CT, and a control group (28 patients), composed of 7 CR (CR-t) and 21 true non-responders (PD-t) to taxane-based CT. True non-responders were defined as progressive disease (PD) within the first three cycles of CT. Archival tumor samples of these patients were collected, biological markers evaluated and their status correlated with response to therapy. HER-2 and topo-II gene status were evaluated by FISH (Vysis multi-color probe-positivity cut-off: >/=2 ratio for HER-2 and >/=1.5 for topo-II), topo-II protein was evaluated by IHC (positivity cut-off >10%). All cases in which HER-2 gene was non-amplified did not show topo-II gene aberrations. No association was found between HER-2 gene amplification and response to anthracyclines (5/14 (36%) CR and 5/17 (29%) PD to anthracycline-based CT were HER-2+). The topo-II gene was amplified in 3/14 (21%) CR but only in 1/17 (6%) PD to anthracyclines. Amplification of the topo-II gene was seen in 1/7 (14%) CR and in 3/21 (14%) PD to a taxane-based CT. Topo-II protein was overexpressed in 6/11 (55%) CR and in 2/17 (12%) PD to anthracyclines, while in the control group, overexpression was seen in 5/7 (71%) CR and 8/20 (40%) PD. IN CONCLUSION: i) HER-2 gene amplification did not seem to be correlated with response to anthracyclines. ii) Both topo-II gene amplification and protein overexpression seem to correlate with response to anthracyclines, although other factors, such as p53 and cell proliferation, are most likely to be involved. iii) The role of combined evaluation of several relevant markers and of potential 'molecular signatures' are currently being evaluated in prospective randomized clinical trials.

Cutaneous cysts: a plea for systematic analysis.

So-called cutaneous cysts are extremely frequent tumours that could need surgical attention. Most of the time, due to their quite pathognomonic clinical presentation and indolent course, they are simply enucleated. Often, the clinical diagnosis is easily confirmed at surgery by the typical appearance of a cystic formation filled with a creamy fluid. It is frequent for such "typical" lesions to escape histological investigation following removal. However, some mimicking lesions could also be found as "cutaneous cysts" and have quite different prognoses. This paper present five patients with such lesions, three basal cell carcinomas, one benign proliferating trichilemmal cyst and a malignant proliferating trichilemmal cyst. None of the lesions was clinically distinguishable from a classical epidermis cyst.

What's new in the field of cancer vaccines?

The observation that in some cases tumors undergo spontaneous regression concomitantly with autoimmune manifestations has been interpreted as an indication of the involvement of the immune system in tumor rejection. This raised the conceptual possibility that the immune system could be used against the tumor. However, since tumor cells are poorly immunogenic by themselves, early attempts to develop immune-based approaches for cancer therapy saw the use of tumor cells transduced with genes coding for cytokines or costimulatory molecules to enhance in vivo immunity. The identification of cytotoxic T lymphocyte (CTL)-defined tumor-associated antigens has allowed the development of new strategies for cancer immunotherapy. Novel adjuvants have been identified, and different modes of antigen delivery were devised which aim at inducing efficient CTL responses in patients. This review will discuss some of what is currently considered as relevant aspects of antitumor immunization.

The evaluation of mixtures of yeast and potato extracts in growth media for biomass production of lactic cultures.

The effectiveness of yeast extracts (YE) and potato extracts (PE) to promote growth of seven lactic cultures was evaluated by automated spectrophotometry (AS). Two aspects of the growth curve were analysed: (1) maximum biomass obtained (using ODmax) and (2) highest specific growth rate mu(max)) Eleven lots from the same PE-manufacturing process were examined for lot-to-lot variability. The ODmax values of three of the seven strains were significantly affected by lot source, but mu(max) was not significantly affected. The growth of bacteria was systematically lower in base medium containing 100% PE than in base medium containing 100% YE for both ODmax or mu(max) data, which could be related to the lower content in nitrogen-based compounds in PE. In AS assays, highest OD values for Lactobacillus casei EQ28, Lactobacillus rhamnosus R-011, Lactobacillus plantarum EQ12, and Streptococcus thermophilus R-083 were obtained with a mixture of PE and YE. Fermentations (2 L) were also carried out to determine the accuracy of AS to predict biomass levels obtained under fermentation trials. In these fermentations, replacement of 50% YE with PE was shown to enable good growth of S. thermophilus. With L. rhamnosus R-011, a high correlation (R2 = 0.95) was found between ODmax data obtained in the AS assays and that of the 2-L bioreactor when the same growth medium was used for both series of fermentations. However, AS was not as efficient when industrial media were used for the bioreactor assays. The relationship was still good for ODmax between AS data and that of the bioreactor data with L. rhamnosus R-011 in industrial LBS medium (R2 = 0.87), but was very poor with the S. thermophilus R-083 on Rosell #43 industrial medium (R2 = 0.33). Since PE cost 40% less than YE, there are strong economic advantages in considering such a partial replacement of YE by PE.

Different hepatitis C virus nonstructural protein 3 (Ns3)-DNA-expressing vaccines induce in HLA-A2.1 transgenic mice stable cytotoxic T lymphocytes that target one major epitope.

The immunogenicity of the Hepatitis C virus (HCV) nonstructural protein 3 (NS3) was investigated using different DNA-based strategies and a preclinical mouse model transgenic for the HLA-A2.1 molecule. Plasmids expressing NS3 either as a wild-type protein, as a fusion with murine lysosome-associated-membrane protein-1 specific sequences, or under the control of the Semliki Forest virus replicase were evaluated in vitro and in vivo. All plasmids were shown to express the expected size protein. These 3 NS3-expressing vaccines induced overall comparable levels of CTLs when measured at different times postvaccination although mice injected with the NS3-LAMP expressing plasmid showed a particularly homogeneous and overall vigorous response (specific lysis ranged from 60% to 90 % for an E:T ratio of 33.3:1 with a mean CTL precursor frequency of 1:2.10(5) cells). Out of the four HLA-A2.1-restricted NS3 epitopes previously described in HCV infected patients (aa 1073-1081, aa 1406-1415; aa 1169-1177 and aa 1287-1296), the NS3-DNA generated CTLs were predominantly targeted at the aa 1073-1081 epitope. Peptide-based immunization showed that the mouse repertoire was intact for all epitopes tested except one (aa 1287-1296). In conclusion, the 3 NS3-DNA vaccines although based on different mode of action, shared a comparable efficacy at inducing CTL. Surprisingly, the breadth of such response was restricted to a single, major epitope.

Expression of gp100, MART-1, tyrosinase, and S100 in paraffin-embedded primary melanomas and locoregional, lymph node, and visceral metastases: implications for diagnosis and immunotherapy. A study conducted by the EORTC Melanoma Cooperative Group.

With the recent availability of novel antibodies against melanoma antigens tyrosinase and MART-1, it is important to validate their usefulness in pathology practice and in screening patients for immunotherapy treatment. In the present study conducted by the Melanoma Cooperative Group of the European Organization for Research and Treatment of Cancer (EORTC-MCG), immunohistochemical staining for gp100 (antibodies NKI-beteb and HMB-45), MART-1 (A103), tyrosinase (T311), and S100 (S100) was compared on formalin-fixed and paraffin-embedded tumour lesions from 80 patients with 130 malignant melanoma lesions, comprising 44 primary tumours, 18 locoregional metastases, 41 lymph node metastases, and 27 visceral metastases from the lung, liver, and brain. A score between 0 and 5 was allocated to each immunohistochemically stained section. These scores were evaluated in a statistical analysis. S100 was by far the most sensitive marker in all four types of lesions tested. Apart from a significantly better performance for T311 in primary melanomas compared with HMB-45, no significant differences were observed between the four remaining antigens tested. Three settings were next investigated to determine whether the expression of melanoma antigens decreases with tumour progression. First, within the primary melanomas, only NKI-beteb and A103 staining showed a nearly significant negative correlation with Clark's level of invasion and a similar tendency was observed for these antibodies with Breslow thickness. Second, when comparing primary melanoma-metastasis pairs from the same patient, lymph node metastases showed less staining with NKI-beteb, HMB-45, A103, and T311, at a level near significance. This difference was not significant when comparing the primary tumour with visceral metastases, probably due to the lower numbers of pairs. Third, regarding tumour progression from primary melanoma to locoregional, to lymph node, to visceral metastasis, a significant decrease with progression was found only for T311. The apparently stable expression of most of the melanoma antigens, and the small contribution of decreased expression in melanoma tumour progression, supports the rationale for immunotherapy based on the melanoma immunogens gp100, MART-1, and tyrosinase.

Expression of genes coding for the tumor necrosis factor and lymphotoxin ligand-receptor system in non-Hodgkin's lymphomas.

Excessive production of the tumor necrosis factor (TNF) ligand-receptor system has been found to contribute to the severity of non-Hodgkin's lymphoma (NHL). We therefore investigated the expression of TNF, lymphotoxin alpha (LTalpha), lymphotoxin beta (LTbeta), and their receptor (p55, p75, LTbeta-R) transcripts within the tumor tissue in different NHL histological subtypes. The constitutive expression of genes coding for TNF-related ligands and receptors was found in almost all 31 NHL samples studied. Semi-quantitative reverse transcription/polymerase chain reaction and computed densitometry assays revealed that the amounts of TNF, LTalpha, p55, and LTbeta-R mRNA were higher in follicular NHL than in other histological entities. Therefore tumor cell immunopurification was performed in representative follicular NHL samples and consistent results were obtained. The pattern of LTbeta gene expression was different from that of the other molecules, indicating the existence of distinct mechanisms of gene regulation. These results indicate that the transcription of genes coding for the TNF ligand-receptor system in NHL tumor tissue is more widespread than originally thought and that the heterogeneity of their expressions might be related to histological features. The expression of TNF-related ligands and receptors in tumor tissues is likely to contribute to the clinicopathological features of lymphoid-derived malignancies.

Use of conventional or replicating nucleic acid-based vaccines and recombinant Semliki forest virus-derived particles for the induction of immune responses against hepatitis C virus core and E2 antigens.

Replicating and nonreplicating nucleic acid-based vaccines as well as Semliki Forest-recombinant Viruses (rSFVs) were evaluated for the development of a vaccine against hepatitis C virus (HCV). Replicating SFV-DNA vaccines (pSFV) and rSFVs expressing HCV core or E2 antigens were compared with classical CMV-driven plasmids (pCMV) in single or bimodal vaccine protocols. In vitro experiments indicated that all vaccine vectors produced the HCV antigens but to different levels depending on the antigen expressed. Both replicating and nonreplicating core-expressing plasmids induced, upon injection in mice, specific comparable CTL responses ranging from 10 to 50% lysis (E:T ratio 100:1). Comparison of different injection modes (intramuscular versus intraepidermal) and the use of descalating doses of DNA (1-100 microgram) did not show an increased efficacy of the core-SFV plasmid compared with the CMV-driven one. Surprisingly, rSFVs yielded either no detectable anticore CTL or very low anti-E2 antibody titers following either single or bimodal administration together with CMV-expressing counterparts. Prime-boost experiments revealed, in all cases, the superiority of DNA-based only vaccines. The anti-E2 antibody response was evaluated using three different assays which indicated that all generated anti-E2 antibodies were targeted at similar determinants. This study emphasizes the potential of DNA-based vaccines for induction of anti-HCV immune responses and reveals an unexpected and limited benefit of SFV-based vaccinal approaches in the case of HCV core and E2.

Adhesion molecule profiles in atopic dermatitis vs. allergic contact dermatitis: pharmacological modulation by cetirizine.

BACKGROUND: Experimental data suggest that there is an imbalance between Th1 and Th2 cells in atopic dermatitis (AD) skin compared to allergic contact dermatitis (ACD). This imbalance (Th2 and Th1 predominance, respectively) implies the production of different cytokines in these two conditions leading to different expression of adhesion molecules on skin endothelial cells. OBJECTIVE: The expression of VCAM-1 (IL-4/Th2-dependent) and ICAM-1 (INF-gamma/IL-1) on dermal vessels was compared in six patients with AD and six patients with ACD. The effect of cetirizine, a highly selective H1-receptor antagonist on the expressions was studied. METHODS: Six patients with AD were challenged with Dermatophagoides pteronyssimus (DPT patch tests applied to clinically normal skin) and six patients with ACD challenged in the same way with allergens of the European standard series. Skin biopsies at challenged sites were performed before and 6, 24 and 48 h after challenge. The experiment was carried out under double-blind cross-over conditions during a 4-day treatment with a placebo and cetirizine. RESULTS: In AD patients, the scores for both VCAM-1 and ICAM-1 were high before and after challenge. In ACD patients, the ICAM-1 score was high at each experimental time, but the VCAM-1 score, which was significantly lower before challenge, increased at 6, 24 and 48 h after challenge. The administration of cetirizine significantly reduced the VCAM-1 expression in AD patients at each experimental time. CONCLUSION: It is concluded that the increased VCAM-1 expression in AD patients compared to ACD may reflect greater IL-4 and/or IL-13 production in situ. The study also confirms the existence of a modulating effect of cetirizine in vivo on adhesion molecule expression.

Modulation of costimulatory molecules on follicular lymphoma cells by TNF and CD40.

TNF has recently been implicated in the formation of germinal center cells in lymphoid organs. Follicular lymphoma (FL) is thought to represent the pathological counterpart of germinal center B-cell. High levels of TNF and its soluble receptors were found in the plasma of FL patients whereas the transcripts of these molecules were previously found to be present in FL patients lymph nodes. We therefore studied here the effects of TNF on the expression of costimulatory molecules implicated in the cytotoxic T cell response on purified FL cells. In contrast to results described with B-type chronic lymphocytic leukemia, also characterized by high levels of circulating TNF, none of the tested samples showed a regulation of CD80, CD86, CD27 and CD70 in response to TNF. To confirm that the lack of regulation of these molecules was not due to the FL cells inability to modulate their expression, we therefore analyzed costimulatory molecules expression after CD40 pathway stimulation. After culture with human CD40L-transfected L-cells, an up-regulation of CD80, CD86 and CD70 expression was observed, while TNF addition in this model did not influence these changes. In this context, the CD27 molecule was down-regulated except in a single case, where its expression was increased. Taken together, this data demonstrates that in vitro expression of costimulatory molecules such as CD80, CD86, CD27 and CD70, which are implicated in the anti-tumoral response, can be regulated by CD40 ligand but not by TNF.

Characterization of germinal center dendritic cells in follicular lymphoma.

A subset of dendritic cells called germinal center dendritic cells (GCDC) has recently been described inside germinal center from reactive lymphoid organs. We investigated this newly recognized population in follicular lymphoma (FL), which is considered to be the pathologic counterpart of germinal center B cells. Immunohistochemistry analysis with a panel of antibodies demonstrated the presence of a cell population with the peculiar GCDC phenotype in FL biopsies and a similar localization of these cells inside tumoral and reactive follicles. Therefore, we analyzed the relationships between GCDC and the other cell subsets of the tumor follicles. Some of CD4+ and CD8+ T lymphocytes present inside the follicle were found to be in close association with GCDC, suggesting a potential implication of GCDC in their activation. In addition, the distribution of GCDC inside FL and reactive follicles did not appear disrupted, in contrast to follicular dendritic cells, the other follicle dendritic cell type. Finally, we demonstrated that GCDC could be detected from FL lymph node cell suspension by flow cytometry. Taken together, these results indicate that FL development is not associated with a disappearance of GCDC or with a lack of physical interactions between GCDC and T cells inside the follicles. In addition, the fact that GCDC can be observed in FL samples by flow cytometry should allow their purification to further study their putative role in FL development and maintenance.

Morphological and molecular changes in the inner hair cell region of the rat cochlea after amikacin treatment.

This study investigates the morphological and molecular changes that occur in the inner hair cell area of the rat cochlea following aminoglycoside treatment. Rats were injected daily with 500 mg/kg of amikacin between postnatal day 9 (PND9) and PND16. Cochleae were examined at PND16 to PND120 using both scanning and transmission electron microscopy and molecular fluorescent labeling. The inner hair cells showed obvious signs of apoptosis in response to amikacin treatment and most of them were missing by one week after the end of the aminoglycoside exposure period. Concomitantly, the epithelium became scarred as the surrounding supporting cells expanded and filled the space vacated by the missing IHCs. The mid-basolateral region of these modified supporting cells was surrounded by many afferent and efferent terminals. However, these cells expressed neither calbindin nor SNAP25, proteins that are both expressed by IHCs in the normal, untreated organ of Corti in the rat. In addition, these supporting cells remained attached to the basal lamina by a thin cytoplasmic process. The supporting cells surrounding the inner hair cells therefore appear unable to convert directly into inner hair cells following aminoglycoside induced hair-cell loss but may be able to provide trophic support for the remaining afferent and efferent neurites.

CD40 regulation of death domains containing receptors and their ligands on lymphoma B cells.

Within the tumour necrosis factor (TNF) family the induction of apoptosis is restricted to some ligand-receptors pairs, including TNF-TNF receptor type I (TNFRI/p55), FasL-Fas, TNF-related apoptosis-inducing ligand (TRAIL) and its death-receptors (DR)-4 and -5. The pair CD40L-CD40 belongs to the same family but rescues B cells from apoptosis. To investigate how these opposing actions are cross-linked, purified follicular lymphoma (FL) cells were activated upon a human CD40L-transfected murine fibroblastic layer, then RNA messengers for the above molecules were analysed using RT-PCR. The observed down-modulation of TRAIL and up-regulation of TNF and Fas transcripts might account for CD40-CD40L-mediated FL cell survival.

[Death from myocardial metastasis of thyroid cancers (insular, papillary with undifferentiated foyers)]. / Décès par métastase myocardique de cancers thyroïdiens (insulaire, papillaire avec foyers d'indifférenciation).

Two patients, both 70 years old, operated for differentiated thyroid cancer with foci of undifferentiated tumor (one papillary containing pseudosarcomatoid foci, the other with insular pattern containing undifferentiated foci) suddenly died. In both cases, for both of them metastatic involvement of the myocardium and endocardium. These original findings suggest that elderly patients suffering rom well differentiated thyroid cancer, containing undifferentiated foci, therefore suspected to have metastasized, would benefit from non-invasive cardiac work-up (sonogram) in order to plan their multidisciplinary treatment.