Various histological variants of papillary thyroid carcinoma have been reported, some with clinical implications, some with peculiar, sometimes misleading morphologies. One of these rare and poorly characterized variants is papillary thyroid carcinoma with nodular fasciitis-like stroma, of which fewer than 30 cases have been documented, mostly as isolated reports. It is a dual tumor comprising a malignant epithelial proliferation that harbors typical features of conventional papillary thyroid carcinoma, admixed with a prominent mesenchymal proliferation resembling nodular fasciitis or fibromatosis. Thus, the terms papillary thyroid carcinoma with nodular fasciitis-like stroma and papillary thyroid carcinoma with fibromatosis-like stroma are used interchangeably; however, the former term suggests a self-limited and regressing disease, whereas the latter one suggests a recurrent and potentially aggressive one. Better genetic and ultrastructural characterization could lead to more appropriate terminology and management. We performed detailed clinicopathological and molecular analyses of two cases of PTC with prominent mesenchymal proliferation that developed in the thyroid gland of two male patients aged 34 and 48. In both cases, the epithelial component harbored a heterozygous somatic activating BRAF mutation (p.V600E). Also, in both cases, the mesenchymal component showed typical aberrant nuclear and cytoplasmic immunoreactivity for β-catenin and harbored a heterozygous somatic activating mutation in the corresponding CTNNB1 gene (p.S45P). This mutation has never been reported in thyroid stroma; in other tissues, it is typical of desmoid-type fibromatosis rather than nodular fasciitis-like stroma. We therefore propose that in cases of papillary thyroid carcinoma with a prominent mesenchymal component, mutations in CTNNB1 should be sought; when they are present, the term 'papillary thyroid carcinoma with desmoid-type fibromatosis' should be used. As the mesenchymal component of these tumors is not expected to concentrate radioactive iodine, special considerations apply to clinical evaluation and follow-up, which should be brought to the attention of the treating specialist.

Several authors have demonstrated an increased number of mitotic figures in breast cancer resection specimen when compared with biopsy material. This has been ascribed to a sampling artifact where biopsies are (i) either too small to allow formal mitotic figure counting or (ii) not necessarily taken form the proliferating tumor periphery. Herein, we propose a different explanation for this phenomenon. Biopsy and resection material of 52 invasive ductal carcinomas was studied. We counted mitotic figures in 10 representative high power fields and quantified MIB-1 immunohistochemistry by visual estimation, counting and image analysis. We found that mitotic figures were elevated by more than three-fold on average in resection specimen over biopsy material from the same tumors (20 ± 6 vs 6 ± 2 mitoses per 10 high power fields, P ¼ 0.008), and that this resulted in a relative diminution of post-metaphase figures (anaphase/telophase), which made up 7% of all mitotic figures in biopsies but only 3% in resection specimen (Po0.005). At the same time, the percentages of MIB-1 immunostained tumor cells among total tumor cells were comparable in biopsy and resection material, irrespective of the mode of MIB-1 quantification. Finally, we found no association between the size of the biopsy material and the relative increase of mitotic figures in resection specimen. We propose that the increase in mitotic figures in resection specimen and the significant shift towards metaphase figures is not due to a sampling artifact, but reflects ongoing cell cycle activity in the resected tumor tissue due to fixation delay. The dwindling energy supply will eventually arrest tumor cells in metaphase, where they are readily identified by the diagnostic pathologist. Taken together, we suggest that the rapidly fixed biopsy material better represents true tumor biology and should be privileged as predictive marker of putative response to cytotoxic chemotherapy.

The membrane-bound serine protease CAP2/Tmprss4 has been previously identified in vitro as a positive regulator of the epithelial sodium channel (ENaC). To study its in vivo implication in ENaC-mediated sodium absorption, we generated a knockout mouse model for CAP2/Tmprss4. Mice deficient in CAP2/Tmprss4 were viable, fertile, and did not show any obvious histological abnormalities. Unexpectedly, when challenged with sodium-deficient diet, these mice did not develop any impairment in renal sodium handling as evidenced by normal plasma and urinary sodium and potassium electrolytes, as well as normal aldosterone levels. Despite minor alterations in ENaC mRNA expression, we found no evidence for altered proteolytic cleavage of ENaC subunits. In consequence, ENaC activity, as monitored by the amiloride-sensitive rectal potential difference (ΔPD), was not altered even under dietary sodium restriction. In summary, ENaC-mediated sodium balance is not affected by lack of CAP2/Tmprss4 expression and thus, does not seem to directly control ENaC expression and activity in vivo.

28 29 Blockade of inhibitory receptors (IR), overexpressed by T-cells, can activate anti-tumor 30immune responses resulting in the most promising therapeutic approaches, particularly in 31 bladder cancer, currently able to extend patient survival. Thanks to their ability to cross-32 present antigens to T cells, dendritic cells (DC) are an immune cell population playing a 33 central role in the generation of effective anti-tumor T-cell responses. While function and 34 expression of IRs have been mostly investigated in T cells, very few data are available for 35 DC. Therefore, we analyzed whether DC may express IRs able to decrease their functions. 36For that purpose, we investigated several IR: PD-1, CTLA-4, BTLA, TIM-3 and CD160, in 37 patients. pDC and conventional CD1c + and CD141 + DC were identified using a combination 89 of phenotypic markers ( Supplementary Fig. 1) and expression of IR was determined. PD-1, 90CTLA-4 and CD160 were not expressed by any subtype of DC from HD or UCa patients 91 (data not shown). In contrast, BTLA was observed in all DC subsets, albeit at a very low level 92 in CD1c + DC and TIM-3 was only expressed by CD1c + and CD141 + DC, in HD. Comparison 93 to UCa patients showed that BTLA was significantly overexpressed by CD141 + DC and pDC, 94Chevalier et al. European Urology -Revised manuscript whereas only a slight increase of TIM-3 expression was observed in CD141 + DC (Fig. 1A). 95This result suggests that bladder tumor microenvironment may increase BTLA and TIM-3 96 expression on DC. In order to have more insights into BTLA and TIM-3 expression by DC, 97 we segregated the data from UCa patients in two groups, according to the stage of the disease 98 (Supplementary Table 1): non-muscle invasive bladder cancer (NMIBC) and MIBC patients. 99A significantly higher expression of TIM-3 was only found in CD141 + DC from MIBC 100 patients as compared to HD, suggesting that UCa-mediated overexpression of TIM-3 is later 101 than for BTLA, which was overexpressed in CD141 + DC and pDC from both types of patients 102 (Supplementary Fig. 2). 103Seeking further evidence that BTLA and TIM-3 expression may be altered by the bladder 104 tumor microenvironment, we analyzed their expression on tissue-infiltrating DC 105 subpopulations from bladder tumor and paired non-tumoral adjacent tissue from surgical 106 specimen recovered after cystectomy. Since DC subtypes from tissue are phenotypically 107 different than circulating DC, we focused on CD14 + CD11c + and CD14 neg CD11c + tissue-108 infiltrating DC [7, 8] (Fig. 1B). Notably, we observed a significant overexpression of TIM-3 109 in both types of bladder DC and a higher frequency of BTLA + CD14 neg CD11c + bladder DC 110 within tumor tissue (Fig. 1C). Similar results were obtained when comparing non-paired 111 tissue samples (Supplementary Fig. 3). 112We next sought to determine whether BTLA and TIM-3 expressed on DC are functional 113 and could lead to an inhibition of DC function, as monitored by cytokine (IL-12, IL-1β and 114 TNF-α...

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