Aberrant microRNA (miR) expression has an important role in tumour progression, but its involvement in bone marrow fibroblasts of multiple myeloma patients remains undefined. We demonstrate that a specific miR profile in bone marrow fibroblasts parallels the transition from monoclonal gammopathy of undetermined significance (MGUS) to myeloma. Overexpression of miR‐27b‐3p and miR‐214‐3p triggers proliferation and apoptosis resistance in myeloma fibroblasts via the FBXW7 and PTEN/AKT/GSK3 pathways, respectively. Transient transfection of miR‐27b‐3p and miR‐214‐3p inhibitors demonstrates a cooperation between these two miRNAs in the expression of the anti‐apoptotic factor MCL1, suggesting that miR‐27b‐3p and miR‐214‐3p negatively regulate myeloma fibroblast apoptosis. Furthermore, myeloma cells modulate miR‐27b‐3p and miR‐214‐3p expression in fibroblasts through the release of exosomes. Indeed, tumour cell‐derived exosomes induce an overexpression of both miRNAs in MGUS fibroblasts not through a simple transfer mechanism but by de novo synthesis triggered by the transfer of exosomal WWC2 protein that regulates the Hippo pathway. Increased levels of miR‐27b‐3p and miR‐214‐3p in MGUS fibroblasts co‐cultured with myeloma cell‐derived exosomes enhance the expression of fibroblast activation markers αSMA and FAP. These data show that the MGUS‐to‐myeloma transition entails an aberrant miRNA profile in marrow fibroblasts and highlight a key role of myeloma cells in modifying the bone marrow microenvironment by reprogramming the marrow fibroblasts' behaviour. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
It was the objective to determine in this retrospective study whether thymidylate synthase (TS), p53, bcl-2, Ki-67 and p27 in Dukes’ stage B and stage C (AJCC/UICC stage II and III) colorectal adenocarcinoma were predictive of disease-free survival (DFS) and overall survival (OS). Paraffin-embedded specimens from 103 patients with colorectal cancer, treated with surgery between October 1994 and September 1999, were examined for TS expression, p53, bcl-2, Ki-67 and p27 using immunohistochemistry; 51 cases were Dukes’ stage B and 52 cases were Dukes’ stage C disease. Adjuvant 5-FU-based chemotherapy was given to all patients, while 31 having rectal malignancy also received pelvic radiotherapy. Data were associated with the recurrence rate and survival. With a median follow-up of 5 years, 38 patients (36.8%) developed recurrence and as many patients (36.8%) died. TS was overexpressed in 16 cases (15.6%), p53 nuclear oncoprotein accumulation in >10% of cells occurred more frequently [61 of 103 cases (59.3%)], positive expression of bcl-2 protein in >10% of cells was observed in 41 of 103 cases (39.9%), 57 patients (55.4%) showed immunohistochemical expression of Ki-67 and there were 75 cases (72.9%) with p27 accumulation. The pathological stage was the only independent prognostic factor for DFS (p = 0.042). Sex, as well as age and biological prognostic factors, had no significant impact value on DFS and OS. A multivariate analysis of OS demonstrated that stage C, p53 negative and Ki-67 positive were associated significantly with an unfavorable outcome and a worse median OS (p = 0.035 and t ratio = 2.48). Some biological characteristics such as p53 and Ki-67 status may provide useful prognostic information in addition to the classical clinicopathological parameters. However, further studies are needed to clarify the value of adopting biological prognostic factors into clinical practice.
A n U n u s u a l , R e c u r r i n g B r e a s t T u m o r W i t h F e a t u r e s o f E c c r i n e S p i r a d e n o m a A Case ReportA new case of breast tumor with features of eccrine spiradenoma is described. This neoplasm is exceedingly rare, because only two cases, arising in breast parenchima, have been previously reported. The patient was a 43-year-old woman and she experienced three local recurrences at 7, 20, and 30 months from the first excision. No distant metastases were observed. Microscopically, the tumor was circumscribed and showed a lobulated pattern. Neoplastic lobules consisted of packed, monotonous, basaloid epithelial cells with round to ovoid nuclei and scant cytoplasm. At the periphery, the lobules were delimitated by smaller cells with dark nuclei.Immunohistochemical reactivity in tumoral cells was found for bothThe breast is a gland embryologically related to salivary and sweat glands; therefore, it is not surprising to note how breast tumors sometimes can show features of differentiation toward these structures. These tumors have to be considered true breast neoplasms with "divergent" differentiation and occur infrequently. Most often, they resemble mixed tumors (pleomorphic adenomas) of the salivary gland; 1 " 7 more rarely they share features of several eccrine sweat gland tumors such as syringomatous tumors, 8 " 12 or exceptionally eccrine spiradenoma 1314 and clear cell hidradenoma. 1415 Such lesions are usually regarded as benign, despite occasional local recurrences; 5710 however, they present difficulties in differential diagnosis. The new case reported below is of a locally aggressive and recurring breast tumor resembling an eccrine spiradenoma in a 43-year-old woman.CASE REPORT A 43-year-old woman presented in June 1993 with a 4-month history of a rapidly growing mass in her left breast, located in the areolar area. Address reprint requests to Prof. Guido Pettinato: Universita di Napoli Federico II, Istituto di Patologia, via S. Pansini 5, 80131, Napoli, Italia.cytokeratin and epithelial membrane antigen; vimentin, muscle-specific actin, glial fibrillary acidic protein, S-100 protein, and carcinoembryonal antigen were all negative. Furthermore, the lesion showed a diffuse positivity for estrogen and progesterone receptors and a high growth fraction labelled by MIB-1 (Ki-67) antibody. These findings, in conjunction with the deep location of the tumor, suggest an origin of the neoplasm from the breast epithelium. Because of a potential local aggressive behavior, the excision of a wide rim of uninvolved breast tissue is recommended. (Key words: Breast tumor; Eccrine spiradenoma; Immunohistochemistry; Steroid receptors; MIB-1) Am J Clin Pathol 1996;106:665-669.Clinical examination suggested a benign lesion and an excisional biopsy was performed.In January 1994, the patient noted two nodules in the scar area; mammography failed to reveal any infiltrating lesions or pathologic calcifications, and a fine-needle aspiration (FNA) cytologic examination indicated a recurrence of the ...
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