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© 2021 by the authors., Despite tremendous progress being made in recent years, multiple myeloma (MM) remains a challenging disease. The laboratory plays a critical role in the overall management of patients. The diagnosis, prognosis, clinical monitoring and evaluation of the response are key moments in the clinical care process. Conventional laboratory methods have been and continue to be the basis of laboratory testing in monoclonal gammopathies, along with the serum free light chain test. However, more accurate methods are needed to achieve new and more stringent clinical goals. The heavy/light chain assay is a relatively new test which can overcome some of the limitations of the conventional methods for the evaluation of intact immunoglobulin MM patients. Here, we report an update of the evidence accumulated in recent years on this method regarding its use in MM.

Background Monoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma in virtually every case. However, only a small percentage will progress and at very different rates. In addition, recent data have suggested that MGUS is associated with other comorbidities including infections, suggesting impaired immune function in some MGUS patients. Therefore, we aimed at assessing the value of isotype-matched immunosuppression (IMI; e.g., suppression of an IgAκ in an IgAλ patient), a type of immunosuppression more specific than classical immunoparesis (IP; e.g., IgG and/or IgM suppression in an IgA patient), as a prognostic marker for MGUS progression. Methods The Hevylite assay was used to assess IMI and immunoglobulin ratios in 307 serum samples from a cohort of 248 MGUS patients. Follow-up clinical records were available for 154 individuals. Results A greater incidence of IMI (51%) over classical IP (37%) was observed, although both show a progressive increase with higher risk groups. Survival analysis of 154 patients showed that severe IMI (>50% suppression) differentiates 2 groups with significantly different time to progression (P = 0.024) while severe IP does not (P = 0.48). Also, a combination of severe IMI and involved monoclonal immunoglobulin >1.5g/dL by Hevylite (both variables found to be independent prognostic markers in multivariate analysis) identified a group of patients with a median time to progression 6-fold shorter than the remaining group (P < 0.0001). Conclusions These findings indicate a possible role for IMI in the malignant transformation of MGUS patients and a potential utility as a new risk factor.

Several studies have now shown that monoclonal gammopathy of undetermined significance (MGUS) constantly precedes all multiple myelomas (MM). Risk adapted follow-up may increase chances of early diagnosis of progression and, therefore, increase the chances of a better outcome for the patient, as also shown by two long-term follow-up studies. However, in real-life patients it is still difficult to identify MGUS cases at very high risk of progression. On a previous study we showed that Severe Isotype-Matched Immunosuppression (IMI) by Hevylite® was a potential risk factor of progression for MGUS patients. We have now expanded the median follow-up time by an additional year. Methods: The clinical records of 154 MGUS patients for which a Hevylite determination was available together with monoclonal protein quantification by gel electrophoresis (EP) and free light chains by Freelite were reviewed. Samples were analyzed with Hevylite® (The Binding Site, UK) in a BNII analyzer (Siemens) according to the monoclonal protein isotype. Normal ranges were those provided by the manufacturer. Values 50% below the lower normal ranges of the immunoglobulins determined by Hevylite were defined as severe IMI. Statistical analysis done using Graph pad V5. Progression free survival (PFS) curves calculated by Kaplan-Meyer method and curve differences by Log-rank (Mantel Cox) test. Results: The median follow-up of the 154 MGUS patients (150 IgG, 20 IgA, and 27 IgM) was 944 days (range:27-3471), during which 16 progressions to MM, 3 progressions to smoldering (by plasma cell infiltration >10%) and 1 progression to Non-Hodgkin lymphoma were registered. These numbers represent an increase in 366 days of follow-up and 3 extra progressions, with respect to the previous study. The median time to progression of the cohort is now 9,5 years. Severe IMI determined by Hevylite was observed in 14% of the patients while severe immunoparesis (i.e. more than 50% suppression of the immunoglobulins not associated to the isotype of the tumor cells; e.g. suppression of IgA or IgM in an IgG MGUS) was observed in 7% of the patients. The frequency of IMI was very similar among patients of different isotypes: IgG=60%, IgA=69%, IgM=57%, (p=0.37). When patients were analyzed according to the presence/absence of severe IMI or severe immunoparesis (IP), only the presence of severe IMI was observed to be predictive of shorter time to progression (p=0.009; HR=6.3, 95% IC=1.6-24.9) as shown in Fig.1A. Patients with severe IP were as likely to progress as patients without (p=0.604; Fig.1B). Additionally, patients showing simultaneously severe IMI and involved HLC >1.5g/dL showed a median time to progression 4 times shorter than the remaining group (Fig.2). Conclusions The results obtained strengthen the conclusions obtained previously showing that severe IMI is a risk factor for MGUS progression, mainly if combined with an involved HLC greater than 1.5g/dL. This means that, potentially, with one assay, two risk factors could be easily and quickly assessed for, virtually, every MGUS patient. The limitations of this study are its retrospective nature and a moderate over-representation of higher risk MGUS groups, which is expected since, being a real-life study, these are the patients that are most likely to maintain the follow-up with the specialist. Disclosures Barbosa: The Binding Site: Employment. Pais:The Binding Site: Employment. Campos:The Binding Site: Employment.

p48, also called Ptf1a (pancreas-specific transcription factor 1a), is a tissue-restricted bHLH (basic helix loop helix) transcription factor which is critical for pancreatic commitment during development and for the activation and maintenance of the acinar differentiation programme in the exocrine pancreas. High-level expression of exocrine digestive enzymes, a hallmark of mature acinar cells, depends largely on the trimeric complex PTF1, formed by p48, RBP-L (recombination signal-binding protein 1-like) and a class A bHLH protein. In addition, p48 induces cell-cycle exit by controlling G1/S-phase progression. However, the mechanisms that mediate PTF1-dependent gene activation are poorly understood. In the present study, we report that p48 increases transcription through two activation domains located in its N-terminal region by recruiting transcriptional co-activators. The histone acetyltransferase cofactor p/CAF {p300/CBP [CREB (cAMP-response-element-binding protein)-binding protein]-associated factor} interacts with p48 in acinar cells in vivo and is associated with the promoter region of acinar genes targeted by the PTF1 complex. p/CAF potentiates PTF1 transcriptional activity by enhancing selectively the p48 transactivation activity. p/CAF promotes the nuclear accumulation of p48 and its in vivo acetylation in Lys200. The K200R mutation abolishes the transcriptional activity of p48, as well as its capacity to functionally co-operate with RBP-L to ensure effective PTF1-driven transcription, indicating that p/CAF-mediated acetylation of p48 is required for the full transcriptional activity of PTF1. In contrast, p/CAF did not co-operate with p48 in its growth regulatory effects. These results support a critical and selective role of p/CAF in PTF1-dependent gene activation during acinar differentiation.

Background & Aims: Pro-inflammatory polymorphisms within the genes interleukin (IL)-1B and IL-1RN are associated with risk for gastric carcinoma (GC) in Helicobacter pylori —infected individuals. We aimed to determine the association between variation of the tumor necrosis factor ( TNF )-α gene and the risk for chronic atrophic gastritis (CAG) and GC. We also investigated the extent to which the combined effect of proinflammatory genetic polymorphisms ( IL-1B , IL-1RN , and TNF- α), and the combined effect of TNF -α and bacterial genotypes each influence such a risk. Methods: In a case-control study including 306 controls, 221 individuals with chronic gastritis, and 287 GC patients, the TNF- α-308 and IL-1B -511 bi-allelic polymorphisms, the IL-1RN variable number of tandem repeats (VNTR), and the H. pylori genes vacA (s and m regions) and cagA were genotyped. Results: We found that carriers of the TNF- α-308∗A allele are at increased risk for GC development with an odds ratio (OR) of 1.9 (95% confidence interval [CI], 1.3–2.7). For both CAG and GC, the odds of developing disease increased with the number of high-risk genotypes. Individuals carrying high-risk genotypes at the 3 loci are at increased risk for CAG and GC with an OR of 5.8 (95% CI, 1.1–31.0) and 9.7 (95% CI, 2.6–36.0), respectively. The risk for GC was not affected significantly by the combination of bacterial and TNF- α-308 genotypes. Conclusions: These findings show that a proinflammatory polymorphism in the TNF -α gene is associated with increased risk for GC, and that it is possible to define a specific genetic profile associated with highest risk for CAG and GC.