Onychocytic Matricoma: A Clinical, Dermoscopic, and Pathological Analysis of 14 Cases.

ABSTRACT: Onychocytic matricoma (OCM) is a benign neoplasm of the nail matrix. Only 18 cases of this tumor have been reported in the literature to date. We retrospectively analyzed the clinical features of 14 patients with OCM. The most common clinical feature was longitudinal xanthopachyonychia (n = 9), followed by longitudinal leukopachyonychia (=3) and longitudinal pachymelanonychia (n = 2). The most common clinical findings identified following dermoscopy and analysis at high magnification of classical photographs were free-edge thickening of the nail plate without pitting (n = 14), longitudinal ridging (n = 7), round white clods (n = 7), white dots (n = 7), and filiform hemorrhages (n = 7), followed by oval and linear white clods (n = 5), fuzzy lateral border (n = 5), and red-purple blood clods (n = 3). Nail clipping histopathology showed a thickened nail plate with multiple, small, round-to-oval spaces. The tumor expressed immunopositivity for LEF-1. Dermoscopy of the nail plate and nail clipping histology provides useful information with regards to the differential diagnosis with subungual squamous cell carcinoma and nail melanoma. Ex vivo-in vivo correlation facilitates a better dermoscopic assessment of this unique underrecognized disease. However, the differential diagnosis between OCM and onychocytic carcinoma requires biopsy of the tumor. LEF-1 as an onychogenic marker can be used to resolve the differential diagnosis between OCM and subungual longitudinal acanthoma/seborrheic keratosis.

Onychomatricoma: a clinicopathological, immunohistochemical, and molecular study of 10 cases highlighting recurrent RB1 deletion and the potential diagnostic value of LEF-1.

AIMS: Onychomatricoma (OM), an uncommon benign fibroepithelial neoplasm of the nail unit, is sometimes diagnostically challenging for clinicians and pathologists. OM consistently expresses CD34, but no specific immunohistohemical markers or recurrent genetic alterations have been identified to date. Recent studies have suggested that Wnt signalling is a key molecular characteristic of OM. METHODS AND RESULTS: Ten cases were analysed: four classical OM including two with pleomorphic cells; two superficial acral fibromyxoma-like variants of OM; three micropapilliferum variants of OM including one with pleomorphic cells; and one proliferating variant of OM. Immunohistochemically, the spindle cells were positive with CD34 (n = 10) and CD99 (n = 1), with focal reactivity for CD10 (n = 5). The epithelial component of the tumours expressed immunopositivity for LEF-1. Using array comparative genomic hybridization (aCGH), we demonstrated that all OM, including its variants that were tested (n = 8), harboured a few copy number alterations with losses of whole or part of chromosome 13 including the RB1 gene (n = 8) and chromosome 16 (n = 6). CONCLUSION: We report a recurrent loss of RB1 (13q) as a possible driver molecular event in OM indicating a relationship between OM and other lesions of the spectrum of the so-called '13q/RB1' family of tumours. We did not identify a role for the Wnt/beta-catenin signalling pathway, as has been proposed in a recent study. LEF-1 could be a potential sensitive and specific marker of OM and should be used in the differential diagnosis between OM, superficial acral fibromyxoma, and the CD34-positive fibrosing family of tumours.

Machine-learning approach for prediction of pT3a upstaging and outcomes of localized renal cell carcinoma (UroCCR-15).

OBJECTIVES: To assess the impact of pathological upstaging from clinically localized to locally advanced pT3a on survival in patients with renal cell carcinoma (RCC), as well as the oncological safety of various surgical approaches in this setting, and to develop a machine-learning-based, contemporary, clinically relevant model for individual preoperative prediction of pT3a upstaging. MATERIALS AND METHODS: Clinical data from patients treated with either partial nephrectomy (PN) or radical nephrectomy (RN) for cT1/cT2a RCC from 2000 to 2019, included in the French multi-institutional kidney cancer database UroCCR, were retrospectively analysed. Seven machine-learning algorithms were applied to the cohort after a training/testing split to develop a predictive model for upstaging to pT3a. Survival curves for disease-free survival (DFS) and overall survival (OS) rates were compared between PN and RN after G-computation for pT3a tumours. RESULTS: A total of 4395 patients were included, among whom 667 patients (15%, 337 PN and 330 RN) had a pT3a-upstaged RCC. The UroCCR-15 predictive model presented an area under the receiver-operating characteristic curve of 0.77. Survival analysis after adjustment for confounders showed no difference in DFS or OS for PN vs RN in pT3a tumours (DFS: hazard ratio [HR] 1.08, P = 0.7; OS: HR 1.03, P > 0.9). CONCLUSIONS: Our study shows that machine-learning technology can play a useful role in the evaluation and prognosis of upstaged RCC. In the context of incidental upstaging, PN does not compromise oncological outcomes, even for large tumour sizes.

Oncocytoma on renal mass biopsy: is it still the same histology when surgery is performed? Results from UroCCR-104 study.

PURPOSE: To describe clinical features of patients with oncocytoma on renal biopsy (RMB), correlation with final histology on surgically treated patients, and predictive factors of discrepancy between RMB and final histology. METHODS: This was a retrospective study conducted in the framework of the UroCCR project (NCT03293563). All tumors with oncocytoma on RMB were selected and all pathological reports were reviewed. Patients with the RMB simultaneously performed with a focal treatment, synchronous bilateral tumors and ambiguous RMB report were excluded. Discrepancy between RMB and definitive histology was evaluated using a uni- and multivariable logistic regression analyses model. RESULTS: Overall, 119 tumors with oncocytoma on RMB, from 15 centers, were included. Of those, 54 (45.4%) had upfront surgery and 65 (54.6%) had active surveillance (AS). In renal masses with initial active surveillance, with a median follow-up of 28 months, 23 (19.3%) underwent surgery, 4 (3.4%) received focal treatment and 38 (31.9%) remained on AS. On final pathology, only 51 of the 75 surgically treated tumors (68.0%) had oncocytoma, while 24 presented malignant tumors (mainly chromophobe carcinoma (19.2%), and hybrid oncocytic/chromophobe tumor (HOCT) (6.8%)) leading to a discrepancy of 32.0% between RMB and final pathology. The only predictive factor of a discrepancy between RMB and definitive histology was a biopsy done outside of the center (Odds ratio: 3.22 [95%-confidence interval: 1.08-9.61], p = 0.03). CONCLUSION: Despite the increase of RMB in more and more centers, histologic discrepancy between RMB and definitive histology remains significant. This information should be discussed with patients and taken into consideration before treatment decision.

Comprehensive study of nine novel cases of TFEB-amplified renal cell carcinoma: an aggressive tumour with frequent PDL1 expression.

AIMS: First described in 2014, renal cell carcinoma (RCC) with TFEB amplification (6p21) is a rare molecular subgroup whose diagnosis is challenging. The prognosis and therapeutic implications remain unclear. METHODS: We report here the clinical, histological, immunohistochemical, and genetic features of nine novel cases. The pathological and immunohistochemical features were centrally reviewed by expert uropathologists. Fluorescence in situ hybridisation (FISH) confirmed the diagnosis and comparative genomic hybridisation (CGH) was performed to determine quantitative genomic alterations. We also performed an exhaustive review of the literature and compiled our data. RESULTS: TFEB-amplified RCC were locally advanced, with initial lymph node involvement in one case and liver metastasis in another case. They were high-grade eosinophilic tumours with papillary/pseudopapillary architecture, frequent positivity for melanocytic markers, and frequent PDL1 expression. FISH demonstrated high-level TFEB amplification in six cases. One case showed concomitant TFEB translocation. CGH analysis identified complex alterations with frequent losses of 1p, 2q, 3p, 6p, and frequent 6p and 8q gains. VEGFA coamplification was identified in all cases with a lower level than TFEB. The prognosis was poor, with five patients having lymph node or distant metastases. CONCLUSION: TFEB-amplified RCC is a rare molecular subgroup with variable morphology whose diagnosis is confirmed by FISH analysis. The complex alterations identified by CGH are consistent with an aggressive clinical behaviour. The coamplification of VEGFA and the expression of PDL1 could suggest a potential benefit from antiangiogenics and targeted immunotherapy in combination for these aggressive tumours.

Cancer-associated fibroblasts in renal cell carcinoma: implication in prognosis and resistance to anti-angiogenic therapy.

OBJECTIVES: To investigate the role of cancer-associated fibroblasts (CAFs) in clear cell renal cell carcinoma (ccRCC) with respect to tumour aggressiveness, metastasis development, and resistance to anti-angiogenic therapy (vascular endothelial growth factor receptor-tyrosine kinase inhibitors [VEGFR-TKI]). PATIENTS AND METHODS: Our study involved tissue samples from three distinct and independent cohorts of patients with ccRCC. The presence of CAFs and tumour lymphangiogenesis was investigated, respectively, by transcriptional signatures and then correlated with tumour development and prognosis. The effect of these CAFs on tumour cell migration and VEGFR-TKI resistance was analysed on co-cultures of ccRCC cells with CAFs. RESULTS: Results from our cohorts and from in silico investigations showed that VEGFR-TKI significantly increase the number of CAFs in tumours. In the same populations of patients with ccRCC, the proportion of intra-tumoral CAFs correlated to shorter disease-free and overall survival. The presence of CAFs was also correlated with lymphangiogenesis and lymph node metastasis. CAFs increased the migration and decreased the VEGFR-TKI-dependent cytotoxic effect of tumour cells. CONCLUSIONS: Our results show that VEGFR-TKI promote the development of CAFs, and CAFs favour tumour aggressiveness, metastatic dissemination, and resistance to treatment in ccRCC. CAFs could represent a new therapeutic target to fight resistance to treatment of ccRCC. Targeting CAF and immunotherapies combination are emerging as efficient treatments in many types of solid tumours. Our results highlight their relevance in ccRCC.

Pleomorphic Onychomatricoma: A Mimicker of Malignancy.

Pleomorphic onychomatricoma is a rare condition mimicking malignant neoplasms. Given its rarity, the diagnostic and prognostic criteria of this condition are not well established. The aim of this study was to characterize a series of 6 cases of pleomorphic onychomatricoma. In 3 cases the submitting clinical diagnosis was subungual squamous cell carcinoma. For all 6 cases, nail clipping showed typical features of onychomatricoma as a free-edge thickening and pitting of the nail plate with an additional feature of projecting line pattern. Pleomorphic onychomatricoma was diagnosed based on moderate-severe cytological atypia, yet degenerative-appearing with multinucleation or smudged chromatin, no mitotic activity or necrosis, and a Ki67 proliferative index inferior to 5% overall. Other finding s included epithelioid multinucleated cells with deeply eosinophilic cytoplasm mimicking epithelioid malignant cells, overexpression of Ki67 and p53 on atypical cells and diffuse expression of p16. This study describes additional criteria in pleomorphic onychomatricoma, permitting a wider recognition in order to avoid inappropriate treatment.

MiTF/TFE Translocation Renal Cell Carcinomas: From Clinical Entities to Molecular Insights.

MiTF/TFE translocation renal cell carcinoma (tRCC) is a rare and aggressive subtype of RCC representing the most prevalent RCC in the pediatric population (up to 40%) and making up 4% of all RCCs in adults. It is characterized by translocations involving either TFE3 (TFE3-tRCC), TFEB (TFEB-tRCC) or MITF, all members of the MIT family (microphthalmia-associated transcriptional factor). TFE3-tRCC was first recognized in the World Health Organization (WHO) classification of kidney cancers in 2004. In contrast to TFEB-tRCC, TFE3-tRCC is associated with many partners that can be detected by RNA or exome sequencing. Both diagnoses of TFE3 and TFEB-tRCC are performed on morphological and immunohistochemical features, but, to date, TFE break-apart fluorescent in situ hybridization (FISH) remains the gold standard for diagnosis. The clinical behavior of tRCC is heterogeneous and more aggressive in adults. Management of metastatic tRCC is challenging, especially in the younger population, and data are scarce. Efficacy of the standard of care-targeted therapies and immune checkpoint inhibitors remains low. Recent integrative exome and RNA sequencing analyses have provided a better understanding of the biological heterogeneity, which can contribute to a better therapeutic approach. We describe the clinico-pathological entities, the response to systemic therapy and the molecular features and techniques used to diagnose tRCC.

RBM10-TFE3 fusions: A FISH-concealed anomaly in adult renal cell carcinomas displaying a variety of morphological and genomic features: Comprehensive study of six novel cases.

The accurate diagnosis of Xp11-translocation renal cell carcinoma (RCC) in adults is challenging. TFE3 (located on chromosome X) fuses with a partner gene generally located on another chromosome. In rare cases TFE3 may fuse with a neighboring gene: RBM10. Because TFE3 false-positive immunostaining is a common pitfall in many laboratories, demonstration of the chromosomal rearrangement is required in order to ascertain the diagnosis. Fluorescence in situ hybridization (FISH)-that has been considered as the gold standard method-reaches its limits for detecting small Xp11 paracentric inversions. We performed a comprehensive clinical, histological and genomic study of six novel cases of RCC with RBM10-TFE3 fusion. Using FISH, TFE3 rearrangement was equivocal in one case and negative in others. RBM10-TFE3 fusion was discovered using targeted RNA sequencing (RNASeq). As all the previously reported cases (mean age: 50), the six patients were adults (mean age: 42), suggesting an epidemiologic difference between RBM10-TFE3 RCC and tumors harboring some other partner genes, such as ASPSCR1 that rather occur in children. Array-comparative genomic hybridization showed several alterations, notably a gain of 17q in four cases with papillary features and loss of 3p in one case with clear cells. Our study demonstrates that, though rare among adult cases of RCC, RBM10-TFE3 fusion is not exceptional and warrants appropriate molecular detection. Notably, it would be worthy to systemically investigate by RNASeq challenging RCC with type-2 papillary features and 17q gain.

Hypoxia and hypoxia-inducible factors promote the development of neointimal hyperplasia in arteriovenous fistula.

KEY POINTS: Patients with end-stage renal failure need arteriovenous fistulas (AVF) to undergo dialysis. However, AVFs present a high rate of failure as a result of excessive venous thickness. Excessive venous thickness may be a consequence of surgical dissection and change in oxygen concentration within the venous wall. We show that venous cells adapt their metabolism and growth depending on oxygen concentration, and drugs targeting the hypoxic response pathway modulate this response in vitro. We used the same drugs on a mouse model of AVF and show that direct or indirect inhibition of the hypoxia-inducible factors (HIFs) help decrease excessive venous thickness. Hypoxia and HIFs can be targets of therapeutic drugs to prevent excessive venous thickness in patients undergoing AVF surgical creation. ABSTRACT: Because the oxygen concentration changes in the venous wall, surrounding tissue and the blood during surgical creation of arteriovenous fistula (AVF), we hypothesized that hypoxia could contribute to AVF failure as a result of neointimal hyperplasia. We postulated that modulation of the hypoxia-inducible factors (HIF) with pharmacological compounds could promote AVF maturation. Fibroblasts [normal human fibroblasts (NHF)], smooth muscle cells [human umbilical vein smooth muscle cells (HUVSMC)] and endothelial cells [human umbilical vein endothelial cells (HUVEC)], representing the three layers of the venous wall, were tested in vitro for proliferation, cell death, metabolism, reactive oxygen species production and migration after silencing of HIF1/2-α or after treatment with deferioxamine (DFO), everolimus (Eve), metformin (Met), N-acetyl-l-cysteine (NAC) and topoisomerase I (TOPO), which modulate HIF-α stability or activity. Compounds that were considered to most probably modify intimal hyperplasia were applied locally to the vessels in a mouse model of aortocaval fistula. We showed, in vitro, that NHF and HUVSMC can adapt their metabolism and thus their growth depending on oxygen concentration, whereas HUVEC appears to be less flexible. siHIF1/2α, DFO, Eve, Met, NAC and TOPO can modulate metabolism and proliferation depending on the cell type and the oxygen concentration. In vivo, siHIF1/2α, Eve and TOPO decreased neointimal hyperplasia by 32%-50%, 7 days after treatment. Within the vascular wall, hypoxia and HIF-1/2 mediate early failure of AVF. Local delivery of drugs targeting HIF-1/2 could inhibit neointimal hyperplasia in a mouse model of AVF. Such compounds may be delivered during the surgical procedure for AVF creation to prevent early AVF failure.

Experimental and computational modeling for signature and biomarker discovery of renal cell carcinoma progression.

BACKGROUND: Renal Cell Carcinoma (RCC) is difficult to treat with 5-year survival rate of 10% in metastatic patients. Main reasons of therapy failure are lack of validated biomarkers and scarce knowledge of the biological processes occurring during RCC progression. Thus, the investigation of mechanisms regulating RCC progression is fundamental to improve RCC therapy. METHODS: In order to identify molecular markers and gene processes involved in the steps of RCC progression, we generated several cell lines of higher aggressiveness by serially passaging mouse renal cancer RENCA cells in mice and, concomitantly, performed functional genomics analysis of the cells. Multiple cell lines depicting the major steps of tumor progression (including primary tumor growth, survival in the blood circulation and metastatic spread) were generated and analyzed by large-scale transcriptome, genome and methylome analyses. Furthermore, we performed clinical correlations of our datasets. Finally we conducted a computational analysis for predicting the time to relapse based on our molecular data. RESULTS: Through in vivo passaging, RENCA cells showed increased aggressiveness by reducing mice survival, enhancing primary tumor growth and lung metastases formation. In addition, transcriptome and methylome analyses showed distinct clustering of the cell lines without genomic variation. Distinct signatures of tumor aggressiveness were revealed and validated in different patient cohorts. In particular, we identified SAA2 and CFB as soluble prognostic and predictive biomarkers of the therapeutic response. Machine learning and mathematical modeling confirmed the importance of CFB and SAA2 together, which had the highest impact on distant metastasis-free survival. From these data sets, a computational model predicting tumor progression and relapse was developed and validated. These results are of great translational significance. CONCLUSION: A combination of experimental and mathematical modeling was able to generate meaningful data for the prediction of the clinical evolution of RCC.

UBTD1 is a mechano-regulator controlling cancer aggressiveness.

Ubiquitin domain-containing protein 1 (UBTD1) is highly evolutionary conserved and has been described to interact with E2 enzymes of the ubiquitin-proteasome system. However, its biological role and the functional significance of this interaction remain largely unknown. Here, we demonstrate that depletion of UBTD1 drastically affects the mechanical properties of epithelial cancer cells via RhoA activation and strongly promotes their aggressiveness. On a stiff matrix, UBTD1 expression is regulated by cell-cell contacts, and the protein is associated with ß-catenin at cell junctions. Yes-associated protein (YAP) is a major cell mechano-transducer, and we show that UBTD1 is associated with components of the YAP degradation complex. Interestingly, UBTD1 promotes the interaction of YAP with its E3 ubiquitin ligase ß-TrCP Consequently, in cancer cells, UBTD1 depletion decreases YAP ubiquitylation and triggers robust ROCK2-dependent YAP activation and downstream signaling. Data from lung and prostate cancer patients further corroborate the in cellulo results, confirming that low levels of UBTD1 are associated with poor patient survival, suggesting that biological functions of UBTD1 could be beneficial in limiting cancer progression.

Detection of tetraploidization in chromophobe renal cell carcinoma: Insights and pitfalls.

Chromosomal losses resulting in a marked hypodiploidy are a specificity of chromophobe renal cell carcinoma (ChRCC), the third most frequent type of kidney cancer. Its detection is useful in challenging cases. However some ChRCC, especially the eosinophilic variant, do not exhibit hypodiploidy and deserve to be better explored. Using comparative genomic hybridization (array-CGH) we observed chromosomal gains in five cases of nonmetastatic ChRCC. Our objective was to determine whether these apparent chromosomal gains were instead losses within a near-polyploid genome. We performed a retrospective and prospective molecular study of 26 cases of ChRCC retrieved among 643 renal tumors (2012-2019). All tumors were analyzed using array-CGH (Agilent) and array-CGH (Affymetrix) coupled to single nucleotide polymorphism analysis (array-SNP). In silico manual centralization of the fluorescence ratio, fluorescence in situ hybridization (FISH) and next generation sequencing were made in the five cases suspected of polyploidy. Tetraploidization was observed in 19% of our series of ChRCC. None of the methods used individually could identify both chromosomal losses and tetraploidy. Only the combination of manual recentring of array-CGH and FISH provided relevant results. B-allele frequency results indicated that tetraploidization occurred secondarily to chromosomal losses in four cases while it preceded losses in one case. Tetraploidization is a frequent but underestimated phenomenon in ChRCC that may be overlooked using the individual standard genomic methods. Its potential clinical consequences are not identified yet. Whether the mechanisms that induce chromosomal losses in ChRCC are the same that generate tetraploidization is not known.

Cancer incidence in the vicinity of a waste incineration plant in the Nice area between 2005 and 2014.

INTRODUCTION: Few studies on cancer incidence have been conducted since the adoption of the EU 2000/76/EC waste incineration directive which aimed to limit dioxin emission levels to less than 0.1 ng TEQ/m3 before December 31, 2005. OBJECTIVE: To measure cancer incidence among the population exposed to atmospheric emissions from the waste incineration plant near the town of Nice (South-Eastern France), compared to the unexposed population of the Alpes-Maritimes department (A-M). METHODS: All primary invasive cancers and haematological malignancies diagnosed among AM residents between 2005 and 2014 were recorded. The exposed surface was modeled on an average dioxin deposition model ≥4.25 ng/m2/year. Each case was geolocated and assigned to one of 36 predefined geographic units of exposed area, or one of 462 units in the unexposed area. The adjusted incidence rate, the standardized incidence ratio and the Comparative Morbidity Figure were calculated for two periods: 2005-2009/2010-2014. RESULTS: We recorded 80,865 new cancers in the A-M population. Between 2005 and 2009, we observed a higher incidence among exposed women of acute myeloid leukaemia, myelodysplastic syndromes and myeloma and, among exposed men, of soft tissue sarcomas, myeloma and lung cancer. Between 2010 and 2014, there was no excess incidence among women, while among men incidence of myeloma and lung cancer remained higher. CONCLUSION: Only among men, the incidence of myeloma and lung cancer remained higher in the exposed area during the second period. The EU directive resulting in the limitation of atmospheric emissions from incinerators could explain the decrease in incidence of cancers with protracted latency. Consideration of other risk factors and further data collection will be necessary to validate this hypothesis.

Proliferating Onychomatricoma. Clinical, Dermoscopical, and Pathologic Features of Onychomatricoma New Variant Resembling Onycholemmal/Squamous Cell Carcinoma.

Proliferating onychomatricoma is a new challenging variant of onychomatricoma that can clinically and histologically mimic squamous cell carcinoma/onycholemmal carcinoma. This is a retrospective case series study of the clinicopathologic and dermoscopic features of 6 patients with a pathologic diagnosis of proliferating onychomatricoma, which was conducted in the dermatology and dermatopathology departments of 2 university hospitals and a private nail's dermatology consultation. The clinical, histological, and immunohistochemical features and follow-up of 6 patients with proliferating onychomatricoma were analyzed; we compare our finding with 6 cases of conventional onychomatricoma. The female-to-male ratio was 1:1 with involvement of fingers in 4 and toe in 2. Among the symptoms were verrucous lesion simulating squamous cell carcinoma, nail thickening, periungual erythema, and pain; symptom duration ranged from 5 to 8 years. Clinical, dermoscopical en face free-margin view, and nail-clipping histologic findings reveal a nail wall-like pattern with pitting. Intraoperative, noncontact, polarizing, light dermoscopy was available in 1 case and showed the typical signs of onychomatricoma (OM). Histologically, all cases showed a well-differentiated, infiltrative, squamous, proliferative lesion exhibiting a lobulated and cystic pattern of growth in the dermis. Abrupt keratinization reminiscent of trichilemmal keratinization, but corresponding in fact to keratogenous spheres, was noted as well as a dysmaturative epithelial pattern. No atypical cytomorphological changes were found. Proliferating onychomatricoma is a new variant of onychomatricoma, which can be misdiagnosed as squamous cell carcinoma/onycholemmal carcinoma; its proper recognition may minimize morbidity associated with inappropriate treatment. Proliferating OM can be differentiated from conventional OM clinically by a free-edge wall-like pattern and on histology of nail clipping by the relatively small size of the cavities. Dermoscopic and nail clipping attributes as free-edge honeycomb-like cavities associated with conventional OM are well established and permit a diagnosis of OM without an invasive nail biopsy. The free-edge wall-like pattern is a distinct new dermoscopic and nail-clipping pattern that should raise for the others onychogenic neoplasms and prompt the clinician to obtain a biopsy specimen. In addition to proliferating OM, the differential diagnosis includes a micropapilliferum variant of OM, onychocytic matricoma, and onychocytic carcinoma.

Oxytocin Controls Chondrogenesis and Correlates with Osteoarthritis.

This study investigated the relationship of oxytocin (OT) to chondrogenesis and osteoarthritis (OA). Human bone marrow and multipotent adipose-derived stem cells were cultured in vitro in the absence or presence of OT and assayed for mRNA transcript expression along with histological and immunohistochemical analyses. To study the effects of OT in OA in vivo, a rat model and a human cohort of 63 men and 19 women with hand OA and healthy controls, respectively, were used. The baseline circulating OT, interleukin-6, leptin, and oestradiol levels were measured, and hand X-ray examinations were performed for each subject. OT induced increased aggrecan, collagen (Col) X, and cartilage oligomeric matrix protein mRNA transcript levels in vitro, and the immunolabelling experiments revealed a normalization of Sox9 and Col II protein expression levels. No histological differences in lesion severity were observed between rat OA groups. In the clinical study, a multivariate analysis adjusted for age, body mass index, and leptin levels revealed a significant association between OA and lower levels of OT (odds ratio = 0.77; p = 0.012). Serum OT levels are reduced in patients with hand OA, and OT showed a stimulatory effect on chondrogenesis. Thus, OT may contribute to the pathophysiology of OA.

Comprehensive study of three novel cases of TFEB-amplified renal cell carcinoma and review of the literature: Evidence for a specific entity with poor outcome.

The first case of TFEB-amplified renal cell carcinoma was published in 2014. Since then, 29 additional cases have been described. The prognostic and therapeutic implications of this rare entity remain to be determined. We describe here the clinical, histological, and genetic features of three novel cases, and the first complete literature review. Four tumors were examined from three patients selected from the large collection of genetically characterized renal tumors in our institution. The pathological and immunohistochemical features were centrally reviewed by a uropathologist. Quantitative and structural genomic abnormalities were analyzed using comparative genomic hybridization, fluorescence in situ hybridization, and next generation sequencing. The three cases showed high-level amplification but no translocation of TFEB. Histologically, two tumors showed a papillary or pseudopapillary architecture. They did not show similarities with renal cell carcinoma harboring translocation of TFEB. The tumors were locally advanced high-grade lesions. They exhibited a metastatic course, which was rapidly leading to death in one patient. A second patient developed metastatic disease that did not respond to four lines of targeted treatments. The third patient had a protracted history of pulmonary and cardiac metastases. Complete clinical and biological data were examined and compared to those of the reported cases. Within the classification of renal tumors, TFEB-amplified renal cell carcinoma may constitute a novel entity characterized histologically by high-grade, papillary or pseudopapillary architecture, and necrotic remodeling and clinically by a poor outcome. Its pathogenesis has to be further characterized to develop appropriate targeted therapy.

Melanocytes Pattern in the Normal Nail, With Special Reference to Nail Bed Melanocytes.

Previous studies of the density of melanocytes in the normal nail bed have had conflicting results. This is unfortunate because knowing the normal values might help the difficult distinction between a benign subungual melanotic macule and an early melanoma in situ. Five specimens of normal nail unit were analyzed. On hematoxylin and eosin-stained sections the melanocytes were undetectable. We defined the melanocyte count (MC) as the number of melanocytes per 1-mm stretch of nail epithelium. The mean MC for nail matrix was 6.86 with a range of 4-14. The melanocytes were irregularly scattered in the basal and suprabasilar layer of the matrix epithelium. Abundant and uneven cytoplasmic dendrites were focally observed in the matrix. The MC for the nail bed ranged from 0 to 5 with a mean of 0.43. The melanocytes were restricted to the basal layer with thin cytoplasmic dendrites. Two cases showed a complete absence of melanocytes in the nail bed. In the ventral portion of the proximal nail fold, called the eponychium, the MC ranged between 0 and 5/mm with a mean of 2.27/mm. In conclusion, we discovered foci in normal nail beds, in which the melanocytic density can be relatively high and reach the level seen in the matrix. HMB45 is more sensitive than Microphtalmia-associated transcription factor (MITF) for the evaluation of intraepithelial melanocytic density of the nail unit. If MITF is used alone in the nail bed, its weak sensitivity may result in a false-negative interpretation and may be wrongly reassuring in the evaluation of early melanomas. On hematoxylin and eosin sections, basal and suprabasal nail keratinocytes are sometimes crowded, showing oval or elongated dark-staining nucleus and a clear cytoplasm and mimics a melanocytic proliferation. On HMB45 or Melan A staining, the morphology and the distribution of the dendrites of matrical melanocytes can mimic the dendritic pattern usually described in acral melanoma. Therefore, the interpretation of nail melanocytic atypia must be prudent.

CXCL7 is a predictive marker of sunitinib efficacy in clear cell renal cell carcinomas.

BACKGROUND: Sunitinib is one of the first-line standard treatments for metastatic clear cell renal cell carcinoma (ccRCC) with a median time to progression shorter than 1 year. The objective is to discover predictive markers of response to adapt the treatment at diagnosis. METHODS: Prospective phase 2 multi-centre trials were conducted in ccRCC patients initiating sunitinib (54 patients) or bevacizumab (45 patients) in the first-line metastatic setting (SUVEGIL and TORAVA trials). The plasmatic level of CXCL7 at baseline was correlated with progression-free survival (PFS). RESULTS: The cut-off value of CXCL7 for PFS was 250 ng ml-1. Patients with CXCL7 plasmatic levels above the cut-off at baseline (250 ng ml-1) had a significantly longer PFS (hazard ratio 0.323 (95% confidence interval 0.147-0.707), P=0.001). These results were confirmed in a retrospective validation cohort. The levels of CXCL7 did not influence PFS of the bevacizumab-treated patients. CONCLUSIONS: CXCL7 may be considered as a predictive marker of sunitinib efficacy for ccRCC patients.