Next-generation diagnostic instruments in haematology.

Gallo et al. assessed the impact of implementing a clinical decision support tool in a multi-hospital setting. This is one of three important points to unlock the capabilities of the next-generation of diagnostic instruments: (a) integrating diagnostic information from various sources, (b) ensuring accurate development and validation in well-designed clinical studies and (c) seamlessly integrating them into clinical practice. Commentary on: Gallo et al. Clinical decision support to reduce unnecessary diagnostic testing for heparin-induced thrombocytopenia. Br J Haematol 2023 (Online ahead of print). doi: 10.1111/bjh.18902

Current Knowledge on Factor V Leiden Mutation as a Risk Factor for Recurrent Venous Thromboembolism: A Systematic Review and Meta-Analysis.

Background Thrombophilia screening is widely done in clinical practice, and it is claimed that the extent of venous thromboembolism (VTE) recurrence risk in patients with common defects is still not fully understood. Aim We aimed to summarize data of all observational studies prospectively assessing the association of heterozygous factor V Leiden (FVL) mutation and recurrent VTE in patients with VTE, and to calculate pooled relative risks (RR), overall and in various subgroups. Methods We searched MEDLINE and EMBASE databases for cohort studies prospectively assessing VTE recurrence in patients with and without FVL mutation (PROSPERO: CRD42021182800). Data were extracted on cohort and study-level. The methodological quality was assessed using the Newcastle-Ottawa Scale (NOS). RR were calculated overall and in subgroups using a random-effects model. Results From 31 cohorts, 24 studies were finally included summarizing 13,571 patients. Heterozygous FVL mutation was identified in 2,840 individuals (21%). The methodological quality was estimated to be high in 20 studies (83%). The overall RR was 1.46 (95% CI: 1.31, 1.64), consistent across subgroups. Conclusions Pooling all high-quality epidemiological data, the risk of recurrent VTE was increased by 46% in patients with heterozygous FVL mutation. Against the background of established risk factors, the FVL mutation plays only a marginal role in the risk assessment for recurrent VTE

Clinical Impact of Single Nucleotide Polymorphism in CD-19 on Treatment Outcome in FMC63-CAR-T Cell Therapy.

Chimeric antigen receptor (CAR)-T cell therapy is effective in patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) with response rates of 63-84% and complete response observed in 43-54%. Common germline variants of the target antigen CD19 may elicit different responses to CAR-T cell therapy. The CD19 gene single nucleotide polymorphism rs2904880 encoding leucine or valine at amino acid position 174 of the CD19 antigen was prevalent in 51% of the studied DLBCL patients. In a retrospective comparative analysis of clinical outcome, there were significant differences in CD19 L174 versus V174 carriers: the median time of progression-free survival was 22 vs. 6 months (p = 0.06), overall survival was 37 vs. 8 months (p = 0.11), complete response rates were 51% vs. 30% (p = 0.05), and refractory disease rates were 14% vs. 32% (p = 0.04). The single nucleotide polymorphism in CD19 was shown to influence the treatment outcome in FMC63-anti-CD19-CAR-T cell therapy, and the CD19 minor allele L174 predicted a favorable treatment outcome

Determination of the Diagnostic Performance of Laboratory Tests in the Absence of a Perfect Reference Standard: The Case of SARS-CoV-2 Tests

Background: Currently, assessing the diagnostic performance of new laboratory tests assumes a perfect reference standard, which is rarely the case. Wrong classifications of the true disease status will inevitably lead to biased estimates of sensitivity and specificity. Objectives: Using Bayesian’ latent class models (BLCMs), an approach that does not assume a perfect reference standard, we re-analyzed data of a large prospective observational study assessing the diagnostic accuracy of an antigen test for the diagnosis of SARS-CoV-2 infection in clinical practice. Methods: A cohort of consecutive patients presenting to a COVID-19 testing facility affiliated with a Swiss University Hospital were recruited (n = 1465). Two real-time PCR tests were conducted in parallel with the Roche/SD Biosensor rapid antigen test on nasopharyngeal swabs. A two-test (PCR and antigen test), three-population BLCM was fitted to the frequencies of paired test results. Results: Based on the BLCM, the sensitivities of the RT-PCR and the Roche/SD Biosensor rapid antigen test were 98.5% [95% CRI 94.8;100] and 82.7% [95% CRI 66.8;100]. The specificities were 97.7% [96.1;99.7] and 99.9% [95% CRI 99.6;100]. Conclusions: Applying the BLCM, the diagnostic accuracy of RT-PCR was high but not perfect. In contrast to previous results, the sensitivity of the antigen test was higher. Our results suggest that BLCMs are valuable tools for investigating the diagnostic performance of laboratory tests in the absence of perfect reference standard

Secondary prevention of venous thromboembolism: Predictors and outcomes of guideline adherence in a long-term prospective cohort study.

Background Prevention of recurrent venous thromboembolism (VTE) is considered a main goal of VTE management. However, the extent to which physicians adhere to the recommendations from evidence-based guidelines is unknown. Aim From a large, prospective clinical cohort, we aimed to (1) quantify the adherence of treatment recommendations to evidence-based guidelines and establish its predictors, and (2) estimate its impact on clinical outcomes and costs in patients with VTE. Methods We included 6'243 consecutive patients with VTE treated at the university outpatient unit. Detailed clinical characteristics and treatment recommendations were recorded. Adherence of treatment recommendations to evidence-based guidelines at risk assessment was assessed in terms of duration of anticoagulant treatment. Data on death were obtained from the Swiss Central Compensation Office. Health care claims data recorded between 2014 and 2019 were retrieved from Helsana, one of the largest Swiss health insurance companies. Results The adherence to evidence-based guidelines was 36.1%. Among patients with non-adherence, overtreatment was present in 70.1%. Significant patient-related predictors of guideline adherence were (a) age above 50 years, (b) male sex, (c) pulmonary embolism, (d) unprovoked VTE, (e) multiple VTE, (f) laboratory tests not ordered, and (g) various cardiovascular comorbidities. Non-adherence was not significantly associated with mortality, hospitalization, admission to nursing home, and costs. Conclusions The adherence to evidence-based guidelines was low, and several unrelated predictors appeared. Although these results need to be confirmed in other settings, they highlight the need for implementation of evidence-based guidelines in clinical practice

Comparative effectiveness and safety of anticoagulants for the treatment of heparin-induced thrombocytopenia.

BACKGROUND The effectiveness and safety of non-heparin anticoagulants for the treatment of heparin-induced thrombocytopenia (HIT) are not fully established, and the optimal treatment strategy is unknown. In a systematic review and meta-analysis, we aimed to determine precise rates of platelet recovery, new or progressive thromboembolism (TE), major bleeding, and death for all non-heparin anticoagulants and to study potential sources of variability. METHODS Following a detailed protocol (PROSPERO: CRD42020219027), EMBASE and Medline were searched for all studies reporting clinical outcomes of patients treated with non-heparin anticoagulants (argatroban, danaparoid, fondaparinux, direct oral anticoagulants [DOAC], bivalirudin, and other hirudins) for acute HIT. Proportions of patients with the outcomes of interest were pooled using a random-effects model for each drug. The influence of the patient population, the diagnostic test used, the study design, and the type of article was assessed. RESULTS Out of 3194 articles screened, 92 studies with 119 treatment groups describing 4698 patients were included. The pooled rates of platelet recovery ranged from 74% (bivalirudin) to 99% (fondaparinux), TE from 1% (fondaparinux) to 7% (danaparoid), major bleeding from 1% (DOAC) to 14% (bivalirudin), and death from 7% (fondaparinux) to 19% (bivalirudin). Confidence intervals were mostly overlapping, and results were not influenced by patient population, diagnostic test used, study design, or type of article. DISCUSSION Effectiveness and safety outcomes were similar among various anticoagulants, and significant factors affecting these outcomes were not identified. These findings support fondaparinux and DOACs as viable alternatives to conventional anticoagulants for treatment of acute HIT in clinical practice

Long-Term Survival After Venous Thromboembolism: A Prospective Cohort Study.

Background: Little is known about long-term survival after the initial treatment of venous thromboembolism (VTE). In a prospective cohort study, we aimed to assess the long-term mortality and key predictor variables relating to disease severity, treatment intensity, and comorbidities. Materials and Methods: Between 1988 and 2018, 6,243 consecutive patients with VTE from a University outpatient unit were prospectively included and followed until December 2019; clinical characteristics, measures of disease severity, and treatment details were recorded. Dates of death were retrieved from the Swiss Central Compensation Office. Results: Overall, 254 deaths occurred over an observation period of 57,212 patient-years. Compared to the Swiss population, the standardized mortality ratio was 1.30 (95% CI: 1.14, 1.47; overall mortality rate: 4.44 per 1,000 patient-years). The following predictors were associated with increased mortality: Unprovoked VTE (hazard ratio [HR]: 5.06; 95% CI: 3.29, 7.77), transient triggering risk factors (HR: 3.46; 95% CI: 2.18, 5.48), previous VTE (HR: 2.05; 95% CI: 1.60, 2.62), pulmonary embolism (HR: 1.45, 95% CI: 1.10, 1.89), permanent anticoagulant treatment (HR: 3.14; 95% CI: 2.40, 4.12), prolonged anticoagulant treatment (7-24 months; HR: 1.70; 95% CI: 1.16, 2.48), and cardiovascular comorbidities. Unprovoked VTE, previous VTE, permanent and prolonged anticoagulation remain independent risk factors after adjustment for age, sex, and comorbidities. Conclusion: Survival after VTE was significantly reduced compared to the Swiss general population, especially in patients with more severe disease, cardiovascular comorbidities, and longer anticoagulant treatment

Prognostic significance of lymph nodes assessment during pulmonary metastasectomy: a systematic review and meta-analysis.

BACKGROUND Lung metastasectomy is an accepted treatment modality worldwide. Whether the addition of lymph node dissection to the procedure is useful remains, however, unknown. METHODS We performed a systematic review of the literature analyzing MEDLINE, Embase, until 31st October 2021. We included all studies which met the inclusion criteria aiming to determine if the addition of lymph node tissue dissection/sampling to lung metastasectomy offers survival benefits when compared to patients who do receive lymph node tissue dissection. Secondary outcomes were 3- and 5-year overall survival (OS) and disease-free survival (DFS). Each study was assessed for risk of bias. The data collected from the included studies were pooled using reconstruction of individual-level patient data and pooling of reported 5-year odds ratios (ORs). Interstudy heterogeneity was estimated with visual inspection of forest plots and calculation of the I2 inconsistency statistic. RESULTS We found 11 eligible studies that included a total of 3,310 patients. The most common primary tumor type was colorectal cancer (1,740 patients) and the most commonly performed operative procedure was wedge resection (57%) followed by lobectomy (39%). When resection status was reported, R0 resection was achieved in 90% of the cases. Nine studies did not show a statistically significant effect of lymph nodes dissection or sampling on the 5-year OS with a pooled hazard ratio (HR) of 0.94 [95% confidence interval (CI): 0.82, 1.08; I2=26%; 95% prediction interval (PI): 0.70, 1.24]. Regarding DFS, the pooled HR 0.60 (95% CI: 0.44, 0.80; I2=31%; 95% PI: 0.12, 2.09). CONCLUSIONS The addition of lymph node tissue dissection during lung metastasectomy was not associated with a significant benefit in OS and showed a slight tendency towards a better DFS

Role of intrapulmonary lymph nodes in patients with NSCLC and visceral pleural invasion. The VPI 1314 multicenter registry study protocol.

BackgroundIn the lung cancer classification (TNM), the involvement of thoracic lymph nodes is relevant from a diagnostic and prognostic point of view. Even if imaging modality could help in selecting patients who should undergo surgery, a systematic lymph node dissection during lung surgery is mandatory to identify the subgroup of patients who can benefit from an adjuvant treatment.MethodsPatients undergoing elective lobectomy/bilobectomy/segmentectomy) for non-small cell lung cancer and lymphadenectomy with lymph nodes station 10-11-12-13-14 sampling that meet the inclusion and exclusion criteria will be recorded in a multicenter prospective database. The overall incidence of N1 patients (subclassified in: Hilar Lymph nodes, Lobar Lymph nodes and Sublobar Lymph nodes) will be examined as well as the incidence of visceral pleural invasion.DiscussionThe aim of this multicenter prospective study is to evaluate the incidence of intrapulmonary lymph nodes metastases and the possible relation with visceral pleural invasion. Identifying patients with lymph node station 13 and 14 metastases and/or a link between visceral pleural invasion and presence of micro/macro metastases in intrapulmonary lymph nodes may have an impact on decision-making process.Trial registrationClinicalTrials.gov ID: NCT05596578