The notion that plasma cells (PCs) are terminally differentiated has prevented intensive research in multiple myeloma (MM) about their phenotypic plasticity and differentiation. Here, we demonstrated ...in healthy individuals (n=20) that the CD19-CD81 expression axis identifies three bone marrow (BM)PC subsets with distinct age-prevalence, proliferation, replication-history, immunoglobulin-production, and phenotype, consistent with progressively increased differentiation from CD19+CD81+ into CD19-CD81+ and CD19-CD81- BMPCs. Afterwards, we demonstrated in 225 newly diagnosed MM patients that, comparing to normal BMPC counterparts, 59% had fully differentiated (CD19-CD81-) clones, 38% intermediate-differentiated (CD19-CD81+) and 3% less-differentiated (CD19+CD81+) clones. The latter patients had dismal outcome, and PC differentiation emerged as an independent prognostic marker for progression-free (HR: 1.7; P=0.005) and overall survival (HR: 2.1; P=0.006). Longitudinal comparison of diagnostic vs minimal-residual-disease samples (n=40) unraveled that in 20% of patients, less-differentiated PCs subclones become enriched after therapy-induced pressure. We also revealed that CD81 expression is epigenetically regulated, that less-differentiated clonal PCs retain high expression of genes related to preceding B-cell stages (for example: PAX5), and show distinct mutation profile vs fully differentiated PC clones within individual patients. Together, we shed new light into PC plasticity and demonstrated that MM patients harbouring less-differentiated PCs have dismal survival, which might be related to higher chemoresistant potential plus different molecular and genomic profiles.
We investigated the prognostic impact and clinical utility of serum free light chains (sFLC) and serum heavy-light chains (sHLC) in patients with multiple myeloma treated according to the ...GEM2005MENOS65, GEM2005MAS65, and GEM2010MAS65 PETHEMA/GEM phase III clinical trials. Serum samples collected at diagnosis were retrospectively analyzed for sFLC (n = 623) and sHLC (n = 183). After induction or autologous transplantation, 309 and 89 samples respectively were available for sFLC and sHLC assays. At diagnosis, a highly abnormal (HA) sFLC ratio (sFLCr) (<0.03 or >32) was not associated with higher risk of progression. After therapy, persistence of involved-sFLC levels >100 mg/L implied worse survival (overall survival OS, P = 0.03; progression-free survival PFS, P = 0.007). Among patients that achieved a complete response, sFLCr normalization did not necessarily indicate a higher quality response. We conducted sHLC investigations for IgG and IgA MM. Absolute sHLC values were correlated with monoclonal protein levels measured with serum protein electrophoresis. At diagnosis, HA-sHLCrs (<0.29 or >73) showed a higher risk of progression (P = 0.006). Additionally, involved-sHLC levels >5 g/L after treatment were associated with shorter survival (OS, P = 0.001; PFS, P = 0.018). The HA-sHLCr could have prognostic value at diagnosis; absolute values of involved-sFLC >100 mg/L and involved-sHLC >5 g/L could have prognostic value after treatment.
Trypanosoma cruzi infection triggers substantial production of nitric
oxide (NO), which has been shown to have protective and toxic effects
on the host's immune system. Sensing of trypomastigotes by
...phagocytes activates the inducible NO-synthase (NOS2) pathway, which
produces NO and is largely responsible for macrophage-mediated killing
of T. cruzi. NO is also responsible for modulating virtually all steps
of innate and adaptive immunity. However, NO can also cause oxidative
stress, which is especially damaging to the host due to increased
tissue damage. The cytokines IFN-γ and TNF-α, as well as
chemokines, are strong inducers of NOS2 and are produced in large
amounts during T. cruzi acute infection. Conversely, TGF-β and
IL-10 negatively regulate NO production. Here we discuss the recent
evidence describing the mechanisms by which NO is able to exert its
antimicrobial and immune regulatory effects, the mechanisms involved in
the oxidative stress response during infection and the implications of
NO for the development of therapeutic strategies against T. cruzi.
Achieving complete remission (CR) in multiple myeloma (MM) translates into extended survival, but two subgroups of patients fall outside this paradigm: cases with unsustained CR, and patients that do ...not achieve CR but return into a monoclonal gammopathy of undetermined significance (MGUS)-like status with long-term survival. Here, we describe a novel automated flow cytometric classification focused on the analysis of the plasma-cell compartment to identify among newly diagnosed symptomatic MM patients (N=698) cases with a baseline MGUS-like profile, by comparing them to MGUS (N=497) patients and validating the classification model in 114 smoldering MM patients. Overall, 59 symptomatic MM patients (8%) showed an MGUS-like profile. Despite achieving similar CR rates after high-dose therapy/autologous stem cell transplantation vs other MM patients, MGUS-like cases had unprecedented longer time-to-progression (TTP) and overall survival (OS; ~60% at 10 years; P<0.001). Importantly, MGUS-like MM patients failing to achieve CR showed similar TTP (P=0.81) and OS (P=0.24) vs cases attaining CR. This automated classification also identified MGUS patients with shorter TTP (P=0.001, hazard ratio: 5.53) and ultra-high-risk smoldering MM (median TTP, 15 months). In summary, we have developed a biomarker that identifies a subset of symptomatic MM patients with an occult MGUS-like signature and an excellent outcome, independently of the depth of response.
Knowledge about clonal diversity and selection is critical to understand multiple myeloma (MM) pathogenesis, chemoresistance and progression. If targeted therapy becomes reality, identification and ...monitoring of intraclonal plasma cell (PC) heterogeneity would become increasingly demanded. Here we investigated the kinetics of intraclonal heterogeneity among 116 MM patients using 23-marker multidimensional flow cytometry (MFC) and principal component analysis, at diagnosis and during minimal residual disease (MRD) monitoring. Distinct phenotypic subclones were observed in 35/116 (30%) newly diagnosed MM patients. In 10/35 patients, persistent MRD was detected after 9 induction cycles, and longitudinal comparison of patient-paired diagnostic vs MRD samples unraveled phenotypic clonal tiding after therapy in half (5/10) of the patients. After demonstrating selection of distinct phenotypic subsets by therapeutic pressure, we investigated whether distinct fluorescence-activated cell-sorted PC subclones had different clonogenic and cytogenetic profiles. In half (5/10) of the patients analyzed, distinct phenotypic subclones showed different clonogenic potential when co-cultured with stromal cells, and in 6/11 cases distinct phenotypic subclones displayed unique cytogenetic profiles by interphase fluorescence in situ hybridization, including selective del(17p13). Collectively, we unravel potential therapeutic selection of preexisting diagnostic phenotypic subclones during MRD monitoring; because phenotypically distinct PCs may show different clonogenic and cytogenetic profiles, identification and follow-up of unique phenotypic-genetic myeloma PC subclones may become relevant for tailored therapy.
Disappearance of normal bone marrow (BM) plasma cells (PC) predicts malignant transformation of monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) into symptomatic ...multiple myeloma (MM). The homing, behavior and survival of normal PC, but also CD34(+) hematopoietic stem cells (HSC), B-cell precursors, and clonal PC largely depends on their interaction with stromal cell-derived factor-1 (SDF-1) expressing, potentially overlapping BM stromal cell niches. Here, we investigate the distribution, phenotypic characteristics and competitive migration capacity of these cell populations in patients with MGUS, SMM and MM vs healthy adults (HA) aged >60 years. Our results show that BM and peripheral blood (PB) clonal PC progressively increase from MGUS to MM, the latter showing a slightly more immature immunophenotype. Of note, such increased number of clonal PC is associated with progressive depletion of normal PC, B-cell precursors and CD34(+) HSC in the BM, also with a parallel increase in PB. In an ex vivo model, normal PC, B-cell precursors and CD34(+) HSC from MGUS and SMM, but not MM patients, were able to abrogate the migration of clonal PC into serial concentrations of SDF-1. Overall, our results show that progressive competition and replacement of normal BM cells by clonal PC is associated with more advanced disease in patients with MGUS, SMM and MM.
Chagas disease affects 7.7 million people and 28 million people are at risk of acquiring the disease in 15 endemic countries of Latin America. Benznidazole and nifurtimox are drugs that have been ...used to treat the disease. However, both drugs induce severe side effects. Treatment with benznidazole has been recommended for the acute phase (0-4 months after infection), recent chronic phase (children 0-14 years of age, treated 4 months after infection) and congenital infection. Average cure rates for Chagas disease patients obtained from clinical trials were 97.9% (congenital infection, treatment performed 0-6 months of age), 71.5% (acute phase), 57.6% (recent chronic phase, children 0-13 years of age) and 5.9% (late chronic phase, great majority of patients between 15 and 69 years of age). Clinical evidence about the capacity of antiparasitic treatment to avoid, stop or revert heart pathology in indeterminate and cardiac chronic patients is contradictory. The investigation of novel therapeutic strategies against Chagas disease remains a priority in the research of tropical diseases. Unfortunately, Chagas disease remains neglected in the formulation of strategies toward control of this disease. This article focuses on current therapeutic approaches to Chagas disease.
Background and ImportanceSystemic lupus erythematosus (SLE) is a multisystem autoimmune disease with wide-ranging pleuropulmonary manifestations. Acute lupus pneumonitis (ALP) is one of its uncommon ...complications. Systemic steroids associated with immunosuppressive therapy (cyclophosphamide, rituximab, hydroxychloroquine and intravenous immunoglobulin) are the mainstream treatment of ALP.Aim and ObjectivesTo describe the case of a patient with ALP treated with intravenous cyclophosphamide as well as to evaluate the effectiveness and safety of this treatment.Material and MethodsWe report the case of a 67-year-old woman with a medical history of breast cancer and polymyalgia rheumatica treated with corticosteroids. She was referred to the emergency department due to intermittent fever, fatigue, generalised myalgia and arthralgia, mild dyspnoea and dry cough with sputum for the past 3 weeks. Multiple and bilateral lung opacities were present on chest X-ray so she was diagnosed with community-acquired pneumonia. The woman presented slight improvement despite empirical antibiotic and antifungal coverage. Subsequently, laboratory findings showed leukopenia and positive anti-double-stranded-DNA antibodies so the final diagnosis was ALP secondary to SLE. Systemic steroid treatment was initiated with a high-dose of methylprednisolone and hydroxychloroquine. Due to the severity of the pulmonary involvement, it was requested to start treatment with intravenous cyclophosphamide.ResultsThe patient received a total of three doses (600 mg/m2) of intravenous cyclophosphamide. MESNA, ondansetron and oral hydration were prescribed as supportive treatment. Despite the decrease in inflammatory analytical parameters, the woman presented modest reduction of lung injury and symptoms. She reported high-grade myalgia and vomiting after first infusion, which was successfully treated with paracetamol and metoclopramide. Sequential therapy with oral cyclophosphamide was considered, but because it is not funded for ALP and its adverse effect profile, treatment with methotrexate was started. Currently, the patient continues treatment with methotrexate, hydroxychloroquine and oral steroids. Computed tomography, performed 3 months after ending intravenous cyclophosphamide, showed stability of the disease.Conclusion and RelevanceTreatment with intravenous cyclophosphamide has not shown promising results in our patient although its safety profile is good. Because the therapeutic alternatives in patients with ALP are limited, it would have been interesting to verify that sequential therapy with oral cyclophosphamide improves the signs and symptoms of the disease, and long-term adverse effects could also be analysed.References and/or AcknowledgementsConflict of InterestNo conflict of interest.
We investigated the microbial pathways of nitrogen (N) loss in an April 2005 transect through the Peruvian oxygen minimum zone (OMZ) at $12\textdegree S$ latitude using short anaerobic incubations ...with $^{15}N-labeled$ substrates and molecular-ecological and lipid-biomarker studies. In incubations with 15NH4+, immediate production of $^{14}N^{15}N$, but not $^{15}N^{15}N$, indicated that N2 was produced by the pairing of labeled 15NH4+ with in situ $^{14}NO_2^-$ via anaerobic ammonium oxidation (anammox). Supporting this finding, we also found anammox-related 16S ribosomal ribonucleic acid gene sequences similar to those previously known from other marine water columns in which anammox activity was measured. We identified and enumerated anammox bacteria via fluorescence in situ hybridization and quantitative polymerase chain reaction and found ladderane membrane lipids specific to anammox bacteria wherever anammox activity was measured by our isotope tracer method. However, in incubations with 15NO3- or $^{15}NO_2^-$, in which denitrification would have been expected to produce $^{15}N^{15}N$ by pairing of oxidized 15N ions, $^{15}N^{15}N$ production was not detected before 24 h, showing that denitrification of fixed N to N2 was not taking place in our samples. At the time and locality of our study, anammox, rather than denitrification, was responsible for N2 production in the Peruvian OMZ waters.
Chemotherapy-associated osteonecrosis of the jaw caused by bisphosphonates is an exposure of necrotic bone with more than eight weeks of evolution that is attributable to bisphosphonates and no prior ...radiation therapy. Its etiopathogenesis remains unknown, although there are two hypotheses that may explain it: the drug's mechanism of action, and the risk factors that can lead to osteonecrosis. There is a wide range of treatment options for managing chemotherapy-associated osteonecrosis of the jaw, from conservative treatments to surgical procedures of varying levels of invasiveness, which are sometimes supplemented with adjuvant therapies.
The objective of this article is to group the therapeutic options for osteonecrosis of the jaw (ONJ) into seven different protocols and to evaluate their effectiveness in relation to stage of ONJ.
A literature review was carried out in PubMed following the PRISMA criteria. A total of 47 were collected after compiling a series of variables that define ONJ, applied treatments, and the clinical results obtained.
The 47 articles selected have a low to average estimated risk of bias and are of moderate to good quality. According to the data obtained, Protocol 3 (conservative treatment, clinical and radiological follow-up, minimally invasive surgical treatment, and adjuvant therapies) is the most favorable approach for ONJ lesions caused by oral bisphosphonates. For lesions caused by intravenous bisphosphonates, Protocol 2 (conservative treatment, clinical and radiological follow-up, minimally invasive surgical treatment, and no adjuvant therapies) is the best approach. When comparing the different stages of ONJ, Protocol 1 (conservative treatment, clinical and radiological follow-up) promotes better healing of Stage 1 ONJ lesions caused by orally administered bisphosphonates, and Protocol 3 is recommended for Stage II. For ONJ lesions attributable to intravenous bisphosphonates, Protocol 7 (conservative treatment, clinical and radiological follow-up, and adjuvant therapies) provides the best results in Stage 0; in Stages I, II, and III, Protocol 1 gives better results.
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