Genetic landscape of indolent and aggressive Kaposi sarcomas.

BACKGROUND: Kaposi sarcoma (KS) is a rare skin tumour caused by herpesvirus 8 infection and characterized by either indolence or an aggressive course necessitating systemic therapies. The genetic basis of this difference remains unknown. OBJECTIVES: To explore the tumour mutational burden in indolent and aggressive KS. METHODS: We performed whole-exome sequencing on a cohort of 21 KS patients. We compared genetic landscape including tumor mutational burden between the two forms of indolent and agressive KS. RESULTS: Aggressive KS tumours had a significantly higher TMB and a larger cumulative number of deleterious mutations than indolent KS tumours. In addition, all aggressive tumours had at least three deleterious mutations, whereas most indolent tumours harboured only one or no predicted deleterious mutations. Deleterious mutations listed in the Cancer Gene Census were detected exclusively in patients with aggressive disease. An analysis of somatic copy-number alterations (SCNA) revealed a tendency towards higher number of alterations in aggressive KS. CONCLUSIONS: These data suggest that SCNA alterations and an increase in mutational burden promote aggressive KS and that it might be more appropriate to consider indolent KS as an opportunistic skin disease rather than a cancer.

Spleen route accelerates engraftment of human hematopoietic stem cells.

Intravenous injections of human hematopoietic stem cells (hHSCs) is routinely used in clinic and for modeling hematopoiesis in mice. However, unspecific dilution in vascular system and non-hematopoietic organs challenges engraftment efficiency. Although spleen is capable of extra medullar hematopoiesis, its ability to support human HSC transplantation has never been evaluated. We demonstrate that intra-splenic injection results in high and sustained engraftment of hHSCs into immune-deficient mice, with higher chimerisms than with intravenous or intra-femoral injections. Our results support that spleen microenvironment provides a niche for HSCs amplification and offers a new route for efficient HSC transplantation.

Hemoglobin overexpression and splice signature as new features of inflammatory breast cancer?

INTRODUCTION: Inflammatory Breast Cancer (IBC) is the most aggressive form of breast carcinoma characterized by rapid onset of inflammatory signs and its molecular fingerprint has not yet been elucidated. OBJECTIVES: The objective of this study was to detect both gene expression levels and alternate RNA splice variants specific for IBC. METHODS: W e performed splice-sensitive array profiling using Affymetrix Exon Array and quantitative RT-PCR analyses in 177 IBC compared to 183 non-IBC. We also assessed the prognostic value of the identified candidate genes and splice variants. RESULTS: A 5-splice signature (HSPA8, RPL10, RPL4, DIDO1 and EVL) was able to distinguish IBC from non-IBC tumors (p<10-7). This splice signature was associated with poor metastasis-free survival in hormone receptor-negative non-IBC (p=0.02), but had no prognostic value in IBC. PAM analysis of dysregulated genes in IBC compared to non-IBC identified a 10-gene signature highly predictive of IBC phenotype and conferring a poor prognosis in non-IBC. The genes most commonly upregulated in IBC were 3 hemoglobin genes able to reliably discriminate IBC from non-IBC (p<10-4). Hb protein expression in epithelial breast tumor cells was confirmed by immunohistochemistry. CONCLUSION: IBC has a specific spliced transcript profile and is characterized by hemoglobin gene overexpression that should be investigated in further functional studies.

Percutaneous hook wire assistance during laparoscopic excision of an intrarenal mass.

Completely endophytic renal tumours pose challenges in laparoscopic nephron-sparing tumour excisions, with the use of intraoperative imaging techniques (e.g. ultrasound) being crucial when managing such tumours. The use of a percutaneous hookwire for tumour localisations are in use in several other surgical fields, such as breast surgery. An asymptomatic 52-year-old man presented with an incidental small right sided solid 33-mm interpolar renal mass identified on computed tomography. A guided insertion of a percutaneous localisation wire was carried out prior to a laparoscopic partial nephrectomy to assist in intraoperative tumour landmark/margins identification. Operative time was 210 minutes with zero ischaemia time, with an estimated blood loss of 200 ml. No perioperative complications were observed and the patient was discharged two days postoperatively. Histology revealed the mass to be a Fuhrman grade 2 clear-cell carcinoma with a 2-mm clear surgical margin. The patient remained free of recurrence at 16 months of follow-up. We have reported our first experience of wire localisation prior to laparoscopic partial nephrectomy for an intrarenal mass, which to our knowledge could be the first of its kind in renal surgery. Percutaneous wire localisation of endophytic renal tumours is potentially safe and effective and can allow nephron-sparing surgery where laparoscopic ultrasound is not available. Longer-term and further evidence should be encouraged.

The majority of cells in so-called "mesenchymal stem cell" population are neither stem cells nor progenitors.

OBJECTIVES: The first-passage adherent human bone marrow fibroblast-like cell population corresponds, in terms of phenotype and three-lineage differentiation capacity (assayed in bulk culture), to commonly termed "mesenchymal stem cells". Here we determine the proportion of high proliferative capacity multipotent cells present in this population in order to estimate the proportion of cells that can or cannot be considered as stem and progenitor cells. MATERIAL AND METHODS: The single-cell cultures were established starting from human bone marrow-derived first-passage fibroblast-like cells and the proliferating clones were either transferred to secondary cultures to evaluate their further clonogenicity, or split into three wells to assess differentiation into each of the three different lineages. RESULTS: The analysis of 197 single-cell cultures from three different bone marrow donors shows that only∼40% of so-called "mesenchymal stem cells" exhibit multipotency and are capable of sustained clonogenicity in secondary cultures. CONCLUSION: Even in the first ex vivo passage under favorable conditions the majority (∼60%) of so-called "mesenchymal stem cells" are not multipotent and thus do not represent a stem cell entity.

p53 deficiency induces cancer stem cell pool expansion in a mouse model of triple-negative breast tumors.

Triple-negative breast cancer is a heterogeneous disease characterized by the expression of basal cell markers, no estrogen or progesterone receptor expression and a lack of HER2 overexpression. Triple-negative tumors often display activated Wnt/ß-catenin signaling and most have impaired p53 function. We studied the interplay between p53 loss and Wnt/ß-catenin signaling in stem cell function and tumorigenesis, by deleting p53 from the mammary epithelium of K5ΔNßcat mice displaying a constitutive activation of Wnt/ß-catenin signaling in basal cells. K5ΔNßcat transgenic mice present amplification of the basal stem cell pool and develop triple-negative mammary carcinomas. The loss of p53 in K5ΔNßcat mice led to an early expansion of mammary stem/progenitor cells and accelerated the formation of triple-negative tumors. In particular, p53-deficient tumors expressed high levels of integrins and extracellular matrix components and were enriched in cancer stem cells. They also overexpressed the tyrosine kinase receptor Met, a feature characteristic of human triple-negative breast tumors. The inhibition of Met kinase activity impaired tumorsphere formation, demonstrating the requirement of Met signaling for cancer stem cell growth in this model. Human basal-like breast cancers with predicted mutated p53 status had higher levels of MET expression than tumors with wild-type p53. These results connect p53 loss and ß-catenin activation to stem cell regulation and tumorigenesis in triple-negative cancer and highlight the role of Met signaling in maintaining cancer stem cell properties, revealing new cues for targeted therapies.

Kidney cancer focal cryoablation trend: does location or approach matter?

PURPOSE: We evaluated the current indications and surgical and survival outcomes for cryoablation (CA) using either a percutaneous (PCA) or a laparoscopic approach (LCA). We also investigated the ability of the PADUA score to predict the risk of complications and local recurrence. METHODS: A retrospective analysis was performed at two European tertiary referral centers. Parameters analyzed included size, location, approach, operative time, hospital stay, complications, and functional and oncologic outcomes. Univariate and multivariate analyses were performed. An ROC analysis was conducted to evaluate the accuracy of the PADUA score. RESULTS: Eighty patients were included. Mean tumor size was 2.6 cm. PCA was more often performed in posterior (95 vs. 60 %), inferior (72 vs. 32 %), and lateral (87 vs. 55 %) tumors. The global complication rate was 8.75 %, although proximity to the renal sinus resulted in a higher rate (30 vs. 4 %). Mean follow-up was 34 and 23 months for LCA and PCA, respectively. The 5-year recurrence-free survival was 76 and 90 % for LCA and PCA, respectively. Multivariate analysis showed that tumor involvement of the collecting system was predictive of recurrence. Under ROC analysis, PADUA score was a mild predictor for complications (AUC = 0.601) and a good predictor for recurrence (AUC = 0.723); PADUA ≥8 was identified as a cutoff for patients to a higher risk of recurrence. CONCLUSIONS: The percutaneous approach is confirmed to be the preferred CA technique for posterior and lateral tumors. CA in deeper renal lesions and tumors with PADUA score ≥8 might entail a higher risk of recurrence, and closer follow-up should be considered in these patients.

TAF15 is important for cellular proliferation and regulates the expression of a subset of cell cycle genes through miRNAs.

TAF15 (formerly TAFII68) is a member of the FET (FUS, EWS, TAF15) family of RNA- and DNA-binding proteins whose genes are frequently translocated in sarcomas. By performing global gene expression profiling, we found that TAF15 knockdown affects the expression of a large subset of genes, of which a significant percentage is involved in cell cycle and cell death. In agreement, TAF15 depletion had a growth-inhibitory effect and resulted in increased apoptosis. Among the TAF15-regulated genes, targets of microRNAs (miRNAs) generated from the onco-miR-17 locus were overrepresented, with CDKN1A/p21 being the top miRNAs-targeted gene. Interestingly, the levels of onco-miR-17 locus coded miRNAs (miR-17-5p and miR-20a) were decreased upon TAF15 depletion and shown to affect the post-transcriptional regulation of TAF15-dependent genes, such as CDKN1A/p21. Thus, our results demonstrate that TAF15 is required to regulate gene expression of cell cycle regulatory genes post-transcriptionally through a pathway involving miRNAs. The findings that high TAF15 levels are needed for rapid cellular proliferation and that endogenous TAF15 levels decrease during differentiation strongly suggest that TAF15 is a key regulator of maintaining a highly proliferative rate of cellular homeostasis.

Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor.

Kaposi Sarcoma (KS) are opportunistic tumors, associated with human herpes virus 8 (HHV8) infection. KS development is highly favored by immune-depression and remains the second most frequent tumor in acquired immune deficiency syndrome patients. Although it has been shown that experimental expression of the HHV8 G-protein-coupled receptor (vGPCR) in the endothelial compartment is alone sufficient to recapitulate the formation and progression of KS-like lesions, its functional effects on endothelial homeostasis are not fully understood. Here we show that vGPCR expression in endothelial cells induces an increase in paracellular permeability both in vivo and in vitro. By using pharmacological inhibitors and small interference RNA-based knockdown, we demonstrate an essential role for the PI(3)Kinase-γ/Rac nexus in vGPCR-mediated permeability. This was further accompanied by dramatic remodeling of VE-cadherin-dependent cell-cell junctions. Importantly, this in vitro vGPCR-initiated signaling signature was observed in a large panel of human KS. Altogether, our results support the hypothesis that endothelial vGPCR signaling is co-opted in KS, and unveil new key cellular targets for therapeutic intervention.

Autoimmune bullous skin diseases occurring under anti-tumor necrosis factor therapy: two case reports.

BACKGROUND: Anti-tumor necrosis factor (TNF) agents are increasingly being used for a rapidly expanding number of rheumatic and systemic diseases. As a result of this use, and of the longer follow-up periods of treatment, there are a growing number of reports of the development of autoimmune processes related to anti-TNF agents. The use of anti-TNF agents has been associated with more and more cases of autoimmune diseases, principally cutaneous vasculitis, lupus-like syndrome, systemic lupus erythematosus and interstitial lung disease. OBSERVATIONS: We report 2 cases of autoimmune bullous skin disease occurring in patients undergoing TNF-targeted therapy: a bullous pemphigoid and a pemphigus foliaceus. Both patients were treated by anti-TNF agents for rheumatoid arthritis and showed improvement following interruption of that treatment. Here, we discuss the relationship between anti-TNF therapy and the occurrence of autoimmune bullous disease. CONCLUSION: Anti-TNF agents should be considered as a potential cause of drug-induced autoimmune bullous skin disease.

Adhesion of K88ab fimbriated E. coli in piglet small intestines in relation with iron transport molecules.

Enteropathogenic K88 fimbricated E. coli colonize the piglet small intestine. In swine, it has been previously established that some pigs lack intestinal receptors for K88 lectins and that these animals are resistant to infections by K88-positive E. coli. The receptor is inherited as a simple mendelian character. The interactions established between the glycoconjugate receptors of pig brush borders and K88 lectins are mediated by O- and N-linked glycoproteins which differ between adhesive and non-adhesive piglets. In this study the adhesion of E. coli K88+ in crossbred F2 (LW x MS) x (LW x MS) populations. By using in vitro brush border test, we observed modulation of the adhesion of K88 fimbriae and distinguished high and low affinity receptors. Furthermore, we correlated the attachment with glycoprotein pattern of epithelial cells and mucus. Epithelial cells and mucus contained several glycopeptides (from 42 to 74 kDa) recognized by K88ab fimbriae. The 74 kDa glycoprotein was characteristic of adhesive phenotype and was a mucosal transferrin (iTf). It appeared that iTf was more abundant in adhesive intestines than in non-adhesive ones, suggesting that susceptibility/resistance phenotype could be related to iron metabolism in the intestinal tract. Furthermore, we visualized the intestinal transferrin receptors on the brush border membrane of epithelial cells, probably implicated in iron absorption.

Characterization of O-glycan moieties of the 210 and 240 kDa pig intestinal receptors for Escherichia coli K88ac fimbriae.

The porcine brush border glycoproteins of 210 and 240 kDa, recognized by Escherichia coli K88ac fimbriae, contained O-linked oligosaccharides. The carbohydrate moieties were analysed by deglycosylation, lectin-binding and agglutination assays. Neuraminidase susceptibility of the 210 kDa receptor suggested that a sialoglycoprotein may act as receptor for the K88ac fimbriae. In contrast, K88ac-binding to the 210 and 240 kDa glycoproteins totally disappeared after fucosidase treatment, indicating the critical role of fucosyl residues at the receptor sites. Among the oligosaccharides extracted from these O-glycoproteins, K88ac fimbriae showed affinity for neutral sugar chains while sialylated species were not recognized. Our data suggest a possible role of the polypeptide backbone in the definition of receptor sites. Specific agglutination by K88ac-fimbriated E. coli of the erythrocytes of the hamster Mesocricetus auratus was inhibited by the anti-T peanut lectin and the lectins of Datura stramonium, Aleuria aurantia and Maackia amurensis. Hence, we propose that Gal beta 1-3GalNAc- and Fuc alpha 1-2Gal beta 1-3/4GlcNAc- are the main sequences mediating K88ac fimbrial binding. These structures were not detected in the non-adhesive piglet brush borders characterized by a high carbohydrate content. Additional oligosaccharides probably masked the underlying receptor structures.

[Wegener's granulomatosis with urethral-penile location. Apropos of a case]. / Granulomatose de Wegener à localisation urétro-pénienne. A propos d'un cas.

The authors report a case of Wegener granulomatosis presenting as a necrotizing urethral tumor in a 44 year-old man. Involvement of the urethra by Wegener granulomatosis in unusual which explains the delay in diagnosis particularly when the urethral localization is isolated. The prognosis is severe despite urinary diversion and appropriate therapy. Five cases from the literature are reviewed. Prednisone and cyclophosphamide therapy for Wegener granulomatosis now gives dramatic results, but an urethral localization could occur in the subsequent course of the disease with the same severe prognosis.

[Atrophicus sclerosis lichen and cancer of the glans]. / Lichen scléro-atrophique et cancer du gland.

Two cases of glans penis epidermoid carcinoma after lichen sclerosus and atrophicus or balanitis xerotica obliterans are discussed. Relationship between both diseases are analysed but remain not clear. Balanitis xerotica obliterans gives foreskin and urethral meatus stenosis that required circumcision. Glans carcinoma can be observed many years later even after circumcision. The knowledge of lichen sclerosus and atrophicus is important to do circumcision at the beginning of the disease with a long term follow-up of these patients to realize a glans penis biopsy if necessary. Most of lichen sclerosus and atrophicus are not recognized and the frequency would be higher than reported.

[Cancer of the bladder after cystitis due to cyclophosphamide. Apropos of a case]. / Cancer de vessie après cystite au cyclophosphamide. A propos d'une observation.

Since 1960, cyclophosphamide has been widely used in the treatment of solid malignant tumors, certain hematological and systemic diseases and indeed even in renal transplantation. However, while the efficacy of the product is certain, it became rapidly apparent that this molecule had a definite toxicity for urinary endothelium, in particular that of the bladder. This toxicity is due to certain metabolites of the molecule and to the fact that urine stagnates in the bladder reservoir. It is manifested principally by hemorrhagic cystitis which is always difficult to treat and which is sometimes life threatening for the patient. However, cyclophosphamide can also induce malignant bladder tumors with a poor prognosis. Since 1971, 56 cases of bladder cancer due to cyclophosphamide have been published. It is therefore a rare lesion generally manifesting itself by hematuria and sometimes occurring a long time after discontinuation of treatment. At the time of first examination, 2/3 of these tumors were widely infiltrating and despite major surgery (50% of cases required immediate total cystectomy) the prognosis was very poor due to the fact that the bladder cancer added its own degree of gravity to that of the initial disease which justified the introduction of treatment. All the authors who have studied this problem therefore stress the necessity of avoiding cyclophosphamide when another molecule may be effective and especially when it is not a malignant condition which is being considered.

[Flexible ureteroscopy. Diagnostic and therapeutic significance. Apropos of 15 cases]. / L'urétéroscopie souple. Intérêts diagnostique et thérapeutique. A propos de 15 observations.

The authors analyse the results of a preliminary report of 15 cases of ureteric stones treated by flexible ureterorenoscopy and one case of radiolucent renal stone in the left lower renal calyx. Stone fragmentation was complete in 11 cases with 1 small residual fragment in the lower ureter, 1 perforation was immediately operated without any further complication and in one case, it was impossible to advance into the ureter. Flexible ureterorenoscopy is valuable for diagnosis of filling defects in the lower calyx and for treatment of stones in the upper and middle ureter.

[Penile metastasis disclosing cancer of the rectum. Apropos of a case]. / Métastase pénienne révélatrice d'un cancer du rectum. A propos d'un cas.

A case report of penile metastasis from a rectal cancer in a 58 year old man is described. The authors insist on the rarity of this penile metastatic localization. Many primary tumors can be involved in this penile localization, mainly urinary tract tumors such as bladder or prostate, but rectal cancer is very rare and only 47 cases have been reported to date. The modalities of extension are analysed: direct invasion or venous extension. The prognosis of such metastases is very poor, but some long-term survivals (from 21 months to 9 years) have been seen after aggressive surgical treatment when the primary tumor was rectal cancer. Radiotherapy and are not effective.

Bilateral traumatic renal artery rupture: emergency surgical repair and long-term evolution.

In one case of bilateral traumatic renal artery rupture, the role of clinical and radiographic explorations is discussed to reduce the duration of renal ischemia. The diagnosis of bilateral traumatic renal artery rupture requires the performance of pyelography if the patient is oliguric or exhibits microscopic hematuria, or of conventional aortography if there is no renal secretion. Renal artery repair must be done as soon as possible, but a review of the literature shows that delay in treatment is not rare. Everything must be done to reduce this delay in order to improve renal function after surgery.