Cancer dissemination and distant metastasis most frequently require the release of tumor cells into the blood circulation, both in solid tumors and most hematological malignancies, including plasma ...cell neoplasms. However, detection of blood circulating tumor cells in solid tumors and some hematological malignancies, such as the majority of mature/peripheral B-cell lymphomas and monoclonal gammopathies, has long been a challenge due to their very low frequency. In recent years, the availability of highly-sensitive and standardized methods for the detection of circulating tumor plasma cells (CTPC) in monoclonal gammopathies, e.g., next-generation flow cytometry (NGF), demonstrated the systematic presence of CTPC in blood in virtually every smoldering (SMM) and symptomatic multiple myeloma (MM) patient studied at diagnosis, and in the majority of patients with newly-diagnosed monoclonal gammopathies of undetermined significance (MGUS). These methods set the basis for further detailed characterization of CTPC vs. their bone marrow counterpart in monoclonal gammopathies, to investigate their role in the biology of the disease, and to confirm their strong impact on patient outcome when measured both at diagnosis and after initiating therapy. Here, we review the currently available techniques for the detection of CTPC, and determine their biological features, physiopathological role and clinical significance in patients diagnosed with distinct diagnostic categories of plasma cell neoplasms.
Background: Whereas, in most patients with multiple myeloma (MM), achieving undetectable MRD anticipates a favorable outcome, some others relapse shortly afterwards. Although one obvious explanation ...for this inconsistency is the use of nonrepresentative marrow samples due to hemodilution, there is no guidance on how to evaluate this issue. Methods: Since B-cell precursors, mast cells and nucleated red blood cells are normally absent in peripheral blood, we analyzed them in 1404 bone marrow (BM) aspirates obtained in numerous disease settings and in 85 healthy adults (HA). Results: First, we confirmed the systematic detection of the three populations in HA, as well as the nonreduced numbers with aging. Pairwise comparisons between HA and MM patients grouped according to age and treatment showed significant variability, suggesting that hemodilution should be preferably evaluated with references obtained from patients treated with identical regimens. Leveraging the MRD results from 118 patients, we showed that a comparison with HA of similar age could also inform on potential hemodilution. Conclusions: Our study supports the routine assessment of BM cellularity to evaluate hemodilution, since reduced BM-specific cell types as compared to reference values (either treatment-specific or from HA if the former are unavailable) could indicate hemodilution and a false-negative MRD result.
Legionella testing conducted at environmental laboratories plays an essential role in assessing the risk of disease transmission associated with water systems. However, drawbacks of culture-based ...methodology used for Legionella enumeration can have great impact on the results and interpretation which together can lead to underestimation of the actual risk. Up to 20% of the samples analysed by these laboratories produced inconclusive results, making effective risk management impossible. Overgrowth of competing microbiota was reported as an important factor for culture failure. For quantitative polymerase chain reaction (qPCR), the interpretation of the results from the environmental samples still remains a challenge. Inhibitors may cause up to 10% of inconclusive results. This study compared a quantitative method based on immunomagnetic separation (IMS method) with culture and qPCR, as a new approach to routine monitoring of Legionella.
First, pilot studies evaluated the recovery and detectability of Legionella spp using an IMS method, in the presence of microbiota and biocides. The IMS method results were not affected by microbiota while culture counts were significantly reduced (1.4 log) or negative in the same samples. Damage by biocides of viable Legionella was detected by the IMS method. Secondly, a total of 65 water samples were assayed by all three techniques (culture, qPCR and the IMS method). Of these, 27 (41.5%) were recorded as positive by at least one test. Legionella spp was detected by culture in 7 (25.9%) of the 27 samples. Eighteen (66.7%) of the 27 samples were positive by the IMS method, thirteen of them reporting counts below 10(3) colony forming units per liter (CFU l(-1)), six presented interfering microbiota and three presented PCR inhibition. Of the 65 water samples, 24 presented interfering microbiota by culture and 8 presented partial or complete inhibition of the PCR reaction. So the rate of inconclusive results of culture and PCR was 36.9 and 12.3%, respectively, without any inconclusive results reported for the IMS method.
The IMS method generally improved the recovery and detectability of Legionella in environmental matrices, suggesting the possibility to use IMS method as valuable indicator of risk. Thus, this method may significantly improve our knowledge about the exposure risk to these bacteria, allowing us to implement evidence-based monitoring and disinfection strategies.
Telomeres are considered potential anti-cancer targets. Most studies have focused on telomerase inhibition, but this strategy has largely failed in clinical trials. Direct disruption of the shelterin ...complex through TRF1 inhibition can block tumorigenesis in cancer mouse models by a mechanism that involves DNA damage induction and reduction of proliferation and stemness. Any anti-cancer target, however, must fulfill the requisite of not showing deleterious effects in healthy tissues. Here, we show that Trf1 genetic deletion in wild-type and cancer-prone p53- and Ink4Arf-deficient mice does not affect organismal viability and only induces mild phenotypes like decreased body weight and hair graying or hair loss, the skin being the most affected tissue. Importantly, we found that Trf1 is essential for tumorigenesis in p53- and Ink4Arf-deficient mice, as we did not find a single tumor originating from Trf1-deleted cells. These findings indicate a therapeutic window for targeting Trf1 in cancer treatment.
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•Trf1 deletion does not affect organism viability in WT and cancer-prone mouse models•Trf1 deletion only induces mild phenotypes in adult tissues, especially in the skin•No tumors originate from Trf1-deleted cells
Cancer; Model Organism; Safety Assessment
Approximately 25% of the adult population worldwide and 49.8% of Mexican adults have metabolic syndrome. Metabolic syndrome is the result of unhealthy dietary and sleeping patterns, sedentary ...behaviors, and physical inactivity. The objective of our study was to evaluate the association between sedentary behaviors as screen-based sedentary time (SBST) and each component of metabolic syndrome among adults who participated in the Mexico National Survey of Health and Nutrition Mid-way 2016.
We analyzed sociodemographic, clinical, and physical activity data from 3,166 adults aged 20 years or older. The International Physical Activity Questionnaire was used to evaluate sedentary behavior. SBST was obtained by counting minutes per week spent watching television, playing video games, and interacting with computers and smartphones. We used Poisson regression to estimate the prevalence ratio of time in front of screens as a continuous variable and its association with metabolic syndrome.
The mean (SD) hours per day of SBST in men was 3.6 (0.4) and in women was 2.8 (0.2). The prevalence of metabolic syndrome was 59.6%. In men, the risk for metabolic syndrome increased 4% (P < .05) for each hour of SBST. Similarly, for each hour of SBST, the risk of abdominal obesity increased by 4% (P < .01). In women, we observed that the risk of hypertension or high-density lipoprotein cholesterol deficiency increased for each hour of SBST, and the risk of abdominal obesity increased for each hour of SBST in those who were inactive.
Sedentary behavior based on screen time is associated with metabolic syndrome and its components among Mexicans, depending on hours of sleep. Current public health policies should consider strategies for reducing SBST.
Monoclonal gammopathy of undetermined significance (MGUS) is the earliest discernible stage of multiple myeloma (MM) and Waldenström's macroglobulinemia (WM). Early diagnosis of MG may be compromised ...by the low-level infiltration, undetectable to low-sensitive methodologies. Here, we investigated the prevalence and immunophenotypic profile of clonal (c) plasma cells (PC) and/or cB-lymphocytes in bone marrow (BM) and blood of subjects with a serum M-component from the iSTOPMM program, using high-sensitive next-generation flow cytometry (NGF), and its utility in the diagnostic classification of early-stage MG. We studied 164 paired BM and blood samples from 82 subjects, focusing the analysis on: 55 MGUS, 12 smoldering MM (SMM) and 8 smoldering WM (SWM). cPC were detected in 84% of the BM samples and cB-lymphocytes in 45%, coexisting in 39% of cases. In 29% of patients, the phenotypic features of cPC and/or cB-lymphocytes allowed a more accurate disease classification, including: 19/55 (35%) MGUS, 1/12 (8%) SMM and 2/8 (25%) SWM. Blood samples were informative in 49% of the BM-positive cases. We demonstrated the utility of NGF for a more accurate diagnostic classification of early-stage MG.
Despite recent advances in multiple myeloma (MM), the incorporation of novel agents and measurable residual disease (MRD) monitoring in low-income countries remains a challenge. Although lenalidomide ...maintenance (M-Len) after autologous stem cell transplantation (ASCT) has been associated with improved outcomes and MRD has refined the prognosis of complete response (CR) cases, until now, there have been no data on the benefits of these approaches in Latin America. Here, we evaluate the benefits of M-Len and MRD using next-generation flow cytometry (NGF-MRD) at Day + 100 post-ASCT (
= 53). After ASCT, responses were evaluated based on the International Myeloma Working Group criteria and NGF-MRD. MRD was positive in 60% of patients with a median progression-free survival (PFS) of 31 months vs. not reached (NR) for MRD-negative cases (
= 0.05). The patients who received M-Len continuously had a significantly better PFS and overall survival (OS) than those without M-Len (median PFS: NR vs. 29 months,
= 0.007), with progression in 11% vs. 54% of cases after a median follow-up of 34 months, respectively. In a multivariate analysis, MRD status and M-Len therapy emerged as independent predictors of PFS (median PFS of M-Len/MRD
vs. no M-Len/MRD
of NR vs. 35 months, respectively;
= 0.01). In summary, M-Len was associated with improved survival outcomes in our real-world MM cohort in Brazil, with MRD emerging as a useful reproducible tool to identify patients at an earlier risk of relapse. The inequity in drug access remains a hurdle in countries with financial constraints, with a negative impact on MM survival.
Assessing measurable residual disease (MRD) has become standard with many tumors, but the clinical meaning of MRD in multiple myeloma (MM) remains uncertain, particularly when assessed by ...next-generation flow (NGF) cytometry. Thus, we aimed to determine the applicability and sensitivity of the flow MRD-negative criterion defined by the International Myeloma Working Group (IMWG).
In the PETHEMA/GEM2012MENOS65 trial, 458 patients with newly diagnosed MM had longitudinal assessment of MRD after six induction cycles with bortezomib, lenalidomide, and dexamethasone (VRD), autologous transplantation, and two consolidation courses with VRD. MRD was assessed in 1,100 bone marrow samples from 397 patients; the 61 patients without MRD data discontinued treatment during induction and were considered MRD positive for intent-to-treat analysis. The median limit of detection achieved by NGF was 2.9 × 10
. Patients received maintenance (lenalidomide ± ixazomib) according to the companion PETHEMA/GEM2014MAIN trial.
Overall, 205 (45%) of 458 patients had undetectable MRD after consolidation, and only 14 of them (7%) have experienced progression thus far; seven of these 14 displayed extraosseous plasmacytomas at diagnosis and/or relapse. Using time-dependent analysis, patients with undetectable MRD had an 82% reduction in the risk of progression or death (hazard ratio, 0.18; 95% CI, 0.11 to 0.30;
< .001) and an 88% reduction in the risk of death (hazard ratio, 0.12; 95% CI, 0.05 to 0.29;
< .001). Timing of undetectable MRD (after induction
intensification) had no impact on patient survival. Attaining undetectable MRD overcame poor prognostic features at diagnosis, including high-risk cytogenetics. By contrast, patients with Revised International Staging System III status and positive MRD had dismal progression-free and overall survivals (median, 14 and 17 months, respectively). Maintenance increased the rate of undetectable MRD by 17%.
The IMWG flow MRD-negative response criterion is highly applicable and sensitive to evaluate treatment efficacy in MM.
Ingestion of water has been associated with general wellbeing. When water intake is insufficient, symptoms such as thirst, fatigue and impaired memory result. Currently there are no instruments to ...assess water consumption associated with wellbeing. The objective of our study was to develop and validate such an instrument in urban, low socioeconomic, adult Mexican population.
To construct the Water Ingestion-Related Wellbeing Instrument (WIRWI), a qualitative study in which wellbeing related to everyday practices and experiences in water consumption were investigated. To validate the WIRWI a formal, five-process procedure was used. Face and content validation were addressed, consistency was assessed by exploratory and confirmatory psychometric factor analyses, repeatability, reproducibility and concurrent validity were assessed by conducting correlation tests with other measures of wellbeing such as a quality of life instrument, the SF-36, and objective parameters such as urine osmolality, 24-hour urine total volume and others.
The final WIRWI is composed of 17 items assessing physical and mental dimensions. Items were selected based on their content and face validity. Exploratory and confirmatory factor analyses yielded Cronbach's alpha of 0.87 and 0.86, respectively. The final confirmatory factor analysis demonstrated that the model estimates were satisfactory for the constructs. Statistically significant correlations with the SF-36, total liquid consumption and simple water consumption were observed.
The resulting WIRWI is a reliable tool for assessing wellbeing associated with consumption of plain water in Mexican adults and could be useful for similar groups.
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