Natural killer (NK) cells, effector lymphocytes of the innate immunity, have been shown to be altered in several cancers, both at tissue and peripheral levels. We have shown that in Non-Small Cell Lung Cancer (NSCLC) and colon cancer, tumour associated circulating NK (TA-NK) and tumour infiltrating NK (TI-NK) exhibit pro-angiogenic phenotype/functions. However, there is still a lack of knowledge concerning the phenotype of peripheral blood (PB) NK (pNK) cells in prostate cancer (PCa). Here, we phenotypically and functionally characterized pNK from PCa patients (PCa TA-NKs) and investigated their interactions with endothelial cells and monocytes/macrophages. NK cell subset distribution in PB of PCa patients was investigated, by multicolor flow cytometry, for surface antigens expression. Protein arrays were performed to characterize the secretome on FACS-sorted pNK cells. Conditioned media (CM) from FACS-sorted PCa pTA-NKs were used to determine their ability to induce pro-inflammatory/pro-angiogenic phenotype/functions in endothelial cells, monocytes, and macrophages. CM from three different PCa (PC-3, DU-145, LNCaP) cell lines, were used to assess their effects on human NK cell polarization in vitro, by multicolor flow cytometry. We found that PCa pTA-NKs acquire the CD56brightCD9+CD49a+CXCR4+ phenotype, increased the expression of markers of exhaustion (PD-1, TIM-3) and are impaired in their degranulation capabilities. Similar effects were observed on healthy donor-derived pNK cells, exposed to conditioned media of three different PCa cell lines, together with increased production of pro-inflammatory chemokines/chemokine receptors CXCR4, CXCL8, CXCL12, reduced production of TNFα, IFNγ and Granzyme-B. PCa TA-NKs released factors able to support inflammatory angiogenesis in an in vitro model and increased the expression of CXCL8, ICAM-1, and VCAM-1 mRNA in endothelial cells. Secretome analysis revealed the ability of PCa TA-NKs to release pro-inflammatory cytokines/chemokines involved in monocyte recruitment and M2-like polarization. Finally, CMs from PCa pTA-NKs recruit THP-1 and peripheral blood CD14+ monocyte and polarize THP-1 and peripheral blood CD14+ monocyte-derived macrophage towards M2-like/TAM macrophages. Our results show that PCa pTA-NKs acquire properties related to the pro-inflammatory angiogenesis in endothelial cells, recruit monocytes and polarize macrophage to an M2-like type phenotype. Our data provides a rationale for a potential use of pNK profiling in PCa patients.
Purpose: We describe a select group of asymptomatic patients w i t h fragments a n d dust 3 months after extracorporeal treatment, who were followed t o evaluate the long-term outcome and therapeutic implications.Materials a n d Methods: A total of 129 patients with dust and residual fragments (less than 4 mm.) at 3 months w a s re-examined at 12 months, and 95 were also evaluated at 2 4 months. Followup examinations consisted of radiographic studies, renal ultrasonography and urine culture. D u s t a n d residual fragments were sought, and patients were defined as free or as h a v i n g persistent lithiasis or stone regrowth. At 24 m o n t h s recurrences in the patients stone-free at 1 2 months also were considered.Results: At the 12-month followup 60 patients (46.5%) were stone-free and 56 (43.5%) still had dust o r residual fragments. The localization of the stones o r fragments at 3 m o n t h s a n d their sizes did not have a significant influence on the stone-free rate but regrowth was greater in patients with stones larger t h a n 1 0 mm. (11 of 40 patients, 27.5% versus 2 of 89,2.2%, p = 0.001). The probability of eliminating residual lithiasis at 12 m o n t h s w a s significantly greater in patients with dust than in those with residual fragments ( 4 2 of 79 patients, 58% versus 18 of 50, 36%, p = 0.026). Regrowth of residual lithiasis w a s observed in 13 patients (10%).Conclusions: Based on o u r results, we do not believe that patients with fragments require systematic re-treatment in the short term but t h e y m a y be followed long t e r m and re-treated if symptoms persist or stones recur.KEY WORDS: extracorporeal shockwave lithotripsy, calculiThe therapeutic efficacy of shock wave lithotripsy in the treatment of renal and ureteral stones is undisputed 15 years after its introduction in clinical practice.' This method represents a revolution in the management of patients with lithiasis.2 However, since the first large series was presented, evaluation of the results of extracorporeal treatment has been controversial. Still more controversial is the approach to patients whose stones are not completely eliminated but in whom small fragments (less than 5 mm.) or dust persists, defined by some authors as clinically insignificant residual fragments.3-7 Such fragments are found at the renal level in 851c of patients at discharge after extracorporeal treatment, and are considered a factor that favors progression of lithiasis,R.g and an increased risk for significant symptomatic episodes or need for intervention.10 We describe a select group of asymptomatic patients with fragments and dust 3 months after extracorporeal treatment, who were followed to evaluate the long-term outcome and therapeutic implications. PATIENTS AND METHODSFor this study we considered 467 patients who underwent treatment with Dornier HM3 modified and MPL 9000 lithotriptors for a single radiopaque renal stone 15 mm. or less between 1991 and 1994. Other selection criteria were the absence of morphological alterations of the ...
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