Liquid biopsy for molecular characterization of diffuse large B-cell lymphoma and early assessment of minimal residual disease.

Circulating tumour DNA (ctDNA) allows genotyping and minimal residual disease (MRD) detection in lymphomas. Using a next-generation sequencing (NGS) approach (EuroClonality-NDC), we evaluated the clinical and prognostic value of ctDNA in a series of R-CHOP-treated diffuse large B-cell lymphoma (DLBCL) patients at baseline (n = 68) and after two cycles (n = 59), monitored by metabolic imaging (positron emission tomography combined with computed tomography [PET/CT]). A molecular marker was identified in 61/68 (90%) ctDNA samples at diagnosis. Pretreatment high ctDNA levels significantly correlated with elevated lactate dehydrogenase, advanced stage, high-risk International Prognostic Index and a trend to shorter 2-year progression-free survival (PFS). Valuable NGS data after two cycles of treatment were obtained in 44 cases, and 38 achieved major molecular response (MMR; 2.5-log drop in ctDNA). PFS curves displayed statistically significant differences among those achieving MMR versus those not achieving MMR (2-year PFS of 76% vs. 0%, p < 0.001). Similarly, more than 66% reduction in ΔSUVmax by PET/CT identified two subgroups with different prognosis (2-year PFS of 83% vs. 38%; p < 0.001). Combining both approaches MMR and ΔSUVmax reduction, a better stratification was observed (2-year PFS of 84% vs. 17% vs. 0%, p < 0.001). EuroClonality-NDC panel allows the detection of a molecular marker in the ctDNA in 90% of DLBCL. ctDNA reduction at two cycles and its combination with interim PET results improve patient prognosis stratification.

Wound vacuum-assisted closure temporization after tumor resection of soft tissue sarcomas-A cost analysis in a propensity-score matched population.

BACKGROUND: Vacuum-assisted closure (VAC) temporization is a technique associated with high local control rates used in myxofibrosarcoma. We sought to compare the costs and postoperative outcomes of VAC temporization and single-stage (SS) excision/reconstruction. METHODS: We conducted a retrospective analysis of patients with myxofibrosarcoma surgically treated at our institution between 2000 and 2022. Variables of interest included total, direct, and indirect costs for initial episode of care, 90 days and 1 year after initial admission, and postoperative outcomes. Costs were compared between the VAC temporization and SS groups. RESULTS: After matching, 13 patients in the SS group and 23 in the VAC group were analyzed. We found no difference in median and mean total inpatient costs, between the VAC temporization and SS group. While total 90-day and 1-year costs were higher in the VAC group compared to the SS group, mean costs were similar. There were no differences in postoperative complications between groups. A subanalysis of the entire cohort (n = 139) revealed lower local recurrence and overall death rates in the VAC temporization group. CONCLUSION: VAC temporization had similar inpatient costs and postoperative outcomes to SS excision/reconstruction. While median 90-day and 1-year costs were higher in the VAC group, mean costs did not differ.

What is the diagnostic accuracy of fluorescence-guided surgery for margin assessment in appendicular bone and soft tissue tumors? - A systematic review of clinical studies.

BACKGROUND: Fluorescence-guided surgery (FGS) is a novel technique to successfully assess surgical margins intraoperatively. Investigation and adoption of this technique in orthopaedic oncology remains limited. METHODS: The PRISMA guidelines were followed for this manuscript. Our study was registered on PROSPERO (380520). Studies describing the use of FGS for resection of bone and soft tissue sarcomas (STS) on humans were included. Diagnostic performance metrics (sensitivity, specificity, positive predictive value [PPV], negative predictive value [NPV] and accuracy) and margin positivity rate were the outcomes assessed. RESULTS: Critical appraisal using the Joanna Brigs Institute checklists showed significant concerns for study quality. Sensitivity of FGS ranged from 22.2 % to 100 % in three of the four studies assessing his metrics; one study in appendicular tumors in the pediatric population reported 0 % sensitivity in the three cases included. Specificity ranged from 9.38 % to 100 %. PPV ranged from 14.6 % to 70 % while NPV was between 53.3 % and 100 %. The diagnostic accuracy ranged from 21.62 % to 92.31 %. Margin positivity rate ranged from 2 % to 50 %, with six of the seven studies reporting values between 20 % and 50 %. CONCLUSIONS: FSG is a feasible technique to assess tumor margins in bone and STS. Reported performance metrics and margin positivity rates vary widely between studies due to low study quality and high heterogeneity in dying protocols. LEVEL OF EVIDENCE: Level III, diagnostic study.

Environmental assessment model for scrubbers versus alternative mitigation systems for feeder vessels in liner shipping.

Implementation of the Global Sulphur Cap (GSC), in January 2020, boosted scrubber installation in vessels to fulfill the new air emission limitations. This increase in scrubbers' use has intensified concern about its environmental performance. Even though achievement of GSC requirements through this mitigation system has been widely proven, the impact of wash water discharge on the marine environment remains under discussion. In this paper, an assessment environmental model is introduced to quantify in monetary terms the performance of feeder vessels that operate with several mitigation systems. This model attempts to improve traditional air emission evaluations by including the impact of scrubbers' discharges on the marine environmental. In this way, the analysis not only allows different mitigations systems to be ranked by considering their capacity to reduce air emissions, but also provides further information about the marine eutrophication and ecotoxicity impact from scrubbers' discharge. Through the model's application to a regular shipping line between the Canary Islands and the Iberian Peninsula, it was found that, the scrubber, regardless of its operation mode (open- or closed loop), is the most efficient mitigation option after the Liquefied Natural Gas (LNG) fuel shift. The impact of scrubbers' discharge was not as significant as expected on the feeder vessel's total pollution since this provides similar relative weight to the methane emissions from a dual-engine option by operating with LNG. The results also show the need to more closely research the marine eutrophication impact of closed-loop scrubbers. Finally, this paper warns about a significant dispersion on the monetary values of marine ecotoxicity and eutrophication, due to a high dependence of the results on the frameworks' localization. Consequently, further research is needed on the homogenization of pollution monetization in the marine environment.

Cost-Effectiveness of Therapeutic Drug Monitoring of Anti-TNF Therapy in Inflammatory Bowel Disease: A Systematic Review.

Infliximab and adalimumab are monoclonal antibodies against tumor necrosis factor (anti-TNF) used to manage inflammatory bowel disease (IBD). Therapeutic Drug Monitoring (TDM) has been proven to prevent immunogenicity, to achieve better long-term clinical results and to save costs in IBD treatment. The aim of this study was to conduct a systematic review on cost-effectiveness analyses of studies that apply TDM of anti-TNF in IBD and to provide a critical analysis of the best scientific knowledge available in the literature. The quality of the included studies was assessed using Consolidated Health Economic Evaluation Reporting Standards (CHEERS). Cost-effectiveness of the TDM strategies was presented as total costs, cost savings, quality-adjusted life-years (QALY) and incremental cost-effectiveness ratio (ICER). Thirteen studies that examined the health economics of TDM of anti-TNF in IBD from 2013 to 2021 were included. Eight of them (61.5%) achieved a score between 17 and 23 on the CHEERS checklist. The comparison between the TDM strategy and an empirical strategy was cost saving. The ICER between reactive TDM and an empirical strategy was dominated (favorable) by reactive TDM, whereas the ICER value for proactive TDM compared to an empirical strategy ranged from EUR 56,845 to 3,901,554. This systematic review demonstrated that a TDM strategy is cost-effective or cost-saving in IBD.

Interlaboratory Analytical Validation of a Next-Generation Sequencing Strategy for Clonotypic Assessment and Minimal Residual Disease Monitoring in Multiple Myeloma.

CONTEXT.­: Minimal residual disease (MRD) is a major prognostic factor in multiple myeloma, although validated technologies are limited. OBJECTIVE.­: To standardize the performance of the LymphoTrack next-generation sequencing (NGS) assays (Invivoscribe), targeting clonal immunoglobulin rearrangements, in order to reproduce the detection of tumor clonotypes and MRD quantitation in myeloma. DESIGN.­: The quantification ability of the assay was evaluated through serial dilution experiments. Paired samples from 101 patients were tested by LymphoTrack, using Sanger sequencing and EuroFlow's next-generation flow (NGF) assay as validated references for diagnostic and follow-up evaluation, respectively. MRD studies using LymphoTrack were performed in parallel at 2 laboratories to evaluate reproducibility. RESULTS.­: Sensitivity was set as 1.3 tumor cells per total number of input cells. Clonality was confirmed in 99% and 100% of cases with Sanger and NGS, respectively, showing great concordance (97.9%), although several samples had minor discordances in the nucleotide sequence of rearrangements. Parallel NGS was performed in 82 follow-up cases, achieving a median sensitivity of 0.001%, while for NGF, median sensitivity was 0.0002%. Reproducibility of LymphoTrack-based MRD studies (85.4%) and correlation with NGF (R2 > 0.800) were high. Bland-Altman tests showed highly significant levels of agreement between flow and sequencing. CONCLUSIONS.­: Taken together, we have shown that LymphoTrack is a suitable strategy for clonality detection and MRD evaluation, with results comparable to gold standard procedures.

The Design and Development of Recycled Concretes in a Circular Economy Using Mixed Construction and Demolition Waste.

This research study analysed the effect of adding fine-fMRA (0.25% and 50%)-and coarse-cMRA (0%, 25% and 50%)-mixed recycled aggregate both individually and simultaneously in the development of sustainable recycled concretes that require a lower consumption of natural resources. For this purpose, we first conducted a physical and mechanical characterisation of the new recycled raw materials and then analysed the effect of its addition on fresh and hardened new concretes. The results highlight that the addition of fMRA and/or cMRA does not cause a loss of workability in the new concrete but does increase the amount of entrained air. Regarding compressive strength, we observed that fMRA and/or cMRA cause a maximum increase of +12.4% compared with conventional concrete. Tensile strength increases with the addition of fMRA (between 8.7% and 5.5%) and decreases with the use of either cMRA or fMRA + cMRA (between 4.6% and 7%). The addition of fMRA mitigates the adverse effect that using cMRA has on tensile strength. Regarding watertightness, all designed concretes have a structure that is impermeable to water. Lastly, the results show the feasibility of using these concretes to design elements with a characteristic strength of 25 MPa and that the optimal percentage of fMRA replacement is 25%.

Variances in BCG protection against COVID-19 mortality: A global assessment.

The BCG vaccine is known to impart nonspecific immunological benefits alongside conferring protection to tuberculosis in endemic regions. It is also known to protect against bladder cancer and other respiratory tract infections. During the coronavirus disease 2019 (COVID-19) pandemic, the BCG vaccine has gained attention due to its role in conferring protective immunity. We demonstrate the potential immunological protective mechanisms that play a role against COVID-19. We conduct a global assessment of the countries that have the highest and lowest mortality rates determined by an a priori methodology. Lastly, we discuss the potential limitations of incorporating BCG vaccines as potential strategies against COVID-19 and provide recommendations regarding their use in ongoing and future epidemics.

Comparison of next-generation sequencing (NGS) and next-generation flow (NGF) for minimal residual disease (MRD) assessment in multiple myeloma.

Detecting persistent minimal residual disease (MRD) allows the identification of patients with an increased risk of relapse and death. In this study, we have evaluated MRD 3 months after transplantation in 106 myeloma patients using a commercial next-generation sequencing (NGS) strategy (LymphoTrack®), and compared the results with next-generation flow (NGF, EuroFlow). The use of different marrow pulls and the need of concentrating samples for NGS biased the applicability for MRD evaluation and favored NGF. Despite that, correlation between NGS and NGF was high (R2 = 0.905). The 3-year progression-free survival (PFS) rates by NGS and NGF were longer for undetectable vs. positive patients (NGS: 88.7% vs. 56.6%; NGF: 91.4% vs. 50%; p < 0.001 for both comparisons), which resulted in a 3-year overall survival (OS) advantage (NGS: 96.2% vs. 77.3%; NGF: 96.6% vs. 74.9%, p < 0.01 for both comparisons). In the Cox regression model, NGS and NGF negativity had similar results but favoring the latter in PFS (HR: 0.20, 95% CI: 0.09-0.45, p < 0.001) and OS (HR: 0.21, 95% CI: 0.06-0.75, p = 0.02). All these results reinforce the role of MRD detection by different strategies in patient prognosis and highlight the use of MRD as an endpoint for multiple myeloma treatment.

Combined assessment of the TNM stage and BRAF mutational status at diagnosis in sporadic colorectal cancer patients.

The prognostic impact of KRAS mutations and other KRAS-related and non-related genes such as BRAF, NRAS and TP53, on sporadic colorectal cancer (sCRC) remain controversial and/or have not been fully established. Here we investigated the frequency of such mutations in primary sCRC tumors and their impact on patient progression-free survival (PFS) and overall survival (OS). Primary tumor tissues from 87 sCRC patients were analysed using a custom-built next generation sequencing (NGS) panel to assess the hotspot mutated regions of KRAS/NRAS (exons 2, 3 and 4), BRAF (exon 15) and TP53 (all exons). Overall, mutations in these genes were detected in 46/87 sCRC tumors analyzed (53%) with the following frequencies per gene: TP53, 33%; KRAS, 28%; BRAF, 7%; and NRAS, 1%. A significant association was found between KRAS mutations and right side colon tumor location (p=0.05), well-differentiated tumors (p=0.04) and absence of lymphovascular invasion (p=0.05). In turn, BRAF-mutated tumors frequently corresponded to poorly- or moderately-differentiated sCRC (p=0.02) and showed a higher frequency of peritoneal carcinomatosis (p=0.006) and microsatellite instability (p=0.007). From the prognostic point of view, the BRAF mutational status together with the TNM stage were the only variables that showed an independent adverse impact on patient outcome in the multivariate analyses for both PFS and OS. Based on these results a scoring system was built and patients were classified into three prognostic subgroups with different PFS rates at 2 years: 91% vs. 77% vs. 0%, respectively (p<0.0001). Additional prospective studies in larger series of sCRC patients where mutations in genes other than those investigated here are required to validate the utility of the proposed predictive model.

Satisfaction with life and with food-related life in central Chile.

BACKGROUND: Eating is one of the most frequent human behaviors, but there are few studies that relate eating and subjective well-being. Typologies of people were distinguished and characterized according to their level of satisfaction with life and food in central Chile. METHOD: A survey was applied to a sample of 1,277 people in the main municipalities of this area, distributed proportionally by municipality. The questionnaire included the SWLS scales (Satisfaction with Life Scale), SWFL (Satisfaction with Food-related Life), Health-Related Quality of Life Index (HRQOL), Subjective Happiness Scale (SHS), and respondents' demographic characteristics and eating habits were also ascertained. RESULTS: Using hierarchical cluster analysis, three typologies were distinguished with significant differences in the scores on the SWLS, SWFL, SHS, self-perception of health, days with physical or mental problems in the last month, sociodemographic characteristics and frequency with which the family eats together. CONCLUSIONS: The results suggest that a higher level of general subjective well-being, and eating is associated with better health, greater family interaction around meals, higher levels of happiness, and with some sociodemographic characteristics.

[Economic evaluation of rituximab added to fludarabine plus cyclophosphamide versus fludarabine plus cyclophosphamide for the treatment of chronic lymphocytic leukemia]. / Evaluación económica de rituximab en combinación con fludarabina y ciclofosfamida en comparación con fludarabina y ciclofosfamida en el tratamiento de la leucemia linfática crónica.

OBJECTIVES: We evaluated the cost-effectiveness of rituximab added to the chemotherapy regimen of fludarabine plus cyclophosphamide (R-FC) versus fludarabine plus cyclophosphamide (FC) for the treatment of patients with previously untreated or relapsed/refractory chronic lymphocytic leukemia (CLL). METHODS: Two Markov models were built, using published results on progression-free survival (PFS) in patients receiving first- or second-line therapy with R-FC vs FC, rates of disease progression and mortality rates in Spain. Patient-elicited utilities were applied to PFS and progressed health states. The cost of drugs, supportive care, and quality-adjusted life years (QALY) were estimated over a 10-year period. Univariate and probabilistic (Monte Carlo) sensitivity analyses were performed. RESULTS: The addition of rituximab to chemotherapy in first- and second-line therapy increased life-years gained (LYG) and QALYs compared with chemotherapy. The incremental cost per LYG and QALY gained was €20,703 and €19,343 for first-line treatment and was €23,183 and €24,781 for second-line treatment. CONCLUSION: In patients with previously untreated or relapsed/refractory CLL, the addition of rituximab to the FC regimen increased life expectancy and quality-adjusted life expectancy. In both types of patient, the treatment was cost-effective.

Clinical and prognostic value of discrepancies in microsatellite DNA regions between recipient and donor in human leukocyte antigen-identical allogeneic transplantation setting.

BACKGROUND: Detection of recipient versus donor disparities in microsatellite DNA regions (short tandem repeats [STR]) allows for sensitive and specific monitorization of the degree of hematopoietic chimerism. It is well known that disparities between donor and recipient in various polymorphic systems (mainly human leukocyte antigen [HLA]) are associated with an increased incidence of graft-versus-host disease (GvHD). However, the possible biological role of STR discrepancies in GvHD development has not yet been well established. METHODS: We evaluated 149 consecutive patients with hematologic malignancies receiving peripheral blood stem-cell transplantation from a human leukocyte antigen-identical sibling donor. A total of 15 STR regions were analyzed using the PowerPlex16 kit and classified as identical when recipient and donor share the same alleles, and mismatched when at least one of the alleles differed. RESULTS: Higher severity of acute GvHD (II-IV, P=0.043) and shorter 5-year overall survival (P=0.016) was found in patients displaying more than 10 mismatches with respect to their donor. Additionally, higher risk of transplant-related mortality (P=0.019) was found in recipient-donor pairs with discrepancies in the D13S317 STR marker. CONCLUSION: The present data suggest that genetic incompatibilities outside the human leukocyte antigen region between donors and recipients influence the outcome of patients receiving stem-cell transplantation. In addition, disparities in the neighboring D13S317 region could influence transplant-related mortality.

[Financial analysis of intraarterial procedures in acute stroke]. / Análisis económico del intervencionismo en el ictus agudo.

INTRODUCTION: Since the most decisive factor related to the cost of stroke is disability, any acute phase intervention to reduce disability will probably be cost-effective. The present acute stroke phase analysis is the first cost-benefit study on intraarterial procedures in acute stroke phase. METHOD: Case-control study focusing on the cost of stroke including acute stroke patients subjected to interventionism in Hospital Virgen del Rocío in 2003-2004 was conducted. The data obtained was subsequently extrapolated to the number of patients who would have been treated if intraarterial procedures could be performed on a 24 hour-day basis. RESULTS: 32 patients were treated in 2003-2004. Direct cost (devices and human resources) of each treated patient was 10,502 euros and global saving in hospital stay and rehabilitation was 11,069 euros, resulting in 567 euros net saving per patient. Nevertheless, 92 patients would have been treated if intraarterial procedures could have been performed on a 24 hour-day basis, resulting in better financial results with 5,792 saving for each treated patient. CONCLUSIONS: Intracraneal procedures in acute stroke has been shown to be cost-effective since cost of material and human resources is greatly exceeded by the saving in hospitalization and rehabilitation as a result of reduction in patient disability.