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Abstract Peritoneal carcinomatosis (PC) is a complex manifestation of abdominal cancers, with a poor prognosis and limited treatment options. Recent work identifying high concentrations of the cytokine interleukin-6 (IL-6) and its soluble receptor (sIL-6-Rα) in the peritoneal cavity of patients with PC has highlighted this pathway as an emerging potential therapeutic target. This review article provides a comprehensive overview of the current understanding of the potential role of IL-6 in the development and progression of PC. We discuss mechansims by which the IL-6 pathway may contribute to peritoneal tumor dissemination, mesothelial adhesion and invasion, stromal invasion and proliferation, and immune response modulation. Finally, we review the prospects for targeting the IL-6 pathway in the treatment of PC, focusing on common sites of origin, including ovarian, gastric, pancreatic, colorectal and appendiceal cancer, and mesothelioma.

Background:. Fat grafting is an effective treatment for craniofacial deformities. Stromal vascular fraction (SVF) is a concentrated form of adipose derived stem cells that can be isolated from fat. The aim of this clinical trial was to assess the impact of SVF enrichment on craniofacial fat grafting. Methods:. Twelve subjects with at least two regions of craniofacial volume deficit were enrolled, and they underwent fat grafting with SVF-enriched or standard fat grafting to each area. All patients had bilateral malar regions injected with SVF-enriched graft on one side and control standard fat grafting to the contralateral side. Outcome assessments included demographic information, volume retention determined by CT scans, SVF cell populations assessed by flow cytometry, SVF cell viability, complications, and appearance ratings. Follow-up was 9 months. Results:. All patients had improvement in appearance. There were no serious adverse events. There was no significant difference in volume retention between the SVF-enriched and control regions overall (50.3% versus 57.3%, P = 0.269) or comparing malar regions (51.4% versus 56.7%, P = 0.494). Patient age, smoking status, obesity, and diagnosis of diabetes did not impact volume retention. Cell viability was 77.4% ± 7.3%. Cellular subpopulations were 60.1% ± 11.2% adipose derived stem cells, 12.2 ± 7.0% endothelial cells, and 9.2% ± 4.4% pericytes. A strong positive correlation was found between CD146+ CD31-pericytes and volume retention (R = 0.863, P = 0.027). Conclusions:. Autologous fat transfer for reconstruction of craniofacial defects is effective and safe, leading to reliable volume retention. However, SVF enrichment does not significantly impact volume retention.

Objective: The goal of this study was to determine whether antiIL-6Rα block (tocilizumab) will alter the pleural secretome and will diminish tumor-specific immune responses. Methodology: Pleural T cells were isolated from freshly drained pleural effusions (n=6). Autologous pleural tumor was expanded in vitro using the Mammary Epithelial Growth Medium (Lonza). Pleural T cells were stimulated using anti-CD3/CD28 Dynal beads and low dose IL-2 (60 Cetus U/ml) for 2,4,7, 14 or 21 days in the presence of tocilizumab for the last 48h (0, 0.35, 0.72, 1.43, 2.86 and 5.72ug/ml). Pleural T cell effectors were counted and plated on tumor targets at 12.5:1 E:T in the presence of tocilizumab. Results: Ex vivo expanded pleural T cells were effector-memory phenotype (CD45RA-CD27-) and were highly cytotoxic against autologous tumor (89-100%). The majority of CD8+ T cells were central memory (CD45RA-/CD27-) or effector memory (CD45RA+/CD27-); the majority co-expressed granzyme B, perforin, 20-60% expressed PD-1. Most CD4+ co-expressed granzyme B and perforin and were PD-1+, suggesting cytotoxic CD4+ T cells. The presence of tocilizumab reversed tumor EMT but did not alter cytotoxicity. Conclusion: We show that the IL-6/IL-6Rα axis is prominent in MPE, drives tumor growth and inhibits anti-tumor immunity. Pleural T cells are neither exhausted nor dysfunctional but are suppressed by the pleural environment. Ex vivo expanded MPE CD8 and CD4 T cells are highly cytotoxic against autologous tumor. Anti-IL-6Rα block reverses tumor EMT but does not inhibit effector responses.

The immunomodulatory drugs, lenalidomide and pomalidomide yield high response rates in multiple myeloma patients, but are associated with a high rate of thrombocytopenia and increased risk of secondary hematologic malignancies. Here, we demonstrate that the immunomodulatory drugs induce self-renewal of hematopoietic progenitors and upregulate megakaryocytic colonies by inhibiting apoptosis and increasing proliferation of early megakaryocytic progenitors via down-regulation of IKZF1. In this process, the immunomodulatory drugs degrade IKZF1 and subsequently down-regulate its binding partner, GATA1. This results in the decrease of GATA1 targets such as ZFPM1 and NFE2, leading to expansion of megakaryocytic progenitors with concomitant inhibition of maturation of megakaryocytes. The down-regulation of GATA1 further decreases CCND1 and increases CDKN2A expression. Overexpression of GATA1 abrogated the effects of the immunomodulatory drugs and restored maturation of megakaryocytic progenitors. Our data not only provide the mechanism for the immunomodulatory drugs induced thrombocytopenia but also help to explain the higher risk of secondary malignancies and long-term cytopenia induced by enhanced cell cycling and subsequent exhaustion of the stem cell pool.