Maternal and Fetal Outcomes of Pregnancies in Women with Atypical Hemolytic Uremic Syndrome.

Atypical HUS (aHUS) is a disorder most commonly caused by inherited defects of the alternative pathway of complement, or the proteins that regulate this pathway, and life-threatening episodes of aHUS can be provoked by pregnancy. We retrospectively and prospectively investigated 27 maternal and fetal pregnancy outcomes in 14 women with aHUS from the Vienna Thrombotic Microangiopathy Cohort. Seven pregnancies (26%) were complicated by pregnancy-associated aHUS (p-aHUS), of which three appeared to be provoked by infection, bleeding, and curettage, and three individuals were considered to have preeclampsia/HELLP syndrome before the definitive diagnosis of p-aHUS was made. Mutations in genes that encode the complement alternative pathway proteins or the molecules that regulate this pathway were detected in 71% of the women, with no relationship to pregnancy outcome. Twenty-one pregnancies (78%) resulted in a live birth, two preterm infants were stillborn, and four pregnancies resulted in early spontaneous abortions. Although short-term renal outcome was good in most women, long-term renal outcome was poor; among the 14 women, four had CKD stage 1-4, five had received a renal allograft, and three were dialysis-dependent at study end. We prospectively followed nine pregnancies of four women and treated six of these pregnancies with prophylactic plasma infusions (one pregnancy resulted in p-aHUS, one intrauterine fetal death occurred, and seven pregancies were uneventful). Our study emphasizes the frequency of successful pregnancies in women with aHUS. Close monitoring of such pregnancies for episodes of thrombotic microangiopathy is essential but, the best strategy to prevent these episodes remains unclear.

Women with homozygous AT deficiency type II heparin-binding site (HBS) are at high risk of pregnancy loss and pregnancy complications.

Data regarding outcome and therapy of pregnancies in patients with homozygous antithrombin (AT) deficiency are very rare. We conducted a retrospective, descriptive investigation with emphasis on the obstetric history of eight women with homozygous AT deficiency heparin-binding site (HBS), who had at least one pregnancy. The aim of the study was to get a better insight into the outcome and identify suitable management procedures of pregnancy in this rare disease. All patients suffered from homozygous AT deficiency caused by the mutation c.391C>T p.Leu131Phe in the AT gene (SERPINC1). The women reported in total 23 pregnancies; one pregnancy was excluded because of induced abortion. We found that only seven out of the 22 analyzed pregnancies ended with a live infant, all of them were born preterm. Among the 15 negative outcomes, seven were early pregnancy losses and eight were intrauterine fetal deaths. We found no clear association between treatment protocols and outcome. Eight pregnancies were not treated at all; all of them ended with pregnancy loss. We conclude that homozygous AT deficiency HBS, a form of severe thrombophilia, is associated with high risk of pregnancy loss and preterm delivery. Rigorous anticoagulation and/or replacement of AT during pregnancy may improve the outcome.

Screening for Fabry Disease by Urinary Globotriaosylceramide Isoforms Measurement in Patients with Left Ventricular Hypertrophy.

BACKGROUND: Left ventricular hypertrophy (LVH) is a frequent echocardiographic feature in Fabry disease (FD) and in severe cases may be confused with hypertrophic cardiomyopathy (HCM) of other origin. The prevalence of FD in patients primarily diagnosed with HCM varies considerably in screening and case finding studies, respectively. In a significant proportion of patients, presenting with only mild or moderate LVH and unspecific clinical signs FD may remain undiagnosed. Urinary Gb3 isoforms have been shown to detect FD in both, women and men. We examined whether this non-invasive method would help to identify new FD cases in a non-selected cohort of patients with various degree of LVH. METHODS AND RESULTS: Consecutive patients older than 18 years with a diastolic interventricular septal wall thickness of ≥12mm determined by echocardiography were included. Referral diagnosis was documented and spot urine was collected. Gb3 was measured by mass spectroscopy. Subjects with an elevated Gb3-24:18 ratio were clinically examined for signs of FD, α-galactosidase-A activity in leukocytes was determined and GLA-mutation-analysis was performed. We examined 2596 patients. In 99 subjects urinary Gb3 isoforms excretion were elevated. In these patients no new cases of FD were identified by extended FD assessment. In two of three patients formerly diagnosed with FD Gb3-24:18 ratio was elevated and would have led to further diagnostic evaluation. CONCLUSION: Measurement of urinary Gb3 isoforms in a non-selected cohort with LVH was unable to identify new cases of FD. False positive results may be prevented by more restricted inclusion criteria and may improve diagnostic accuracy of this method.

Influence of proton pump inhibitors and VKORC1 mutations on CYP2C9-mediated dose requirements of vitamin K antagonist therapy: a pilot study.

Interindividual variations in dose requirements of oral vitamin K antagonists (VKA) are attributed to several factors, including genetic variant alleles of vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9), but also interaction with co-medications. In this context, proton pump inhibitor (PPI)-related alterations of VKA maintenance dose requirements have been published. The present investigation aimed to test for an interaction profile of oral VKA-therapy and PPIs in relation to the CYP2C9 genotype. Median weekly stable VKA dose requirements over 1 year were recorded in 69 patients. Patients were genotyped for CYP2C9*2, CYP2C9*3, VKORC1c.-1639G>A and VKORC1c.174-136C>T and assessed for an association with PPI use and total VKA maintenance dose requirements. PPI users with CYP2C9 genetic variations required significantly lower weekly VKA maintenance doses than those with the wild-type genotype (t-test: P = 0·02). In contrast, in subjects without PPI use, the CYP2C9 genotype had no significant influence on oral VKA dose requirements. Further, the combined CYP2C9/VKORC1 genotype was a significant predictor for VKA dose requirements [linear regression: estimate: -1·47, standard error: 0·58 (P = 0·01)]. In conclusion, in carriers of CYP2C9 gene variations, the interference with the VKA metabolism is modified by PPI co-medication and the VCKORC1 genotype. Preceding knowledge of the genetic profile and the awareness for potentially occurring severe over-anticoagulation problems under PPI co-medication could contribute to a safer and personalized VKA pharmacotherapy.

Pregnancy outcomes of Fabry disease in Austria (PROFABIA)-a retrospective cohort-study.

BACKGROUND: Pregnancy and delivery outcomes in women with Fabry disease are not well described. METHODS: Retrospective cohort-study of women with Fabry disease in Austria using a specific questionnaire and the Austrian Mother-Child Health Passport. RESULTS: Out of a total of 44 enrolled women (median age at study entry 44 years, p25: 30, p75: 51), 86.4% showed signs and symptoms of Fabry disease with an increase in pain burden during pregnancy, primarily in women with moderate pain before pregnancy. Thirty-two of 44 women with Fabry disease reported a total of 70 pregnancies (median age at first pregnancy 24 years, p25: 21, p75: 31), 61 (87.1%) of which resulted in 64 live births including 3 sets of twins, six miscarriages (8.6%) in five women, and three induced abortions (4.3%) in two women. Risk factors for poor maternal and foetal outcomes during pregnancy, overrepresented in our cohort as compared to the general population, were hypertension (n = 10, 16.4%), proteinuria (n = 17, 27.9%) and smoking (n = 24, 39.3%). Preeclampsia was reported in 7 pregnancies (11.5%). Fifty-one (79.7%) children were born at term and 13 (20.3%) were preterm (including one neonatal death), with a median gestational age of 39 weeks (p25: 38, p75: 40) and delivery by C-section in 15 pregnancies (24.6%). Thirteen (20.3%) children presented with low birth weight and 18 (28.1%) were small for their gestational age. In comparison to global and national data-sets, preeclampsia, prematurity, low birth weight, being small for their gestational age as well as inpatient stay were significantly more common in patients with Fabry disease. CONCLUSIONS: Our cohort-study in women with Fabry disease shows an increase of pain burden during pregnancies and clearly points to an increased risk for preeclampsia, prematurity, and neonates small for gestational age. With a substantial number of high-risk pregnancies, neonatal outcomes are somewhat worse in Fabry disease than in the general public. Thus, we provide valuable data enabling informed decision-making in pregnancy counselling for Fabry disease.

Identification of Genetic Risk Factors for Keratinocyte Cancer in Immunosuppressed Solid Organ Transplant Recipients: A Case-Control Study.

Because of long-term immunosuppression, solid organ transplant recipients are at increased risk for keratinocyte cancer. We matched solid organ transplant patients (n = 150), cases with keratinocyte cancers and tumor-free controls, considering the most important risk factors for keratinocyte cancer in solid organ transplant recipients. Using whole exome data of germline DNA from this patient cohort, we identified several genetic loci associated with the occurrence of multiple keratinocyte cancers. We found one genome-wide significant association of a common single nucleotide polymorphism located in EXOC3 (rs72698504). In addition, we found several variants with a p-value of less than 10-5 associated with the number of keratinocyte cancers. These variants were located in the genes CYB561, WASHC1, PITRM1-AS1, MUC8, ABI3BP, and THBS2-AS1. Using whole exome sequencing data, we performed groupwise tests for rare missense variants in our dataset and found robust associations (p < 10-6, Burden Zeggini test) between MC1R, EPHA8, EPO, MYCT1, ADGRG3, and MGME1 and keratinocyte cancer. Thus, overall, we detected genes involved in pigmentation/UV protection, tumor suppression, immunomodulation, intracellular traffic, and response to UV as genetic risk factors for multiple keratinocyte cancers in solid organ transplant recipients. We also grouped selected genes to pathways and found a selection of genes involved in the "cellular response to UV" to be significantly associated with multiple keratinocyte cancers.

Complement-Mediated Thrombotic Microangiopathy Related to COVID-19 or SARS-CoV-2 Vaccination.

Introduction: Infectious diseases and vaccinations are trigger factors for thrombotic microangiopathy. Consequently, the COVID-19 pandemic could have an effect on disease manifestation or relapse in patients with atypical hemolytic syndrome/complement-mediated thrombotic microangiopathy (aHUS/cTMA). Methods: We employed the Vienna TMA cohort database to examine the incidence of COVID-19 related and of SARS-CoV-2 vaccination-related relapse of aHUS/cTMA among patients previously diagnosed with aHUS/cTMA during the first 2.5 years of the COVID-19 pandemic. We calculated incidence rates, including respective confidence intervals (CIs) and used Cox proportional hazard models for comparison of aHUS/cTMA episodes following infection or vaccination. Results: Among 27 patients with aHUS/cTMA, 13 infections triggered 3 (23%) TMA episodes, whereas 70 vaccinations triggered 1 TMA episode (1%; odds ratio 0.04; 95% CI 0.003-0.37, P = 0.01). In total, the incidence of TMA after COVID-19 or SARS-CoV-2 vaccination was 6 cases per 100 patient years (95% CI 0.017-0.164) (4.5/100 patient years for COVID-19 and 1.5/100 patient years for SARS-CoV-2 vaccination). The mean follow-up time was 2.31 ± 0.26 years (total amount: 22,118 days; 62.5 years) to either the end of the follow-up or TMA relapse (outcome). Between 2012 and 2022 we did not find a significant increase in the incidence of aHUS/cTMA. Conclusion: COVID-19 is associated with a higher risk for aHUS/cTMA recurrence when compared to SARS-CoV-2 vaccination. Overall, the incidence of aHUS/cTMA after COVID-19 infection or SARS-CoV-2 vaccination is low and comparable to that described in the literature.

Cumulative UV Exposure or a Modified SCINEXA™-Skin Aging Score Do Not Play a Substantial Role in Predicting the Risk of Developing Keratinocyte Cancers after Solid Organ Transplantation-A Case Control Study.

The risk of keratinocyte cancer is determined by intrinsic and extrinsic factors, which also influence skin aging. Few studies have linked skin aging and UV exposure with the incidence of non-melanoma skin cancer (NMSC). We evaluated signs of actinic skin damage and aging, individual UV burden, and melanocortin-1 receptor (MC1R) variants. A total of 194 organ transplant recipients (OTR) who suffered from NMSC were compared to 194 tumor-free controls matched for gender, age, type of transplanted organ, post-transplantation (TX) period, and immunosuppressive therapy. Compared with the cases, the controls scored higher in all skin aging scores and there were no differences in UV burden except for intentional whole-body UV exposure for specific UV scenarios and periods of life in favor of cases. The number of NMSCs correlated with all types of skin aging scores, the extent of intentional sun exposure, older age, longer post-TX period, shorter interval from TX to first NMSC, and specific MC1R risk groups. Multivariable models revealed a 7.5-fold risk of developing NMSC in individuals with actinic keratosis; 4.1- or 3.6-fold in those with green or blue eyes, respectively; and a 1.9-fold increased risk in the MC1R medium- + high-risk group. In the absence of skin aging contributing to NMSC development, certain MC1R risk types may identify OTR at risk for high tumor burden.

Pregnancy in Complement-Mediated Thrombotic Microangiopathy: Maternal and Neonatal Outcomes.

Rationale & Objective: Pregnancy, delivery, and neonatal outcomes in women with complement-mediated thrombotic microangiopathy (cTMA) have not been well described. A better understanding of these outcomes is necessary to provide women with competent pregnancy counseling. Study Design: Cohort study. Setting and Participants: Women with a history of cTMA and pregnancies enrolled into the Vienna thrombotic microangiopathy cohort. Exposure: New onset or relapses of cTMA. Outcomes: Pregnancy, delivery, and neonatal outcomes of pregnancies in women (a) before cTMA manifestation, (b) complicated by pregnancy-associated cTMA (P-cTMA), and (c) after first manifestation of cTMA or P-cTMA. Analytical Approach: Mixed models were used to adjust the comparison of pregnancy, delivery, and neonatal outcomes between conditions (before, with, and after cTMA) for repeated pregnancies using the mother's ID as random factor. In addition, the fixed factors, mother's age and neonate's sex, were used for adjustment. For (sex-adjusted and age-adjusted) centile outcomes, only the mother's age was used. Adjusted odds ratios were derived from a generalized linear mixed model with live birth as the outcome. Least squares means and pairwise differences between them were derived from the linear mixed models for the remaining outcomes. Results: 28 women reported 74 pregnancies. Despite higher rates of fetal loss before the diagnosis of P-cTMA and preterm births with P-cTMA, most of the women were able to conceive successfully. Neonatal development in all 3 conditions of pregnancies was excellent. Pregnancy and neonatal outcomes were better in women with a pregnancy after the diagnosis of cTMA. Limitations: Although our data set comprises a considerable number of 74 pregnancies, the effective sample size is lower because only 28 mothers with multiple pregnancies were observed. The statistical power for detecting clinically relevant effects was probably low. A recall bias for miscarriages cannot be ruled out. Conclusions: Prepregnancy counseling of women with a history of cTMA can be supportive of their desire to become pregnant.

Bleeding phenotype in nonsevere hemophilia by International Society on Thrombosis and Haemostasis bleeding assessment tool, bleeding frequency, and the joint status.

Background: Although the phenotype of severe hemophilia has been well studied, there are still knowledge gaps in nonsevere hemophilia. Objectives: The objective of this study was to characterize the clinical bleeding phenotype in nonsevere hemophilia and its association with different factor VIII/IX assessments. Methods: This was a cross-sectional, multicenter study to investigate the bleeding phenotype in adults with nonsevere hemophilia by the number of bleeding and joint bleeding in the past 5 years, a joint score, and the International Society on Thrombosis and Haemostasis bleeding assessment tool (ISTH-BAT). Factor levels were analyzed by 1-stage (lowest in history and at study inclusion) and chromogenic assay (at study inclusion). Patients were enrolled between March 2015 and May 2019. Results: Of the 111 patients (86 with mild and 25 with moderate hemophilia), 57 patients (54.8%) reported any bleeding and 24 (23.1%) any joint bleeding in the past 5 years. A joint score ≥1 was found in 44 patients (41.9%), an ISTH-BAT ≥4 in 100 patients (90.1%), and an ISTH-BAT joint item ≥1 in 50 patients (45.0%). Within the ISTH-BAT, muscle and joint bleeds showed the largest difference between mild and moderate hemophilia. The lowest factor VIII/IX level in patients' history was best associated with bleeding outcomes. Factor was inversely associated with joint bleeds (incidence rate ratio 0.88; 95% CI, 0.79-0.98), joint score, and ISTH-BAT (odds ratios from proportional odds ordinal logistic regression 0.92; 95% CI, 0.87-0.97; and 0.89; 95% CI, 0.86-0.93, respectively). Conclusion: The occurrence of joint bleeding differentiated persons with mild and moderate hemophilia. The ISTH-BAT and lowest factor in patients' history provided valuable information of the bleeding phenotype in nonsevere hemophilia.

Eculizumab use in a tertiary care nephrology center: data from the Vienna TMA cohort.

BACKGROUND: Practice patterns of eculizumab use are not well described. We examined indications for, and outcomes of, eculizumab therapy in a tertiary care nephrology center. METHODS: We used the "Vienna TMA cohort" and the hospital pharmacy database at the Medical University of Vienna to identify patients that received eculizumab treatment between 2012 and 2019. We describe clinical characteristics, details of eculizumab use, and outcomes of patients with complement gene-variant mediated TMA (cTMA), secondary TMA (sTMA) and C3 glomerulopathy (C3G). RESULTS: As of December 2019, 23 patients received complement blockade at the Division of Nephrology and Dialysis: 15 patients were diagnosed with cTMA, 6 patients with sTMA and 2 patients with C3G. Causes of sTMA were bone marrow transplantation (n = 2), malignant hypertension, malignant tumor, systemic lupus erythematosus, antiphospholipid syndrome and lung transplantation (each n = 1). Across all indications, patients had a median age of 31 and were predominantly female (78%) and the median duration of treatment was 227 days. Hematological recovery was seen in most patients, while renal response was best in patients with cTMA. Adverse events were recorded in 26%. CONCLUSIONS: In summary, eculizumab is the treatment of choice for cTMA patients that do not respond to plasma therapy. In patients with sTMA and C3G, the response rates to therapy are much lower and therefore, the decision to start therapy needs to be considered carefully.

Targeted temperature management after cardiac arrest is associated with reduced metabolism of pantoprazole - A probe drug of CYP2C19 metabolism.

OBJECTIVE: Targeted temperature management (TTM) is part of standard post-resuscitation care. TTM may downregulate cytochrome enzyme activity and thus impact drug metabolism. This study compared the pharmacokinetics (PK) of pantoprazole, a probe drug of CYP2C19-dependent metabolism, at different stages of TTM following cardiac arrest. METHODS: This prospective controlled study was performed at the Medical University of Vienna and enrolled 16 patients following cardiac arrest. The patients completed up to three study periods (each lasting 24 h) in which plasma concentrations of pantoprazole were quantified: (P1) hypothermia (33 °C) after admission, (P2) normothermia after rewarming (36 °C, intensive care), and (P3) normothermia during recovery (normal ward, control group). PK was analysed using non-compartmental analysis and nonlinear mixed-effects modelling. RESULTS: 16 patients completed periods P1 and P2; ten completed P3. The median half-life of pantoprazole was 2.4 h (quartiles: 1.8-4.8 h) in P1, 2.8 h (2.1-6.8 h, p = 0.046 vs. P1, p = 0.005 vs. P3) in P2 and 1.2 h (0.9 - 2.3 h, p = 0.007 vs. P1) in P3. A two-compartment model described the PK data best. Typical values for clearance were estimated separately for each study period, indicating 40% and 29% reductions during P1 and P2, respectively, compared to P3. The central volume of distribution was estimated separately for P2, indicating a 64% increase compared to P1 and P3. CONCLUSION: CYP2C19-dependent drug metabolism is downregulated during TTM following cardiac arrest. These results may influence drug choice and dosing of similarly metabolized drugs and may be helpful for designing studies in similar clinical situations.

The endocardial binary appearance ('binary sign') is an unreliable marker for echocardiographic detection of Fabry disease in patients with left ventricular hypertrophy.

AIMS: The binary sign, a binary appearance of the left ventricular endocardial border, was suggested to be an echocardiographic hallmark in diagnosing Fabry disease, a hereditary, lysosomal storage disorder. The aim of the present study was to examine the reliability of the binary sign as a screening tool to identify patients with Fabry disease. METHODS AND RESULTS: In total 309 subjects with an interventricular septum (IVS) thickness of ≥12 mm were investigated, of which 14 had a confirmed diagnosis of Fabry disease. Urinary globotriaosylceramide testing was used to rule out Fabry disease in the control group. From all patients echocardiographic images of the apical four-chamber view were analysed offline by a blinded observer. A binary sign was seen in 63 patients (20%), 4 had Fabry disease and 59 belonged to the control group. Although the proportion of binary signs in patients with Fabry disease was higher (29%) compared with the control group (20%) this difference was not statistically significant. The sensitivity and specificity were 28% (95% confidence interval (CI): 12-65%) and 80% (95% CI: 76-85%), respectively. In a logistic regression model adjusted for age, sex and presence of Fabry disease, the occurrence of a binary sign was highly dependent on the IVS thickness (odds ratio: 1.21; 95% CI: 1.1-1.35; P<0.001). CONCLUSION: The endocardial binary appearance is associated with the degree of septal hypertrophy but cannot adequately distinguish between patients with Fabry disease and patients with other causes of left ventricular hypertrophy.

Pregnancies in kidney transplant recipients with complement gene variant-mediated thrombotic microangiopathy.

BACKGROUND: Pregnancies in patients with complement gene variant-mediated thrombotic microangiopathy (cTMA) are challenging, and pregnancies in such patients after kidney transplantation (KTX) are even more so. METHODS: We identified nine pregnancies following KTX of three genetically high-risk cTMA patients enrolled in the Vienna thrombotic microangiopathy cohort. Preventive plasma therapy was used in three pregnancies, and one patient had ongoing eculizumab (ECU) therapy during two pregnancies. RESULTS: Seven out of nine pregnancies (78%) resulted in the delivery of healthy children. The other two included one early abortion at gestational Week 12 during ongoing ECU therapy and one late foetal death at gestational Week 33 + 3, most likely not related to complement dysregulation. Kidney transplant function after delivery remained stable in all but one pregnancy. In the aforementioned case, a severe cTMA flare occurred after delivery despite use of preventive plasma infusions. Kidney graft function could be rescued in this patient by ECU. As such, successful pregnancies can be accomplished in kidney transplant recipients (KTRs) with a history of cTMA. We used preemptive plasma therapy or ongoing ECU treatment in selected cases. CONCLUSIONS: Thus, becoming pregnant can be encouraged in KTRs with native kidney cTMA. Extensive preconception counselling, however, is mandatory in such cases.

Limitations of a calibrated, quantitative APC-R assay under routine conditions.

INTRODUCTION: The aim of this study was to evaluate the Hemoclot Quanti. V-L assay in various clinical conditions. METHODS: We compared the Hemoclot Quanti.V-L assay with DNA testing and with the Pefakit assay in 60 normal (no mutation) vs carriers of the factor V (FV) Leiden mutation (56 heterozygous and three homozygous). We further investigated the interference of lupus anticoagulant on test results in normal and heterozygous individuals and of direct oral anticoagulants (DOACs) at trough and peak levels. Additionally, DOAC-Remove was tested in samples containing DOACs at peak levels. We further evaluated the influence of FV deficiency on this quantitative assay. RESULTS: There was a 100% agreement between the Quant. V-L assay and DNA testing in 60 normal individuals. However, 1.85% of heterozygous and 33% of homozygous samples were falsely classified with the quantitative assay, and no misclassification was observed with the Pefakit assay. Lupus anticoagulant did not influence the test results of the quantitative assay. DOACs also interfered with test results in heterozygous patients, but this effect was prevented with the DOAC-Remove procedure. Even mild FV deficiency affected the test results of the quantitative assay in heterozygous patients leading either to misclassification or the need for subsequent PCR testing. CONCLUSION: The quantitative FV-L assay has several limitations, especially FV deficiency and the presence of DOACs have to be ruled out before running this quantitative assay.

Pharmacogenetics guided anticoagulation.

Advances in the field of human genetics has made it possible to develop prevention strategies for rare genetic disorders and to tailor pharmacotherapeutic approaches to anticoagulation and certain cancers. However, it is still not clear how genetic variations influence the risk and outcome of common diseases. Data from genome-wide association studies is just beginning to answer these questions. In contrast, pharmacogenetic knowledge is frequently not yet translated into clinical practice, even though in some cases, particularly regarding drugs used in treatment of thrombotic diseases (e.g., coumarines, platelet aggregation inhibitors), it is already known that testing for genetic variants prior to pharmacotherapy may help to prevent severe adverse drug reactions or avoid therapeutic failure. In this review, we address the potential impact that genetic alterations in the genes for vitamin K epoxide reductase and some cytochrome P450 variants may have on therapeutic strategies in anticoagulation.

Dysregulation of tissue and serum microRNAs in organ transplant recipients with cutaneous squamous cell carcinomas.

Micro RNAs (miRNAs) are considered as promising biomarkers for skin cancer. By next generation sequencing (NGS), we measured and compared miRNA expression profiles of tumor, peri-lesional, and control tissue of immunosuppressed organ transplant recipients (OTR), suffering from localized cutaneous squamous cell carcinoma (cSCC). Out of 490 miRNAs detected in cSCC tissue, 23 significantly regulated miRNAs were selected for quantitative targeted analysis in serum samples of our patients and control sera from OTR without cSCC. Two onco-miRNAs (mir-1290, mir-1246), previously identified as crucial drivers for tumor initiation and cancer progression, were significantly and exclusively upregulated in both tumor tissue and serum. This finding suggests that miRNA dysregulation in cSCC tissue is reflected in serum even in patients without advanced disease and highly differentiated cSCCs.

Successful Pregnancies During Ongoing Eculizumab Therapy in Two Patients With Complement-Mediated Thrombotic Microangiopathy.

In patients with pregnancy-associated complement gene variant-mediated thrombotic microangiopathy (cTMA), terminal complement blockade is used for treatment of cTMA flares during pregnancy or following delivery. We report pregnancy and delivery outcomes of 2 genetically high-risk patients with cTMA, including 1 kidney transplant recipient, during ongoing eculizumab therapy. In both patients, the first manifestation of cTMA occurred independent from pregnancy. One patient has a history of 2 uneventful pregnancies with prophylactic plasma infusions, and the other has a history of early abortion during long-term eculizumab therapy following kidney transplantation. Overall, pregnancy and delivery outcomes under ongoing eculizumab therapy in our 2 patients with preserved kidney function were excellent as compared with other patients reported in the literature. Eculizumab plasma concentrations were maintained in the therapeutic range during pregnancy and were also detectable in cord blood. Results of cord blood analysis showed deficient complement activity, with low factor and regulator levels, most likely reflecting the age of the neonates and presence of eculizumab in cord blood. In conclusion, pregnancy during ongoing eculizumab treatment appeared to be safe in 2 women with a history of high-risk genetic cTMA and excellent kidney function, even following kidney transplantation.