Concurrent intestinal plasmablastic lymphoma and diffuse large B-cell lymphoma with a clonal relationship: a case report and literature review.

Herein, we report a case of plasmablastic lymphoma (PBL) and diffuse large B-cell lymphoma (DLBCL) that occurred concurrently in the large intestine. An 84-year-old female presented with a palpable rectal tumor and ileocecal tumor observed on imaging analyses. Endoscopic biopsy of both lesions revealed lymphomatous round cells. Hartmann's operation and ileocecal resection were performed for regional control. The ileocecal lesion consisted of a proliferation of CD20/CD79a-positive lymphoid cells, indicative of DLBCL. In contrast, the rectal tumor showed proliferation of atypical cells with pleomorphic nuclei and abundant amphophilic cytoplasm, with immunohistochemical findings of CD38/CD79a/MUM1/MYC (+) and CD20/CD3/CD138/PAX5 (-). Tumor cells were positive for Epstein-Barr virus- encoded RNA based on in situ hybridization and MYC rearrangement in fluorescence in situ hybridization analysis. These findings indicated the rectal tumor was most likely a PBL. Sequencing analysis for immunoglobulin heavy variable genes indicated a common B-cell origin of the two sets of lymphoma cells. This case report and literature review provide new insights into PBL tumorigenesis.

IgG4-related retroperitoneal fibrosis induced by nivolumab and ipilimumab in a patient with non-small cell lung cancer: A case report.

IgG4-related diseases are adverse events that occur after receiving treatment with immune checkpoint inhibitors (ICI). This study reports the first case of IgG4-related retroperitoneal fibrosis after the administration of chemotherapy with nivolumab and ipilimumab (NI therapy). An 80-year-old man developed lower abdominal pain eight months after NI therapy was initiated. Although the primary lesion maintained its reduced size on computed tomography, there was an increase in the soft tissue shadows intensity around the abdominal aorta, bladder, and seminal vesicles, suggesting retroperitoneal fibrosis. Blood tests showed elevated IgG4 levels. Computed tomography-guided biopsy of the retroperitoneum showed B cell-dominant lymphocyte infiltration consistent with IgG4-related retroperitoneal fibrosis and characteristic CD8-positive lymphocyte infiltration, suggestive of the involvement of cytotoxic T cells. Based on the clinical, imaging, and pathological findings, the patient was diagnosed with IgG4-related retroperitoneal fibrosis due to ICI. Immunotherapy discontinuation alone did not result in improvement; therefore, steroid therapy was initiated. In clinical practice, IgG4-related retroperitoneal fibrosis can occur as an immune-related adverse event when administering anti-PD-1 and anti-CTLA-4 antibodies for cancer immunotherapy. Early steroid therapy could be effective in controlling this immune-related adverse event.

RPTOR, a novel target of miR-155, elicits a fibrotic phenotype of cystic fibrosis lung epithelium by upregulating CTGF.

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, the most frequent of which is F508del-CFTR. CF is characterized by excessive secretion of pro-inflammatory mediators into the airway lumen, inducing a highly inflammatory cellular phenotype. This process triggers fibrosis, causing airway destruction and leading to high morbidity and mortality. We previously reported that miR-155 is upregulated in CF lung epithelial cells, but the molecular mechanisms by which miR-155 affects the disease phenotype is not understood. Here we report that RPTOR (regulatory associated protein of mTOR, complex 1) is a novel target of miR-155 in CF lung epithelial cells. The suppression of RPTOR expression and subsequent activation of TGF-ß signaling resulted in the induction of fibrosis by elevating connective tissue growth factor (CTGF) abundance in CF lung epithelial cells. Thus, we propose that miR-155 might regulate fibrosis of CF lungs through the increased CTGF expression, highlighting its potential value in CF therapy.

Regulation of miR-155 biogenesis in cystic fibrosis lung epithelial cells: antagonistic role of two mRNA-destabilizing proteins, KSRP and TTP.

Cystic fibrosis (CF) is characterized by a massive pro-inflammatory phenotype in the lung arising from profound expression of inflammatory genes, including interleukin-8 (IL-8). We have previously reported that IL-8 mRNA is stabilized in CF lung epithelial cells, resulting in concomitant hyper-expression of IL-8 protein through elevated expression of miR-155. We therefore investigated what factors promote the enhanced aberrant expression of miR-155 in CF. Here we report for the first time, the role of mRNA-destabilizing inflammatory RNA-binding proteins, KSRP and TTP, in the regulation of miR-155 biogenesis in CF lung epithelial cells. We find that KSRP and TTP have an antagonistic role in miR-155 biogenesis. While KSRP promotes enhanced processing of miR-155 precursors to mature miR-155, over-expression of TTP in the CF lung epithelial cells suppresses expression of miR-155. We find that TTP induces the expression of miR-1, which appears to be a regulator of miR-155 biogenesis in CF lung epithelial cells. These data provide novel insights into the mechanisms that induce hyper-inflammatory phenotype of CF, and are potential candidates for anti-inflammatory therapeutics for CF.

Differential regulation of inflammation by inflammatory mediators in cystic fibrosis lung epithelial cells.

Cystic fibrosis (CF) is due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which cause a massively proinflammatory phenotype in the CF airway. The chemical basis of the inflammation is hyperproduction of interleukin-8 (IL-8) by CF airway epithelial cells, based on both an intrinsic mutation-dependent mechanism and by infection. In infection-free, cultured CF lung epithelial cells, high levels of the microRNA (miR), miR-155, is responsible for hyperexpression of IL-8. However, whether infection-induced IL-8 expression in CF cells is also mediated by miR-155 is not known. We have hypothesized that miR-155 might be a general mediator of enhanced IL-8 expression in CF cells, either in response to other cytokine/chemokine mediators of inflammation, or after exposure to infectious agents. Here we find that a reduction in miR-155 accompanies suppression of IL-8 by either the anti-inflammatory cytokine IL-10 or by inhibition of ambient IL-1ß with a neutralizing antibody. However, attempts to elevate IL-8 levels with either intact bacteria [viz. a mucoid strain of Pseudomonas aeruginosa (PA)], or lipopolysaccharide were unable to elevate miR-155 above its intrinsically high level in the absence of these agents. Instead, in response to PA infection, the CF cells modestly suppress the expression of miR-155, and express a novel set of miRs, including miR-215. We find that ex vivo CF lung epithelial cells also express high levels of both miR-155 and miR-215. The predicted module of infection-induced mRNA targets focuses on activation of the NFκB-signaling pathway, and on the proapoptotic p53-signaling pathway. We interpret these data to suggest that that CF lung epithelial cells respond to PA or bacterial cell products with a novel miR program that may carry with it serious challenges to survival.