Rare skin appendage tumour on the right leg: a case of primary cutaneous cribriform carcinoma.

A woman in her 60s presented with a longstanding history of a purplish, fleshy and pedunculated nodule on the right shin on a background of bilateral lower limb lymphoedema. A shave biopsy with double curettage of the base of the lesion revealed a nodular tumour with hyperchromatic basaloid cells arranged in a cribriform pattern and encircling eosinophilic substance. Immunohistochemistry staining showed cells positive for pancytokeratin, low molecular weight keratin, BerEP4 and negative for cytokeratin 20. There were no clinical or radiological features of primary visceral malignancy. These histological and immunohistochemical features favour a diagnosis of primary cribriform carcinoma of the skin. This is a rare, indolent skin appendage tumour of presumed apocrine origin with no reported cases in the literature of metastasis or local recurrence after excision.

Hypertonic saline jet nebulization breathing treatments produce a predictable quantity of aerosolized sodium chloride for inhalation.

PURPOSE: The amount of sodium chloride (NaCl) that escapes a nebulizer cup, intended for patient inhalation, during a 5-min hypertonic saline jet nebulization (HSJN) breathing treatment is apparently unknown in the pure and applied scientific literature. This study aimed to address this void by focusing on NaCl mass changes prior to and after a typical HSJN breathing treatment using an ordinary household, medical-grade air compressor. RESEARCH METHODS: Saline solutions of varying concentrations were nebulized to room air for 5 min. Pre- and post-nebulization NaCl concentrations were determined from measured conductivities via calibration curve. The resulting data were used to quantify NaCl mass changed from the beginning and end of a typical HSJN breathing treatment. MAIN FINDINGS: Conductivity was a reliable metric in NaCl concentrations ranging from 2.10 × 10-1 to 8.16 × 10-3 M. Pre- and post-nebulization NaCl mass differences of 19-114 mg linearly correlated with saline concentration (wt%). The resulting trendline data reasonably predict how much NaCl is available for patient inhalation during a typical HSJN breathing treatment. Linearity in the data suggests that factors such as colligative properties (e.g., osmolarity) have a minimal influence on the amount of NaCl that escapes the nebulizer cup. CONCLUSIONS: These results are the first to quantify how much NaCl escapes a nebulizer cup during a typical HSJN breathing treatment. Furthermore, the results represent a key starting point upon which future studies can be built to explore additional airflow rates, kinetics, and temperature effects. Collectively, these findings will play a critical role in ascertaining the mechanism of action in hypertonic saline breathing treatments.

CD27 mediates interleukin-2-independent clonal expansion of the CD8+ T cell without effector differentiation.

The clonal expansion of antigen-specific CD8+ T cells in response to microbial infections is essential for adaptive immunity. Although IL-2 has been considered to be primarily responsible for this process, quantitatively normal expansion occurs in the absence of IL-2 receptor signaling. Here, we show that ligating CD27 on CD8+ T cells that have been stimulated through the T cell receptor causes their expansion in the absence of IL-2 by mediating two distinct cellular processes: enhancing cell cycling and promoting cell survival by maintaining the expression of IL-7 receptor alpha. This pathway for clonal expansion of the CD8+ T cell is not associated with the development of a capacity either for production of IFN-gamma or for cytotoxic T lymphocyte function and, therefore, is uncoupled from differentiation. Furthermore, ligating CD27 increases the threshold concentration at which IL-2 induces IFN-gamma-producing capability by the CD8+ T cell, suggesting that CD27 signaling may suppress effector differentiation. Finally, CD8+ T cells that have been stimulated by the TCR/CD27 pathway maintain their capacity for subsequent expansion and effector differentiation in response to a viral challenge in vivo. Thus, the TCR/CD27 pathway enables the CD8+ T cell to replicate by a process of self-renewal, which may contribute to the continuous generation of new effector CD8+ T cells in persistent viral infections.

The rationale for the IL-2-independent generation of the self-renewing central memory CD8+ T cells.

Clones of CD8+ T cells that have been selected in the primary response must have a mechanism by which they can continuously or intermittently generate new effector cells. Several years ago, this mechanism was proposed to involve a self-renewing, stem cell-like subset that could avoid the differentiating effects of interleukin-2 (IL-2). The model considered the stem cell subset to be contained within the central memory population of CD8+ T cells (T(CM)). This proposal was inconsistent with subsequent findings suggesting that all antigen-activated CD8+ T cells differentiated to effector cells (T(EFF)) during the primary response and that T(CM) developed during the memory phase by de-differentiating from effector memory cells (T(EM)). However, findings have since been reported that support the stem cell model. First, studies indicate that T(EM) do not serve as the precursors of T(CM). Second, transcriptional repressors of IL-2 signaling do enhance the memory response. Third, memory cells lacking effector functions and with a capacity to replicate in a secondary response develop in the absence of signaling through the IL-2/IL-15 receptor. Taken together, these findings suggest that antigen-activated CD8+ T cells with a stem cell-like capability for maintaining proliferative potential develop by an unknown IL-2-independent process. The challenge is now to identify this unknown pathway of clonal expansion.

BCL6b mediates the enhanced magnitude of the secondary response of memory CD8+ T lymphocytes.

A characteristic of the secondary response of CD8(+) T cells that distinguishes it from the primary response is the generation of greater numbers of effector cells. Because effector CD8(+) T cells are derived from a pool of less differentiated, replicating cells in secondary lymphoid organs, and because IL-2 mediates effector differentiation, the enhanced secondary response may reflect the enlargement of this generative pool by the transient repression of IL-2-mediated differentiation. We have examined for this function the transcriptional repressor BCL6b, a homologue of BCL6 that represses IL-2-induced B cell differentiation. BCL6b is expressed in a small subset of antigen-experienced CD8(+) T cells. Ectopic expression of BCL6b in CD8(+) T cells diminishes their growth in response to IL-2 in vitro. Female mice in which the BCL6b gene has been interrupted have normal primary responses of CD8(+) T cells to infection with vaccinia expressing the H-Y epitope, Uty, but Uty-specific, BCL6b(-/-), memory CD8(+) T cells have diminished recall proliferative responses to this epitope in vitro. BCL6b(-/-) mice also have normal primary CD8(+) T cell responses to influenza infection, but nucleoprotein peptide-specific, BCL6b(-/-), memory CD8(+) T cells have a cell autonomous defect in the number of effector cells generated in response to reinfection. Therefore, BCL6b is required for the enhanced magnitude of the secondary response of memory CD8(+) T cells.