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CD4+ T cell lymphopenia predicts mortality from Pneumocystis pneumonia in kidney transplant patients
(2020)
Background: Pneumocystis jirovecii pneumonia (PcP) remains a life-threatening opportunistic infection after solid organ transplantation, even in the era of Pneumocystis prophylaxis. The association between risk of developing PcP and low CD4+ T cell counts has been well established. However, it is unknown whether lymphopenia in the context of post-renal transplant PcP increases the risk of mortality. Methods: We carried out a retrospective analysis of a cohort of kidney transplant patients with PcP (n = 49) to determine the risk factors for mortality associated with PcP. We correlated clinical and demographic data with the outcome of the disease. For CD4+ T cell counts, we used the Wilcoxon rank sum test for in-hospital mortality and a Cox proportional-hazards regression model for 60-day mortality. Results: In univariate analyses, high CRP, high neutrophils, CD4+ T cell lymphopenia, mechanical ventilation, and high acute kidney injury network stage were associated with in-hospital mortality following presentation with PcP. In a receiver-operator characteristic (ROC) analysis, an optimum cutoff of ≤200 CD4+ T cells/µL predicted in-hospital mortality, CD4+ T cell lymphopenia remained a risk factor in a Cox regression model. Conclusions: Low CD4+ T cell count in kidney transplant recipients is a biomarker for disease severity and a risk factor for in-hospital mortality following presentation with PcP.
Background: High sensitivity cardiac troponin T (hs-cTnT) and NT-pro-brain natriuretic peptide (NT-pro BNP) are often elevated in chronic kidney disease (CKD) and associated with both cardiovascular remodeling and outcome. Relationship between these biomarkers and quantitative imaging measures of myocardial fibrosis and edema by T1 and T2 mapping remains unknown. Methods: Consecutive patients with established CKD and estimated glomerular filtration rate (eGFR) < 59 ml/min/1.73 m2 (n = 276) were compared to age/sex matched patients with eGFR ≥ 60 ml/min/1.73 m2 (n = 242) and healthy controls (n = 38). Comprehensive cardiovascular magnetic resonance (CMR) with native T1 and T2 mapping, myocardial ischemia and scar imaging was performed with venous sampling immediately prior to CMR. Results: Patients with CKD showed significant cardiac remodeling in comparison with both healthy individuals and non-CKD patients, including a stepwise increase of native T1 and T2 (p < 0.001 between all CKD stages). Native T1 and T2 were the sole imaging markers independently associated with worsening CKD in patients [B = 0.125 (95% CI 0.022–0.235) and B = 0.272 (95% CI 0.164–0.374) with p = 0.019 and < 0.001 respectively]. At univariable analysis, both hs-cTnT and NT-pro BNP significantly correlated with native T1 and T2 in groups with eGFR 30–59 ml/min/1.73 m2 and eGFR < 29 ml/min/1.73 m2 groups, with associations being stronger at lower eGFR (NT-pro BNP (log transformed, lg10): native T1 r = 0.43 and r = 0.57, native T2 r = 0.39 and r = 0.48 respectively; log-transformed hs-cTnT(lg10): native T1 r = 0.23 and r = 0.43, native T2 r = 0.38 and r = 0.58 respectively, p < 0.001 for all, p < 0.05 for interaction). On multivariable analyses, we found independent associations of native T1 with NT-pro BNP [(B = 0.308 (95% CI 0.129–0.407), p < 0.001 and B = 0.334 (95% CI 0.154–0.660), p = 0.002 for eGFR 30–59 ml/min/1.73 m2 and eGFR < 29 ml/min/1.73 m2, respectively] and of T2 with hs-cTnT [B = 0.417 (95% CI 0.219–0.650), p < 0.001 for eGFR < 29 ml/min/1.73 m2]. Conclusions: We demonstrate independent associations between cardiac biomarkers with imaging markers of interstitial expansion, which are CKD-group specific. Our findings indicate the role of diffuse non-ischemic tissue processes, including excess of myocardial fluid in addition to diffuse fibrosis in CKD-related adverse remodeling.
Der Artikel stellt aktuelle stilometrische Studien im Delta-Kontext vor. Diskutiert wird, warum die Verwendung des Kosinus-Abstands zu einer Verbesserung der Erfolgsquote führt; durch Experimente zur Vektornormalisierung gelingt es, die Funktionsweise von Delta besser zu verstehen. Anhand von mittelhochdeutschen Texten wird gezeigt, dass auch metrische Eigenschaften zur Autorschaftsattribution eingesetzt werden können. Zudem wird untersucht, inwieweit die mittelalterliche, nicht-normierte Schreibung die Erfolgsquote von Delta beeinflusst. Am Beispiel von arabisch-lateinischen Übersetzungen wird geprüft, inwieweit eine selektive Merkmalseliminierung dazu beitragen kann, das Übersetzersignal vom Genresignal zu isolieren.
Treatment‐related complications contribute substantially to morbidity and mortality in acute myeloid leukemia (AML) patients undergoing induction chemotherapy. Although AML patients are susceptible to fluid overload (FO) (e.g., in the context of chemotherapy protocols, during sepsis treatment or to prevent tumor lysis syndrome), little attention has been paid to its role in AML patients undergoing induction chemotherapy. AML patients receiving induction chemotherapy between 2014 and 2019 were included in this study. FO was defined as ≥5% weight gain on day 7 of induction chemotherapy compared to baseline weight determined on the day of admission. We found FO in 23 (12%) of 187 AML patients undergoing induction chemotherapy. Application of >100 ml crystalloid fluids/kg body weight until day 7 of induction chemotherapy was identified as an independent risk factor for FO. AML patients with FO suffered from a significantly increased 90-day mortality rate and FO was demonstrated as an independent risk factor for 90-day mortality. Our data suggests an individualized, weight-adjusted calculation of crystalloid fluids in order to prevent FO-related morbidity and mortality in AML patients during induction chemotherapy. Prospective trials are required to determine the adequate fluid management in this patient population.
Hyponatremia is the most common and by far underestimated electrolyte disorder in clinical practice. Especially in elderly patients, treatment of symptomatic hyponatremia is challenging. Herein we describe the case of an octogenarian with recurrent symptomatic hyponatremia due to idiopathic syndrome of inappropriate antidiuretic hormone release (SIADH). Fluid restriction was insufficient to prevent repeated episodes of hyponatremia complicated by falls and coma. After introduction of a low-dose therapy with tolvaptan, serum sodium levels as well as the clinical condition were stable under vaptan therapy, without any relapse for more than six years now. This case demonstrates that long-term tolvaptan treatment for hyponatremia caused by SIADH is safe and well tolerated, even in the elderly.
Introduction: Prognosis of survivors from cardiac arrest is generally poor. Acute kidney injury (AKI) is a common finding in these patients. In general, AKI is well characterized as a marker of adverse outcome. In-hospital cardiac arrest (IHCA) represents a special subset of cardiac arrest scenarios with differential predisposing factors and courses after the event, compared to out-of-hospital resuscitations. Data about AKI in survivors after in-hospital cardiac arrest are scarce. Methods: In this study, we retrospectively analyzed patients after IHCA for incidence and risk factors of AKI and its prognostic impact on mortality. For inclusion in the analysis, patients had to survive at least 48 h after IHCA. Results: A total of 238 IHCA events with successful resuscitation and survival beyond 48 h after the initial event were recorded. Of those, 89.9% were patients of internal medicine, and 10.1% of patients from surgery, neurology or other departments. In 120/238 patients (50.4%), AKI was diagnosed. In 28 patients (23.3%), transient or permanent renal replacement therapy had to be initiated. Male gender, preexisting chronic kidney disease and a non-shockable first ECG rhythm during resuscitation were significantly associated with a higher incidence of AKI in IHCA-survivors. In-hospital mortality in survivors from IHCA without AKI was 29.7%, and 60.8% in patients after IHCA who developed AKI (p < 0.01 between groups). By multivariate analysis, AKI after IHCA persisted as an independent predictor of in-hospital mortality (HR 3.7 (95% CI 2.14–6.33, p ≤ 0.01)). Conclusion: In this cohort of survivors from IHCA, AKI is a frequent finding, with adverse impact on outcome. Therefore, therapeutic strategies to prevent AKI in post-IHCA patients are warranted.
In ∼30% of families affected by colorectal adenomatous polyposis, no germline mutations have been identified in the previously implicated genes APC, MUTYH, POLE, POLD1, and NTHL1, although a hereditary etiology is likely. To uncover further genes with high-penetrance causative mutations, we performed exome sequencing of leukocyte DNA from 102 unrelated individuals with unexplained adenomatous polyposis. We identified two unrelated individuals with differing compound-heterozygous loss-of-function (LoF) germline mutations in the mismatch-repair gene MSH3. The impact of the MSH3 mutations (c.1148delA, c.2319−1G>A, c.2760delC, and c.3001−2A>C) was indicated at the RNA and protein levels. Analysis of the diseased individuals’ tumor tissue demonstrated high microsatellite instability of di- and tetranucleotides (EMAST), and immunohistochemical staining illustrated a complete loss of nuclear MSH3 in normal and tumor tissue, confirming the LoF effect and causal relevance of the mutations. The pedigrees, genotypes, and frequency of MSH3 mutations in the general population are consistent with an autosomal-recessive mode of inheritance. Both index persons have an affected sibling carrying the same mutations. The tumor spectrum in these four persons comprised colorectal and duodenal adenomas, colorectal cancer, gastric cancer, and an early-onset astrocytoma. Additionally, we detected one unrelated individual with biallelic PMS2 germline mutations, representing constitutional mismatch-repair deficiency. Potentially causative variants in 14 more candidate genes identified in 26 other individuals require further workup. In the present study, we identified biallelic germline MSH3 mutations in individuals with a suspected hereditary tumor syndrome. Our data suggest that MSH3 mutations represent an additional recessive subtype of colorectal adenomatous polyposis.
Background: Low anterior resection (LAR) is often performed with diverting loop ileostomy (DLI) for anastomotic protection in patients with rectal cancer. We aim to analyze, if older patients are more prone to a decline in kidney function following creation and closure of DLI after LAR for rectal carcinoma versus younger patients.
Methods: A retrospective cohort study from a database including 151 patients undergoing LAR for rectal carcinoma with DLI was used. Patients were divided in two age groups (Group A: <65 years, n = 79; Group B: ≥65 years, n = 72). For 123 patients undergoing DLI reversal prognostic factors for an impairment of serum creatinine (SCr) and estimated glomerular filtration rate (eGFR) 3 months after DLI reversal was analyzed using a multivariate linear regression analysis.
Results: SCr before LAR(T0) was significant higher in Group B (P = 0.04). Accordingly, the eGFR at T0 in group B was significantly lower (P < 0.001). No patients need to undergo hemodialysis after LAR or DLI reversal.
Age and SCr at T0were able to statistically significant predict an increase in SCr (P<0.001) and eGFR (P=0.001) three months after DLI reversal (The R2 for the overall model was .82 (adjusted R2 = .68).
Conclusion: DLI creation may result in a reduction of eGFR in older patients 3 months after DLI closure. Apart from this, patients do not have a higher morbidity after creation and closure of DLI resulting from LAR regardless of their age.
Background: We analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC).
Patients and methods: ALK-rearranged stage IIIB/IV NSCLC patients were analyzed with next-generation sequencing and fluorescence in situ hybridization analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were carried out to exclude confounders.
Results: Among 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients, median PFS and OS were significantly lower compared with TP53 wildtype patients [PFS 3.9 months (95% CI: 2.4–5.6) versus 10.3 months (95% CI: 8.6–12.0), P < 0.001; OS 15.0 months (95% CI: 5.0–24.9) versus 50.0 months (95% CI: 22.9–77.1), P = 0.002]. This difference was confirmed in all treatment-related subgroups including chemotherapy only [PFS first-line chemotherapy 2.6 months (95% CI: 1.3–4.1) versus 6.2 months (95% CI: 1.8–10.5), P = 0.021; OS 2.0 months (95% CI: 0.0–4.6) versus 9.0 months (95% CI: 6.1–11.9), P = 0.035], crizotinib plus chemotherapy [PFS crizotinib 5.0 months (95% CI: 2.9–7.2) versus 14.0 months (95% CI: 8.0–20.1), P < 0.001; OS 17.0 months (95% CI: 6.7–27.3) versus not reached, P = 0.049] and crizotinib followed by next-generation ALK-inhibitor [PFS next-generation inhibitor 5.4 months (95% CI: 0.1–10.7) versus 9.9 months (95% CI: 6.4–13.5), P = 0.039; OS 7.0 months versus 50.0 months (95% CI: not reached), P = 0.001).
Conclusions: In ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.
Background: While recent data show that crizotinib is highly effective in patients with ROS1 rearrangement, few data is available about the prognostic impact, the predictive value for different treatments, and the genetic heterogeneity of ROS1- positive patients.
Patients and methods: 1137 patients with adenocarcinoma of the lung were analyzed regarding their ROS1 status. In positive cases, next-generation sequencing (NGS) was performed. Clinical characteristics, treatments and outcome of these patients were assessed. Overall survival (OS) was compared with genetically defined subgroups of ROS1-negative patients.
Results: 19 patients of 1035 evaluable (1.8%) had ROS1-rearrangement. The median OS has not been reached. Stage IV patients with ROS1-rearrangement had the best OS of all subgroups (36.7 months, p < 0.001). 9 of 14 (64.2%) patients had at least one response to chemotherapy. Estimated mean OS for patients receiving chemotherapy and crizotinib was 5.3 years. Ten patients with ROS1-rearrangement (52.6%) harbored additional aberrations.
Conclusion: ROS1-rearangement is not only a predictive marker for response to crizotinib, but also seems to be the one of the best prognostic molecular markers in NSCLC reported so far. In stage IV patients, response to chemotherapy was remarkable high and overall survival was significantly better compared to other subgroups including EGFR-mutated and ALK-fusion-positive NSCLC.