Efficacy and Safety of Different Immunosuppressive Therapies in Patients With Membranous Nephropathy and High PLA2R Antibody Titer

Background: This study aimed to evaluate clinical features and prognosis and therapy option of patients with different risk ranks based on antibody against the M-type phospholipase-A2-receptor (PLA2Rab) level in seropositive M-type phospholipase-A2-receptor (PLA2R)-associated membranous nephropathy (MN) in a large sample size, multi-center study.Method: Based on the unvalidated cut-off value of PLA2Rab above 150 RU/ml as one of the clinical criteria for high risk of progressive kidney function loss in MN according to 2020 Kidney Disease: Improving Global Outcomes (KDIGO) draft guidelines recommendation, a total of 447 patients who received cyclophosphamide (CTX) or tacrolimus (TAC) combined with corticosteroids treatment for 12 months were divided into high titer (>150 RU/ml) group and non-high titer (20–150 RU/ml) group, which were subdivided into CTX subgroup and TAC subgroup. The overall cohort was classified into CTX group and TAC group as well. Clinical parameters levels and remission rates were recorded at 3, 6, and 12 months follow-up. PLA2Rab was tested by enzyme-linked immunosorbent assay.Results: Patients with high titer PLA2Rab were associated with more severe proteinuria and hypoalbuminemia compared to those with non-high titer antibody, accompanied by lower complete remission (CR) and total remission (TR) rates at 3, 6, and 12 months, which even took longer to remission. Similar remission rates differences between the two titer groups were observed in the CTX and TAC groups, respectively. PLA2Rab level at baseline was an independent predictive factor for CR and TR. In the high titer group, CR and TR rates in the CTX subgroup were significantly higher than those in the TAC subgroup at 12 months, although serious adverse events were more frequent in the former.Conclusion: High-risk rank patients with PLA2Rab level above 150 RU/ml have higher disease activity and worse prognosis among patients with seropositive PLA2R-associated MN, even under different immunosuppressive therapeutic models; moreover, CTX combined with corticosteroids was preferred compared to TAC plus corticosteroids, although serious adverse events were more frequent in the former. Additionally, baseline PLA2Rab level was an independent predictive factor for clinical remission.

The Predictive Value of MAP2K1/2 Mutations on Efficiency of Immunotherapy in Melanoma

BackgroundMAP2K1/2 genes are mutated in approximately 8% of melanoma patients; however, the impact of MAP2K1/2 gene alterations on the efficiency of immunotherapy has not been clarified. This study focused on the correlation between MAP2K1/2 gene mutations and the treatment response.MethodsSix metastatic melanoma clinical cohorts treated with immune checkpoint inhibitors [anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) or anti-programmed cell death-1 (PD-1)] were recruited in this study. RNA expression profiling results from each of these six cohorts and the Cancer Genome Atlas (TCGA) melanoma cohort were analysed to explore the mechanism related to immune activation.ResultsCompared to patients with wild-type MAP2K1/2, those with MAP2K1/2 mutations in an independent anti-CTLA-4-treated cohort had higher objective response rates, longer progression-free survival, and longer overall survival (OS). These findings were further validated in a pooled anti-CTLA-4-treated cohort in terms of the OS. However, there was no correlation between MAP2K1/2 mutations and OS in the anti-PD-1-treated cohort. Subgroup Cox regression analysis suggested that patients with MAP2K1/2 mutations received fewer benefits from anti-PD-1 monotherapy than from anti-CTLA-4 treatment. Furthermore, transcriptome profiling analysis revealed that melanoma tumours with MAP2K mutation was enriched in CD8+ T cells, B cells, and neutrophil cells, also expressed high levels of CD33 and IL10, implying a potential mechanism underlying the benefit of melanoma patients with MAP2K1/2 mutations from anti-CTLA-4 treatment.ConclusionsMAP2K1/2 mutations were identified as an independent predictive factor for anti-CTLA-4 therapy in melanoma patients. Anti-CTLA-4 treatment might be more effective than anti-PD-1 therapy for patients with MAP2K1/2-mutated melanoma.

Prevalence and Factors Associated with Opioid Prescription in Swiss Chronic Hemodialysis Patients

Pain is a common symptom in patients on chronic hemodialysis (HD) but the prevalence of opioid prescriptions in this population has been poorly studied outside the United States. This study assesses the prevalence of opioid prescription in two Swiss dialysis centers. Prescriptions and clinical characteristics were retrospectively retrieved from the medical records of patients on HD for at least six months, treated at Lausanne University Hospital (academic center, AC), and the private center Clinique Cecil (PC) for the study. A total of 117 patients were included; 29.1% received at least one opioid prescription during the study period. Significantly more patients received an opioid prescription in the AC (39.1%) than in the PC (14.6%, p = 0.004). Univariate logistic regression analysis showed that center (Odds Ratio (OR) 3.76; Confidence Interval (CI) 1.48–9.6; p = 0.006), neuropathic pain (OR 2.99; CI 1.28–6.98; p = 0.011), benzodiazepine prescription (OR 2.72; CI 1.14–6.46; p = 0.024), polyneuropathy (OR 2.71; CI 1.14–6.46; p = 0.024) and amputation (OR 4.23; CI 1.1–16.1; p = 0.034) were associated with opioid prescription. The center was the only independent predictive factor in the multivariate analysis. Our results show that opioids are regularly prescribed to Swiss dialysis patients, although important differences exist between centers. The latter finding might suggest that opioid prescribing is more related to the prescriber than to the patient’s condition, but larger-scale studies are necessary to confirm this.

Longitudinal dynamics of SARS-CoV-2-specific cellular and humoral immunity after natural infection or BNT162b2 vaccination

The timing of the development of specific adaptive immunity after natural SARS-CoV-2 infection, and its relevance in clinical outcome, has not been characterized in depth. Description of the long-term maintenance of both cellular and humoral responses elicited by real-world anti-SARS-CoV-2 vaccination is still scarce. Here we aimed to understand the development of optimal protective responses after SARS-CoV-2 infection and vaccination. We performed an early, longitudinal study of S1-, M- and N-specific IFN-γ and IL-2 T cell immunity and anti-S total and neutralizing antibodies in 88 mild, moderate or severe acute COVID-19 patients. Moreover, SARS-CoV-2-specific adaptive immunity was also analysed in 234 COVID-19 recovered subjects, 28 uninfected BNT162b2-vaccinees and 30 uninfected healthy controls. Upon natural infection, cellular and humoral responses were early and coordinated in mild patients, while weak and inconsistent in severe patients. The S1-specific cellular response measured at hospital arrival was an independent predictive factor against severity. In COVID-19 recovered patients, four to seven months post-infection, cellular immunity was maintained but antibodies and neutralization capacity declined. Finally, a robust Th1-driven immune response was developed in uninfected BNT162b2-vaccinees. Three months post-vaccination, the cellular response was comparable, while the humoral response was consistently stronger, to that measured in COVID-19 recovered patients. Thus, measurement of both humoral and cellular responses provides information on prognosis and protection from infection, which may add value for individual and public health recommendations.

Preliminary Application of a Quantitative Collateral Assessment Method in Acute Ischemic Stroke Patients With Endovascular Treatments: A Single-Center Study

Objectives: To develop an efficient and quantitative assessment of collateral circulation on time maximum intensity projection CT angiography (tMIP CTA) in patients with acute ischemic stroke (AIS).Methods: Eighty-one AIS patients who underwent one-stop CTA-CT perfusion (CTP) from February 2016 to October 2020 were retrospectively reviewed. Single-phase CTA (sCTA) and tMIP CTA were developed from CTP data. Ischemic core (IC) volume, ischemic penumbra volume, and mismatch ratio were calculated. The Tan scale was used for the qualitative evaluation of collateral based on sCTA and tMIP CTA. Quantitative collateral circulation (CCq) parameters were calculated semi-automatically with software by the ratio of the vascular volume (V) on both hemispheres, including tMIP CTA VCCq and sCTA VCCq. Spearman correlation analysis was used to analyze the correlation of collateral-related parameters with final infarct volume (FIV). ROC and multivariable regression analysis were calculated to compare the significance of the above parameters in clinical outcome evaluation. The analysis time of the observers was also compared.Results: tMIP CTA VCCq (r = 0.61, p < 0.01), IC volume (r = 0.66, p < 0.01), Tan score on tMIP CTA (r = 0.52, p < 0.01) and mismatch ratio (r = 0.60, p < 0.01) showed moderate negative correlations with FIV. tMIP CTA VCCq showed the best prognostic value for clinical outcome (AUC = 0.93, p < 0.001), and was an independent predictive factor of clinical outcome (OR = 0.14, p = 0.009). There was no difference in analysis time of tMIP CTA VCCq among observers (p = 0.079).Conclusion: The quantitative evaluation of collateral circulation on tMIP CTA is associated with clinical outcomes in AIS patients with endovascular treatments.

Dynamin 3 Gene as a Tumor Suppressor and an Independent Predictive Factor of Poor Prognosis in Patients with Gastric Cancer

Gastric cancer is a leading cause of death from malignant tumors worldwide. With the development of genome sequencing technology, an increasing number of key driver genes and tumor suppressors have been discovered. Some studies have suggested that Dynamin 3 (DNM3) is a novel tumor suppressor; however, the role of DNM3 in malignancy remains unclear. We performed a systematic analysis using The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD) cohorts, and 160 patients with stomach adenocarcinoma at Fujian Medical University Union Hospital (FJMUUH) (48 quantitative PCR [qPCR] and 112 immunohistochemistry). DNM3 expression was found to be downregulated in gastric cancer compared to that in paraneoplastic tissue. Low expression of DNM3 was mainly associated with DNM3 promoter hypermethylation status. Low expression of DNM3 can upregulate the tumor cell cycle and oxidative phosphorylation process and downregulate immune regulation, and Th17 and Th2 immune cell infiltration was increased in patients with lower expression of DNM3. Patients with a lower DNM3 expression had a higher rate of lymph node metastasis and poor prognosis. In summary, DNM3 is a tumor suppressor and an independent predictive factor of poor prognosis that regulates the cell cycle and immunosuppression in the tumor microenvironment in gastric cancer via methylation.

Insights of Worsening Renal Function in Type 1 Cardiorenal Syndrome: From the Pathogenesis, Biomarkers to Treatment

Type-1 cardiorenal syndrome refers to acute kidney injury induced by acute worsening cardiac function. Worsening renal function is a strong and independent predictive factor for poor prognosis. Currently, several problems of the type-1 cardiorenal syndrome have not been fully elucidated. The pathogenesis mechanism of renal dysfunction is unclear. Besides, the diagnostic efficiency, sensitivity, and specificity of the existing biomarkers are doubtful. Furthermore, the renal safety of the therapeutic strategies for acute heart failure (AHF) is still ambiguous. Based on these issues, we systematically summarized and depicted the research actualities and predicaments of the pathogenesis, diagnostic markers, and therapeutic strategies of worsening renal function in type-1 cardiorenal syndrome.

Bridge from central extracorporeal life support is a risk factor of cerebrovascular accidents after durable left ventricular assist device implantation

A bridging strategy from extracorporeal life support (ECLS) is effective in salvage and a bridge to recovery or to a durable left ventricular assist device (LVAD) for acute refractory heart failure. However, the correlation of this strategy with adverse events after durable LVAD implantation has not been fully investigated. This study enrolled 158 consecutive patients who had either the HeartMate II or HeartMate 3 and were implanted for bridge-to-transplantation. These devices were implanted as the primary mechanical support device in 115 patients, whereas the remaining 43 underwent LVAD implantation as the bridge from central ECLS. The primary study endpoint was all-cause mortality and cerebrovascular accidents (CVAs) after durable LVAD implantation, and the secondary endpoints were adverse events. Overall survival was not significantly different between the two groups. In contrast, the probability of CVAs was significantly greater in the bridge group than in the primary group (probability of CVAs, P = 0.002; log-rank test). In Cox multivariate logistic regression analysis, a bridge from central ECLS was an independent predictive factor of CVAs (hazard ratio 4.27, 95% confidence interval 1.43–12.8; P = 0.0095). Patients who are bridged from central ECLS are more frequently complicated by CVAs compared with those who undergo primary implantation of a durable LVAD, but survival is not significantly different between the two groups. A bridge from central ECLS is an independent predictive factor of CVAs post-implantation of an LVAD.

Ultrasound in clinically suspect arthralgia: the role of power Doppler to predict rheumatoid arthritis development

Objective To determine the usefulness of power Doppler (PD) ultrasound (US) to predict rheumatoid arthritis (RA) development in patients with clinically suspect arthralgia (CSA). Methods Retrospective analysis of a US unit cohort over a 1-year period. Patients with CSA and no previous diagnosis of inflammatory arthritis (IA) were included for analysis. All underwent bilateral US examination of the hands and/or feet according to the EULAR guidelines. Active US inflammation was defined as PD synovitis and/or tenosynovitis ≥1 at any location. RA diagnosis according to clinician criteria 6 months after the US examination was checked. Univariate and multivariate logistic regression models were employed to investigate possible predictive factors of RA development. Results A total of 110 CSA patients (80 females, mean age 53.6 years) were included for analysis. After 6 months of follow-up, 14 (12.7%) developed RA and 34 (30.9%) IA. US active inflammation was present in 38 (34.5%) patients (28.2% showed PD synovitis and 18.2% PD tenosynovitis). Multivariate analysis showed that ACPA (OR 1.0003; 95% CI 1.002–1.006) and ESR (OR 1.054; 95% CI 1.016–1.094) were significantly associated with the detection of US active inflammation at baseline. Only PD tenosynovitis was found to be an independent predictive factor of an evolution towards RA (OR 6.982; 95% CI 1.106–44.057) and IA (OR 5.360; 95% CI 1.012–28.390). Conclusion US is able to detect features of subclinical inflammation in CSA patients, especially in those with higher ESR and ACPA values. Only PD tenosynovitis at baseline US assessment was found to be an independent predictor of RA and IA development in CSA patients.

Down-regulation of SOCS6: an unfavorable prognostic factor for gastrointestinal stromal tumor proven by survival analysis

Background Many studies reporting that down-regulation of SOCS6 plays vital roles in promoting progression of malignant tumors have been published. The present study was performed to evaluate whether SOCS6 was significantly associated with prognosis of GIST patients. Methods Immunohistochemical staining was accomplished to evaluate the expression levels of SOCS6 among GIST patients. The impacts of SOCS6 expression on overall survival (OS) and recurrence-free survival (RFS) of GIST patients were assessed by Cox proportional hazard regression model analysis and Kaplan-Meier curve analysis. Results It was demonstrated that the expression level of SOCS6 was significantly associated with tumor size (P=0.001). Then according to Kaplan-Meier curve analysis, low expression of SOCS6 was significantly correlated with worse OS and RFS of GIST patients. Ultimately, it was revealed by Cox proportional regression model analysis that low expression of SOCS6 was an independent predictive factor for OS and RFS. Conclusions Low expression of SOCS6 was an independent prognostic factor for GIST, suggesting its potential as a novel biomarker predicting survival of GIST patients.