In this study, flow cytometry was used to evaluate interleukin-6 (IL-6) production by bone marrow mononuclear cells from 47 patients with multiple myeloma (MM) in different clinical stages and 15 patients with monoclonal gammopathy of undetermined significance. In patients with MM, autocrine IL-6 production paralleled the clinical disease stage. The largest proportion of syndecan-1 ؉ /IL-6 ؉ cells was detected in patients with resistant relapse or primary refractory disease, suggesting that tumor progression involves expansion of myeloma cells producing IL-6. The authors assessed autocrine IL-6 production and in vitro proliferation and apoptosis of myeloma cells in 6 myeloma cell clones (MCCs) and in 2 myeloma cell lines, namely IM-9 and U-266-1970, which showed different sensitivities to the addition of exogenous IL-6. Autocrine IL-6 production was observed in IL-6-independent MCC-2, MCC-3, and MCC-5 cloned from patients with aggressive disease and in the IM-9 cell line. In contrast, IL-6-dependent MCC-1, MCC-4, and MCC-6 were syndecan-1 ؉ and IL-6 ؊ . Blocking experiments with anti-IL-6 monoclonal antibody from clone AH65, which binds IL-6-IL-6R␣ complexes, prevented cell proliferation of IL-6 ؉ MCCs. Flow cytometry evaluations after propidium iodide staining revealed different susceptibilities of MCCs to cell death. IL-6-producing MCCs showed minimal spontaneous and dexamethasone-induced apoptosis, whereas a regular amplitude of apoptosis occurred in the IL-6 ؊ MCCs. These data provide evidence that autocrine IL-6 reflects a highly malignant phenotype of myeloma cells. In fact, autocrine IL-6 production and deregulated apoptosis may induce expansion of selective IL-6 ؉ myeloma cells resistant to spontaneous and drug-induced cell death. IntroductionInterleukin 6 (IL-6), a pleiotropic cytokine produced by a variety of cells, is the most important growth factor for human multiple myeloma (MM). 1-3 Several findings support in vivo and in vitro roles for IL-6 in the disease: specifically, (1) serum IL-6 and IL-6R levels were found to correlate with disease activity 4-6 ; (2) therapy with anti-IL-6 monoclonal antibody (mAb) transiently reversed disease manifestations 7 ; (3) in vitro proliferation of myeloma cells was suppressed by neutralizing mAbs to either IL-6 or its cellular receptors [8][9] ; and (4) inactivation of IL-6 messenger RNA by antisense oligonucleotides inhibited proliferation of plasma cells. 10 Furthermore, other cytokines, such as IL-1, IL-3, and granulocytemacrophage colony-stimulating factor, regulate myeloma cell proliferation in synergy with IL-6 11 or by inducing IL-6 production in myeloma cells or the tumor environment. [12][13] The cellular origin of IL-6 is controversial. Several authors [13][14][15][16] showed that it is produced by the myeloma cells themselves (autocrine hypothesis). Other studies, [17][18][19] however, point to its paracrine production by cells in the bone marrow (BM) and suggest that proliferation of myeloma cells depends on close contact with stromal cells. [20][21...

SUMMARYIntracellular cytokine production by peripheral blood mononuclear cells (PBMC) was analysed in 51 patients with multiple myeloma (MM), 22 with monoclonal gammopathy of undetermined significance (MGUS) and 20 healthy subjects, as a parameter of immunological dysfunction in MM. An increased proportion of T cells and HLA-DR 1 cells producing IL-6 was observed in MM patients with active disease (at diagnosis and relapsing) compared with patients in remission and with MGUS, whereas no difference of IFN-g 1 , IL-2 1 PBMC between patients and controls was evident. Determination of serum cytokine levels demonstrated that the imbalanced IL-6 production by T cells and the defective antitumour Th1 cell activity were related to elevated levels of IL-6 and IL-12. In vitro studies of PHA-and anti-CD3/anti-CD28 MoAbs stimulation of PBMC demonstrated the ability of lymphocytes from MM patients to differentiate towards the Th1 subset in the presence of rIL-12. By contrast, addition of exogenous rIL-6 impaired IFN-g production by rIL-12-prompted T cells. Inhibition of Th1 polarization of the immune response by IL-6 was direct on T cells and not mediated by dendritic cells (DC). Evaluation of the ability of MM-derived DC to stimulate cell proliferation of allogenic T lymphocytes and produce IL-12 in vitro, in fact, suggested that MM-derived DC were functionally active. Taken as a whole, these results indicate that a deregulated cytokine network occurs in active MM. They also suggest that increased IL-6 production by peripheral T lymphocytes contributes to the immune dysfunction observed in MM, and enables tumour cells to escape immune surveillance by preventing the anti-tumour Th1 immune response.

(1) Background: In recent years, immunotherapy has revolutionized the treatment landscape of non-small cell lung cancer (NSCLC), representing a therapeutic breakthrough in this field. Antacid agents such as proton pump inhibitors (PPIs) and histamine-2-receptor antagonists (H2RAs) are commonly prescribed for extended periods in NSCLC patients, and these drugs have the potential to modify the efficacy of immune checkpoint inhibitors (ICIs). (2) Materials and Methods: Herein, we conducted a systematic review and meta-analysis to investigate the impact of PPIs and H2RAs on progression-free survival (PFS) and overall survival (OS) among patients receiving immunotherapy for metastatic NSCLC. Effect measures for OS were Hazard Ratios (HRs) and 95% Confidence Intervals (CIs), which were extracted from available studies. Forest plots were used to assess HRs to describe the relationship between treatment and OS in the specified cohorts of patients. (3) Results: Six studies were included in the analysis, involving 2267 patients. The pooled HRs for OS and PFS were 1.4 (95% CI, 1.25–1.58) and 1.29 (95% CI, 1.17–1.43), respectively, suggesting that PPIs and H2RAs administration was negatively associated with PFS and OS. (4) Conclusion: Concomitant antacid use could modify the activity of ICIs in NSCLC patients.

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Summary. Interleukin 6 (IL-6) is an important survival and growth factor for myeloma cells and exerts its effects by activating several transduction pathways, including the Ras cascade. As farnesylation of the activated Ras oncogene product by protein farnesyltransferase (FTase) is a critical step for Ras functional activity, FTase has emerged as a potential target for the development of new anti-cancer agents. Based on our previous demonstration that IL-6-producing myeloma cells are refractory to drug-induced apoptosis, we have analysed the effect of manumycin, a natural FTase inhibitor, on IL-6-producing myeloma cells resistant to Fas-, dexamethasone-and doxorubicin-induced apoptosis. Treatment of myeloma cells with manumycin prevented cell proliferation and induced apoptosis. Western blotting experiments demonstrated that this effect was related to inhibition of the post-translational Ras processing. Further analysis showed that manumycin-induced apoptosis involved caspase-3. Activation of caspase-3, in fact, was observed in 6 h-treated myeloma cells expressing Apo 2AE7 antigen, the marker of early apoptosis, whereas their treatment with cell-permeable DEVD-fmk, that irreversibly inhibits caspase-3 activity, prevented their apoptosis. Overexpression of caspase-3 was also demonstrated by reverse transcription-polymerase chain reaction. Finally, overexpression of Bcl-2 and its homologue Bcl-xL was observed in manumycin-treated cells as well as in control myeloma cells, implying that the Bcl-2 family is not involved. FTase inhibitors may thus be proposed as a potential pharmacological weapon, as they block the Ras pathway and induce the apoptosis of drug-resistant IL-6-producing myeloma cells.

Breast cancer detection and staging are constantly evolving as technologies improve. Breast cancer surgery is also undergoing continuous refinement, with the objective being to achieve optimal cosmetic results. Surgery has been combined with intraoperative radiation therapy to achieve the best local-disease control with minimal side-effects. The adjuvant strategy of treatment is a 'hot' issue in this 'scenario'. Every 2 years at St Gallen, a nice and cold town in the north of Switzerland, more of 4000 breast cancer experts arrive from every part of the world, to improve their knowledge in this issue. The Consensus Conference with the discussion of 40 international panelists is the zenith of the conference. This report provides a brief presentation and reflections, immediately at the end of the conference, with the objective being to stimulate ideas regarding what should be done tomorrow.

Metastatic breast cancer (MBC) is usually considered an incurable situation, for which treatments chosen to control the disease, should take into account the maintenance of a good quality of life. The end points of treatment of patients with MBC are influenced by consideration about efficacy and toxicity of the different therapeutic options. The availability of markers predicting response to treatment as well as the discovery of new agents have led to the identification of patients likely to obtain significant advantage from different treatment options. Due to the chronic nature of the MBC, the clinical benefit which encompasses objective response and long stabilization of disease has often become a goal in the metastating setting.

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