Previous studies have shown that secondhand smoke induces lung function impairment and increases proinflammatory cytokines. The aim of the present study was to evaluate the acute effects of secondhand smoke on airway acidification and airway oxidative stress in never-smokers. In a randomized controlled cross-over trial, 18 young healthy never-smokers were assessed at baseline and 0, 30, 60, 120, 180 and 240 min after one-hour secondhand smoke exposure at bar/restaurant levels. Exhaled NO and CO measurements, exhaled breath condensate collection (for pH, H(2)O(2) and NO(2)(-)/NO(3)(-) measurements) and spirometry were performed at all time-points. Secondhand smoke exposure induced increases in serum cotinine and exhaled CO that persisted until 240 min. Exhaled breath condensate pH decreased immediately after exposure (p < 0.001) and returned to baseline by 180 min, whereas H(2)O(2) increased at 120 min and remained increased at 240 min (p = 0.001). No changes in exhaled NO and NO(2)/NO(3) were observed, while decreases in FEV(1) (p < 0.001) and FEV(1)/FVC (p < 0.001) were observed after exposure and returned to baseline by 180 min. A 1-h exposure to secondhand smoke induced airway acidification and increased airway oxidative stress, accompanied by significant impairment of lung function. Despite the reversal in EBC pH and lung function, airway oxidative stress remained increased 4 h after the exposure. Clinical trial registration number (EudraCT): 2009-013545-28.

Background. Serum free light chains (sFLC), the most commonly detected paraprotein in CLL, were recently proposed as useful tools for the prognostication of CLL patients. Objective. To investigate the prognostic implication of sFLC and the summated FLC-kappa plus FLC-lambda in a CLL patients' series. Patients and Methods. We studied 143 CLL patients of which 18 were symptomatic and needed treatment, while 37 became symptomatic during follow-up. Seventy-two percent, 18%, and 10% were in Binet stage A, B and C, respectively. Median patients' followup was 32 months (range 4–228). Results. Increased involved (restricted) sFLC (iFLC) was found in 42% of patients, while the summated FLC-kappa plus FLC-lambda was above 60 mg/dL in 14%. Increased sFLC values as well as those of summated FLC above 60 were related to shorter time to treatment (P = 0.0005 and P = 0.000003, resp.) and overall survival (P = 0.05 and P = 0.003, resp.). They also correlated with β2-microglobulin (P = 0.009 and P = 0.03, resp.), serum albumin (P = 0.009 for summated sFLC), hemoglobin (P < 0.001), abnormal LDH (P = 0.037 and P = 0.001, resp.), Binet stage (P < 0.05) and with the presence of beta symptoms (P = 0.004 for summated sFLC). Conclusion. We confirmed the prognostic significance of sFLC in CLL regarding both time to treatment and survival and showed their relationship with other parameters.

BLyS is involved in CLL biology and its low soluble serum levels related to a shorter time to first treatment (TFT). TACI is a BLyS receptor and can be shed from cells' surface and circulate in soluble form (sTACI). We investigated the impact of serum BLyS and sTACI levels at diagnosis in CLL patients and their relationship with disease parameters and patients' outcome. Serum BLyS was determined in 73 patients, while sTACI in 60. Frozen sera drawn at diagnosis were tested by ELISA. sTACI concentrations correlated with BLyS (P = −0.000021), b2-microglobulin (P = 0.005), anemia (P = −0.03), thrombocytopenia (P = 0.04), Binet stage (P = 0.02), and free light chains ratio (P = 0.0003). Soluble BLyS levels below median and sTACI values above median were related to shorter TFT (P = 0.0003 and 0.007). During a ten-year followup, sTACI levels, but not BLyS, correlated with survival (P = 0.048). In conclusion, we confirmed the prognostic significance of soluble BLyS levels with regard to TFT in CLL patients, and, more importantly, we showed for the first time that sTACI is a powerful prognostic marker, related to parameters of disease activity and staging and, more importantly, to TFT and OS.

We evaluated progression-free survival (PFS) rate of patients treated with lenalidomide/dexamethasone (Len/Dex), the efficacy of the combination, and the prognostic significance of treatment at biochemical vs. clinical relapse on PFS in 207 consecutive myeloma patients treated with Len/Dex in second line, according to routine clinical practice in Greece. First-line treatment included bortezomib-based (63.3%) or immunomodulatory drug-based (34.8%) therapies; 25% of patients underwent autologous stem cell transplantation. Overall response rate was 73.4% (17.8% complete response and 23.7% very good partial response); median time to best response was 6.7 months. Overall, median PFS and 12-month PFS rate was 19.2 months and 67.6%, respectively. 67.5% of patients had biochemical relapse and 32.5% had clinical relapse prior to initiation of Len/Dex. Median PFS was 24 months for patients treated at biochemical relapse vs. 13.2 months for those treated at clinical relapse (HR:0.63, p = 0.006) and the difference remained significant after adjustment for other prognostic factors. Type of relapse was the strongest prognostic factor for PFS in multivariate analysis. These real-world data confirm the efficacy of Len/Dex combination at first relapse; more importantly, it is demonstrated for the first time outside a clinical trial setting that starting therapy with Len/Dex at biochemical, rather than at clinical relapse, is a significant prognostic factor for PFS, inducing a 37% reduction of the probability of disease progression or death.

The purpose of this present chapter is to describe the properties of M-Igs and discuss the biologic, clinical and other implications of their presence in the course of B-cell disease entities. 2. Ontogeny of normal and monoclonal Ig-producing B-cells 2.1. B-cell development B-cell maturation is a complex process that comprises both cell differentiation into Ig secreting plasma cells and, in parallel, the rearrangement of the genes responsible for Ig synthesis. Furthermore it includes inherent risks of genetic derailment because it is associated with DNA remodelling with intrinsic instability, thus presenting the possibility of malignant development. B cell development begins in the bone marrow (BM) from gestation week 18 and throughout life. The generation of pro-B cells from a common lymphoid progenitor cell depends on two main transcription factors, E12 and E47 and on the contribution of the transcriptional regulators EBF and Pax-5 [5]. During B-cell evolution the rearrangement of Ig heavy and light chain genes takes place [2]. The Ig heavy gene (IgH) is located on chromosome 14 while Ig light chain (IgL) genes are on chromosomes 2 and 22 for κ (1-40 vκ, 1-5 jκ and 1cκ) and λ (1-30 vλ, 1-4 jλ and 1-4cλ) light chain respectively. Rearrangement of IgH and IgL genes allows variable (V), diversity (D) and joining (J) gene segments rearrangement. V(D)J recombination starts in precursor B cells (pre B-I); recombinase activating genes 1 and 2 (RAG-1 and RAG-2), are essential for this step. The resulting IgVH is frequently not functional therefore the pre-B cell initiates V(D)J recombination at the other allele. If this is successful, the complete IgVH will be expressed as an Igμ H chain in the cytoplasm (Cy-Igμ) and on the membrane, together with a surrogate light chain, the pre B cell receptor complex (pre-BCR). Accordingly the pre-B-II cell proliferates, then looses its pre-BCR and re-express RAG proteins [7]. At that point, the Bcell is transformed into a small pre B-II cell that will subsequently rearrange the IgL variable gene segments and expresses a mature membrane BCR. If the BCR is not strongly self-reactive, the immature B cell leaves the BM as transitional B cell that evolves into naive B cell in the spleen; alternatively, it may mature in the periphery. However, if the immature B cell is still self-reactive, it will remain in the BM for additional IgVL recombination, replacing the selfreactive IgVL by another IgVL and so on. B cells producing self-reactive BCRs are removed from the repertoire during maturation by BM silencing mechanisms [3;4]. Splenic transitional B cells (CD27-CD5+ CD10+ CD24 hi CD38 hi and L-selectin lo) undergo differentiation into mature naive B2, also called follicular (FO) B cells, or marginal zone (MZ) B cells [5]. The aforementioned B-cell population is characterized by limited proliferative capacity and survival upon BCR stimulation; it comprises less than 2% of the peripheral B cells [6]. While maturating in the spleen, transitional B cells loose CD10 and CD5 and start expressing...