We investigated the value of genetic, histopathologic, and early treatment response information in prognosing long-term renal outcome in children with primary steroid-resistant nephrotic syndrome. ...From the PodoNet Registry, we obtained longitudinal clinical information for 1354 patients (disease onset at >3 months and <20 years of age): 612 had documented responsiveness to intensified immunosuppression (IIS), 1155 had kidney biopsy results, and 212 had an established genetic diagnosis. We assessed risk factors for ESRD using multivariate Cox regression models. Complete and partial remission of proteinuria within 12 months of disease onset occurred in 24.5% and 16.5% of children, respectively, with the highest remission rates achieved with calcineurin inhibitor-based protocols. Ten-year ESRD-free survival rates were 43%, 94%, and 72% in children with IIS resistance, complete remission, and partial remission, respectively; 27% in children with a genetic diagnosis; and 79% and 52% in children with histopathologic findings of minimal change glomerulopathy and FSGS, respectively. Five-year ESRD-free survival rate was 21% for diffuse mesangial sclerosis. IIS responsiveness, presence of a genetic diagnosis, and FSGS or diffuse mesangial sclerosis on initial biopsy as well as age, serum albumin concentration, and CKD stage at onset affected ESRD risk. Our findings suggest that responsiveness to initial IIS and detection of a hereditary podocytopathy are prognostic indicators of favorable and poor long-term outcome, respectively, in children with steroid-resistant nephrotic syndrome. Children with multidrug-resistant sporadic disease show better renal survival than those with genetic disease. Furthermore, histopathologic findings may retain prognostic relevance when a genetic diagnosis is established.
Giant cell tumor of bone (GCTB) is a frequently recurring locally aggressive osteolytic lesion, where pathological osteoclastogenesis and bone destruction are driven by neoplastic stromal cells. ...Here, we studied if cell cycle fractions within the mononuclear cell compartment of GCTB can predict its progression-free survival (PFS).
154 cases (100 primaries and 54 recurrent) from 139 patients of 40 progression events, was studied using tissue microarrays. Ploidy and in situ cell cycle progression related proteins including Ki67 and those linked with replication licensing (mcm2), G1-phase (cyclin D1, Cdk4), and S-G2-M-phase (cyclin A; Cdk2) fractions; cell cycle control (p21waf1) and repression (geminin), were tested. The Prentice-Williams-Peterson (PWP) gap-time models with the Akaike information criterion (AIC) were used for PFS analysis.
Cluster analysis showed good correlation between functionally related marker positive cell fractions indicating no major cell cycle arrested cell populations in GCTB. Increasing hazard of progression was statistically associated with the elevated post-G1/S-phase cell fractions. Univariate analysis revealed significant negative association of poly-/aneuploidy (p < 0.0001), and elevated cyclin A (p < 0.001), geminin (p = 0.015), mcm2 (p = 0.016), cyclin D1 (p = 0.022) and Ki67 (B56: p = 0.0543; and Mib1: p = 0.0564 –strong trend) positive cell fractions with PFS. The highest-ranked multivariate interaction model (AIC = 269.5) also included ploidy (HR 5.68, 95%CI: 2.62–12.31, p < 0.0001), mcm2 (p = 0.609), cyclin D1 (HR 1.89, 95%CI: 0.88–4.09, p = 0.105) and cyclin A (p < 0.0001). The first and second best prognostic models without interaction (AIC = 271.6) and the sensitivity analysis (AIC = 265.7) further confirmed the prognostic relevance of combining these markers.
Ploidy and elevated replication licensing (mcm2), G1-phase (cyclin D1) and post-G1 phase (cyclin A) marker positive cell fractions, indicating enhanced cell cycle progression, can assist in identifying GCTB patients with increased risk for a reduced PFS.
•In GCTB, neoplastic stromal cells drive pathological osteoclastogenesis, thus their replication affects tumor progression.•Detection of cell cycle regulation proteins can identify cell cycle fractions in GCTB neoplastic stromal cells.•Unsupervised hierarchical cluster analysis revealed no major defect of cell cycle regulation in GCTB mononuclear cells.•An inverse correlation was found between PFS and elevated post-G1/S-phase mononuclear cell fractions in GCTB.•Ploidy and elevated cyclin D1, mcm2 and cyclin A positive mononuclear cell fractions indicated aggressive GCTB behavior.
Objective
Linagliptin, a dipeptidyl peptidase-4 inhibitor, demonstrated cardiovascular and renal safety in type 2 diabetes mellitus (T2DM) patients with established cardiovascular disease (CVD) with ...albuminuria and/or kidney disease in the multinational CARMELINA
®
trial. We investigated the effects of linagliptin in Asian patients in CARMELINA
®
.
Methods
T2DM patients with HbA1c 6.5–10.0% and established CVD with urinary albumin-to-creatinine ratio (UACR) > 30 mg/g, and/or prevalent kidney disease (estimated glomerular filtration rate eGFR 15–< 45 ml/min/1.73 m
2
or ≥ 45–75 with UACR > 200 mg/g), were randomized to linagliptin or placebo added to usual care. The primary endpoint was time to first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (3-point MACE).
Results
Of the 6979 patients, 555 (8.0%) were Asians living in Asia. During a median follow-up of 2.2 years, 3-point MACE occurred in 29/272 (10.7%) and 33/283 (11.7%) of linagliptin and placebo patients, respectively (hazard ratio HR 0.90; 95% confidence interval CI 0.55–1.48), consistent with the overall population (HR 1.02; 95% CI 0.89–1.17;
P
value for treatment-by-region interaction: 0.3349). Similar neutrality in Asian patients was seen for other cardiorenal events including the secondary kidney endpoint of death from renal failure, progression to end-stage kidney disease, or ≥ 40% eGFR decrease (HR 0.96; 95% CI 0.58–1.59). Linagliptin was associated with a nominal decrease in the risk of hospitalization for heart failure (HR 0.47; 95% CI 0.24–0.95). Overall in Asian patients, linagliptin had an adverse event rate similar to placebo, consistent with the overall population.
Conclusions
Linagliptin showed cardiovascular and renal safety in Asian patients with T2DM and established CVD with albuminuria and/or kidney disease.
Small ubiquitin‐like modifier (SUMO) proteins are covalently attached to target proteins to modify their function. SUMO conjugation participates in processes tightly linked to tumorigenesis. Recently ...USPL1 (ubiquitin‐specific peptidase‐like (1) was identified as a SUMO isopeptidase. We report here on the first exploratory study investigating the relationship between genetic variability in USPL1 and breast cancer. Three potentially functional nonsynonymous coding SNPs (rs3742303, rs17609459, rs7984952) were genotyped in 1,021 breast cancer cases and 1,015 controls from the population‐based GENICA study. We took advantage of multiple genotype imputation based on HapMap and the 1000 Genomes Project data to refine the association screening in the investigated region. Public genetic databases were also used to investigate the relationship with USPL1 expression in lymphoblastoid cell lines and breast tissue. Women homozygous for the minor C allele of rs7984952 showed a lower risk of Grade 3 breast tumors compared to TT homozygotes (OR 0.50, 95% CI 0.30‐0.81). Case‐only analyses confirmed the association between rs7984952 and tumor grade (OR 0.60, 95% CI 0.39‐0.93). Imputation results in a 238 kb region around rs7984952 based on HapMap and the 1000 Genomes Project data were similar. No imputed variant showed an association signal stronger than rs7984952. USPL1 expression in tumor breast tissue increased with the number of C alleles. The present study illustrates the contribution of multiple imputation of genotypes using public data repositories to standard genotyping laboratory. The provided information may facilitate the design of independent studies to validate the association between USPL1 rs7984952 and risk of Grade 3 breast tumors.
What's new?
“Genotype imputation” is a statistical technique used in genetic‐association studies. In this study, the authors used imputation to ask whether certain single‐nucleotide polymorphisms (SNPs) correlate with breast cancer. They focused on SNPs in a gene coding for an enzyme called “ubiquitin‐specific peptidase‐like 1” (USPL1), which is involved in the regulation of SUMOylation. The study found that a SNP called “rs7984952” was associated with risk for grade‐3 breast tumors. The results illustrate the value of multiple genotype imputation using public data repositories.
with USPL1 expression in lymphoblastoid cell lines and breast tissue. Women homozygous for the minor C allele of rs7984952 showed a lower risk of Grade 3 breast tumors compared to TT homozygotes (OR 0.50, 95% CI 0.30‐0.81). Caseonly analyses confirmed the association between rs7984952 and tumor grade (OR 0.60, 95% CI 0.39‐0.93). Imputation results in a 238 kb region around rs7984952 based on HapMap and the 1000 Genomes Project data were similar. No imputed variant showed an association signal stronger than rs7984952. USPL1 expression in tumor breast tissue increased with the number of C alleles. The present study illustrates the contribution of multiple imputation of genotypes using public data repositories to standard genotyping laboratory. The provided information may facilitate the design of independent studies to validate the association between USPL1 rs7984952 and risk of Grade 3 breast tumors.
Empagliflozin reduces the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure with preserved ejection fraction, but additional data are needed about its ...effect on inpatient and outpatient heart failure events.
We randomly assigned 5988 patients with class II through IV heart failure with an ejection fraction of >40% to double-blind treatment with placebo or empagliflozin (10 mg once daily), in addition to usual therapy, for a median of 26 months. We prospectively collected information on inpatient and outpatient events reflecting worsening heart failure and prespecified their analysis in individual and composite end points.
Empagliflozin reduced the combined risk of cardiovascular death, hospitalization for heart failure, or an emergency or urgent heart failure visit requiring intravenous treatment (432 versus 546 patients empagliflozin versus placebo, respectively; hazard ratio, 0.77 95% CI, 0.67-0.87;
<0.0001). This benefit reached statistical significance at 18 days after randomization. Empagliflozin reduced the total number of heart failure hospitalizations that required intensive care (hazard ratio, 0.71 95% CI, 0.52-0.96;
=0.028) and the total number of all hospitalizations that required a vasopressor or positive inotropic drug (hazard ratio, 0.73 95% CI, 0.55-0.97;
=0.033). Compared with patients in the placebo group, fewer patients in the empagliflozin group reported outpatient intensification of diuretics (482 versus 610; hazard ratio, 0.76 95% CI, 0.67-0.86;
<0.0001), and patients assigned to empagliflozin were 20% to 50% more likely to have a better New York Heart Association functional class, with significant effects at 12 weeks that were maintained for at least 2 years. The benefit on total heart failure hospitalizations was similar in patients with an ejection fraction of >40% to <50% and 50% to <60%, but was attenuated at higher ejection fractions.
In patients with heart failure with preserved ejection fraction, empagliflozin produced a meaningful, early, and sustained reduction in the risk and severity of a broad range of inpatient and outpatient worsening heart failure events. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.
Empagliflozin reduces the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, with or without diabetes, but additional ...data are needed about the effect of the drug on inpatient and outpatient events that reflect worsening heart failure.
We randomly assigned 3730 patients with class II to IV heart failure with an ejection fraction of ≤40% to double-blind treatment with placebo or empagliflozin (10 mg once daily), in addition to recommended treatments for heart failure, for a median of 16 months. We prospectively collected information on inpatient and outpatient events reflecting worsening heart failure and prespecified their analysis in individual and composite end points.
Empagliflozin reduced the combined risk of death, hospitalization for heart failure or an emergent/urgent heart failure visit requiring intravenous treatment (415 versus 519 patients; empagliflozin versus placebo, respectively; hazard ratio HR, 0.76; 95% CI, 0.67-0.87;
<0.0001). This benefit reached statistical significance at 12 days after randomization. Empagliflozin reduced the total number of heart failure hospitalizations that required intensive care (HR, 0.67; 95% CI, 0.50-0.90;
=0.008) and that required a vasopressor or positive inotropic drug or mechanical or surgical intervention (HR, 0.64; 95% CI, 0.47-0.87;
=0.005). As compared with placebo, fewer patients in the empagliflozin group reported intensification of diuretics (297 versus 414 HR, 0.67; 95% CI, 0.56-0.78;
<0.0001). Additionally, patients assigned to empagliflozin were 20% to 40% more likely to experience an improvement in New York Heart Association functional class and were 20% to 40% less likely to experience worsening of New York Heart Association functional class, with statistically significant effects that were apparent 28 days after randomization and maintained during long-term follow-up. The risk of any inpatient or outpatient worsening heart failure event in the placebo group was high (48.1 per 100 patient-years of follow-up), and it was reduced by empagliflozin (HR, 0.70; 95% CI, 0.63-0.78;
<0.0001).
In patients with heart failure and a reduced ejection fraction, empagliflozin reduced the risk and total number of inpatient and outpatient worsening heart failure events, with benefits seen early after initiation of treatment and sustained for the duration of double-blind therapy. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.
Sodium-glucose cotransporter 2 inhibitors improve outcomes in patients with heart failure with reduced ejection fraction, but additional information is needed about whether glycemic status influences ...the magnitude of their benefits on heart failure and renal events.
Patients with Class II-IV heart failure and a left ventricular ejection fraction ≤40% were randomized to receive empagliflozin (10 mg daily) or placebo in addition to recommended therapy. We prespecified a comparison of the effect of empagliflozin in patients with and without diabetes.
Of the 3730 patients enrolled, 1856 (50%) had diabetes, 1268 (34%) had prediabetes (hemoglobin A1c HbA1c 5.7-6.4%), and 606 (16%) had normoglycemia (HbA1c <5.7%). The risks of the primary outcome (cardiovascular death or hospitalization for heart failure), total hospitalizations for heart failure, and adverse renal outcomes were higher in patients with diabetes, but were similar between patients with prediabetes and normoglycemia. Empagliflozin reduced the risk of the primary outcome in patients with and without diabetes (hazard ratio, 0.72 95% CI, 0.60-0.87 and 0.78 95% CI, 0.64-0.97, respectively,
-interaction=0.57). Patients with and without diabetes also did not differ with respect to the effect of empagliflozin on total hospitalizations for heart failure, on the decline in estimated glomerular filtration rate over time, and on the risk of serious adverse renal outcomes. Among these end points, the effects of the drug did not differ in patients with prediabetes or normoglycemia. When analyzed as a continuous variable, baseline HbA1c did not significantly modify the benefits of empagliflozin on the primary outcome (
-interaction=0.40). Empagliflozin did not lower HbA1c in patients with prediabetes or normoglycemia and was not associated with increased risk of hypoglycemia.
In EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), empagliflozin significantly improved cardiovascular and renal outcomes in patients with heart failure and a reduced ejection fraction, independent of baseline diabetes status and across the continuum of HbA1c. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.
Supplemental Digital Content is available in the text
The MabThera and Involved field Radiotherapy study investigated efficacy and safety of involved field (IF) radiotherapy in combination with the ...anti‐CD20 antibody Rituximab for early‐stage follicular lymphoma (FL) in a prospective, single‐arm multicenter phase 2 design. Eighty‐five stage I–II FL patients received 8 cycles of Rituximab (375 mg/m2) and IF irradiation (30/40 Gy). The primary endpoint was progression‐free survival (PFS) 2 years from treatment start. Secondary endpoints were overall survival (OS), complete response rates, toxicity, quality of life, and minimal residual disease (MRD) response with protocol defined visits up to month 30. For the primary endpoint, PFS at 2 years was 85% for the intention‐to‐treat set. Long‐term data were captured in selected sites and evaluated as post hoc analysis in the per protocol (PP) set: PFS and OS were 78% and 96% at 5 years with a median follow‐up of 66 or 78 months, respectively. There were 17/76 recurrences in the PP set, of which 14 were outside the radiation volume only. MRD analyses revealed a clonal marker in 36% of patients at diagnosis. All but 1 marker positive patients experienced a molecular treatment response. There were 13 serious adverse events (4 related to the therapy) during the first 30 months. IF radiotherapy combined with Rituximab is well tolerated and highly efficient with low rates of recurrence in the first years in early‐stage FL. The efficacy is comparable with more aggressive therapy approaches without compromising the quality of life and maintains for an extended follow‐up of more than 5 years.
Empagliflozin improves outcomes in patients with heart failure with a preserved ejection fraction, but whether the effects are consistent in patients with and without diabetes remains to be ...elucidated.
Patients with class II through IV heart failure and a left ventricular ejection fraction >40% were randomized to receive empagliflozin 10 mg or placebo in addition to usual therapy. We undertook a prespecified analysis comparing the effects of empagliflozin versus placebo in patients with and without diabetes.
Of the 5988 patients enrolled, 2938 (49%) had diabetes. The risk of the primary outcome (first hospitalization for heart failure or cardiovascular death), total hospitalizations for heart failure, and estimated glomerular filtration rate decline was higher in patients with diabetes. Empagliflozin reduced the rate of the primary outcome irrespective of diabetes status (hazard ratio, 0.79 95% CI, 0.67, 0.94 for patients with diabetes versus hazard ratio, 0.78 95% CI, 0.64, 0.95 in patients without diabetes;
=0.92). The effect of empagliflozin to reduce total hospitalizations for heart failure was also consistent in patients with and without diabetes. The effect of empagliflozin to attenuate estimated glomerular filtration rate decline during double-blind treatment was also present in patients with and without diabetes, although more pronounced in patients with diabetes (1.77 in diabetes versus 0.98 mL/min/1.73m
in patients without diabetes;
=0.01). Across these 3 end points, the effect of empagliflozin did not differ in patients with prediabetes or normoglycemia (33% and 18% of the patient population, respectively). When investigated as a continuous variable, baseline hemoglobin A1c did not modify the effects on the primary outcome (
=0.26). There was no increased risk of hypoglycemic events in either subgroup as compared with placebo.
In patients with heart failure and a preserved ejection fraction enrolled in the EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), empagliflozin significantly reduced the risk of heart failure outcomes irrespective of diabetes status at baseline.
URL: https://www.
gov; Unique identifier: NCT03057951.
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