Management of recurrent Hepatitis C virus (HCV) infection following liver transplantation remains a major challenge. In non-transplanted HCV genotype 1 patients, the introduction of protease ...inhibitor-based regimens has significantly increased the rate of sustained virological response. In this follow-up study, on the first published cohort of post-liver transplant patients treated with telaprevir-based triple therapy, we investigated both efficacy and safety data in follow-up to 24 weeks (SVR 24) after end of treatment (EOT). SVR 24 efficacy and safety data from 9 liver transplant HCV patients being treated with telaprevir, pegylated interferon, and ribavirin, showed 5 of the transplanted patients accomplished the full duration of the 48 week triple therapy. Notable were the 4 patients found to be HCV RNA-negative at week 4, and 8 patients at week 12. Upon EOT, at week 48, 6 patients were HCV RNA-negative. Importantly, at follow-up (24 weeks after EOT), a favorable sustained virological response rate was observed in 5 of these patients with HCV RNA remaining negative, including in one patient who discontinued treatment prematurely. Due to side effects, 2 patients discontinued, 2 suffered from virological breakthrough after the telaprevir treatment phase, and 1 patient had a relapse after EOT. Two thirds of patients exhibited hematological side effects requiring ribavirin dose reductions, administration of erythropoetin, or even blood transfusions. This retrospective analysis provides evidence that--with respect to SVR 24--liver transplant patients suffering from HCV genotype 1 recurrence may benefit from a telaprevir-based triple therapy as this new regimen showed acceptable antiviral efficacy in this small cohort of mostly pre-treated patients. Management of drug-drug interactions is challenging, but feasible. In part severe side effects are frequent during treatment and require therapeutic interventions.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Early detection of severe forms of COVID-19 is absolutely essential for timely triage of patients. We longitudinally followed-up two well-characterized patient groups, hospitalized moderate ...to severe (n = 26), and ambulatory mild COVID-19 patients (n = 16) at home quarantine. Human D-dimer, C-reactive protein (CRP), ferritin, cardiac troponin I, interleukin-6 (IL-6) levels were measured on day 1, day 7, day 14 and day 28. All hospitalized patients were SARS-CoV-2 positive on admission, while all ambulatory patients were SARS-CoV-2 positive at recruitment. Hospitalized patients had higher D-dimer, CRP and ferritin, cardiac troponin I and IL-6 levels than ambulatory patients (
p
< 0.001,
p
< 0.001,
p
= 0.016,
p
= 0.035,
p
= 0.002 respectively). Hospitalized patients experienced significant decreases in CRP, ferritin and IL-6 levels from admission to recovery (
p
< 0.001,
p
= 0.025, and
p
= 0.001 respectively). Cardiac troponin I levels were high during the acute phase in both hospitalized and ambulatory patients, indicating a potential myocardial injury. In summary, D-dimer, CRP, ferritin, cardiac troponin I, IL-6 are predictive laboratory markers and can largely determine the clinical course of COVID-19, in particular the prognosis of critically ill COVID-19 patients.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Fetal tachyarrhythmia can lead to fetal hydrops due to heart failure. Flecainide is often considered as second-line therapy when digoxin monotherapy fails, which is more likely in hydropic fetuses. ...Time to conversion to sinus rhythm (SR) is critical in cases presenting with hydrops.
The aim of this study was to evaluate the efficacy and time to conversion to SR of transplacental treatment, especially flecainide.
This is a retrospective observational study of 46 fetuses with fetal tachyarrhythmia. Treatment was either flecainide (n = 28, 60.9%), digoxin+flecainide combination (n = 4, 8.7%), or digoxin (n = 10, 21.7%). In 4 fetuses (8.7%), no treatment was necessary.
In our study population, 26 of the 32 fetuses (81.2%) that were treated with flecainide as a first-line therapy (flecainide or digoxin+flecainide) converted to SR. The median time to conversion to SR was 3 days (range 1-7 days) with flecainide monotherapy and 11.5 days (range 3-14 days) with a combination therapy. Seventy-two percent (13/18) of hydropic fetuses and 90% (9/10) of nonhydropic fetuses converted to SR when treated with flecainide monotherapy. There was no statistical difference in rates of conversion to SR in hydropic and nonhydropic fetuses (P = .37) or time to conversion to SR in the 2 groups (P = .9). In the majority of the remaining fetuses, there was a partial response with decreased ventricular heart rates that were well tolerated.
Flecainide is highly effective in achieving SR in hydropic and nonhydropic fetuses with supraventricular tachycardia in a median time of 3 days. In our opinion, flecainide should be considered as first-line therapy in fetal supraventricular tachycardia with and without hydrops.
To describe antenatal findings and evaluate prenatal risk parameters for adverse outcome or need for intervention in fetuses with congenital pulmonary airway malformation (CPAM).
In our retrospective ...study all fetuses with a prenatal diagnosis of CPAM detected in our tertiary referral center between 2002 and 2013 were analyzed. Sonographic findings were noted and measurements of mass-to-thorax-ratio (MTR), congenital pulmonary airway malformation volume-ratio (CVR) and observed to expected lung-to head-ratio (o/e LHR) were conducted and correlated to fetal or neonatal morbidity and mortality and/or need for prenatal intervention.
67 fetuses with CPAM were included in the study. Hydropic fetuses were observed in 16.4% (11/67) of cases, prenatal intervention was undertaken in 9 cases; 7 pregnancies were terminated. The survival rate of non-hydropic fetuses with conservatively managed CPAM was 98.0% (50/51), the survival rate for hydropic fetuses with intention to treat was 42.9% (3/7). 10 (18.2%) children needed respiratory assistance. Fetuses with a CVR of <0.91 were significantly less likely to experience adverse outcome or need for prenatal intervention with sensitivity, specificity and positive/negative predictive value of 0.89, 0.71, 0.62 and 0.93, respectively. A MTR (mass-to-thorax-ratio) of < 0.51 had a positive predictive value of 0.54 and a negative predictive value of 0.96 of adverse events with a sensitivity of 0.95 and a specificity of 0.63. The negative predictive value for o/e LHR of 45% was 0.84 with sensitivity, specificity and positive predictive value of 0.73, 0.68 and 0.52, respectively.
The majority of cases with CPAM have a favorable outcome. MTR and CVR are able to identify fetuses at risk, the o/e LHR is less sensitive.
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In primary biliary cholangitis (PBC), antibodies to a peptide of the muscarinic acetylcholine receptor 3 (mAChR3) have been described. Since the mAChR3 is expressed on cholangiocytes and ...mAChR3-signaling is involved in the pathogenesis of chronic inflammatory biliary diseases, we wanted to investigate whether anti-mAChR3-antibodies influence the function of the receptor and the proliferative response of cholangiocytes.
Immunoglobulins were isolated by ammonium sulfate precipitation using sera from patients with PBC (
= 63) and with other chronic liver disorders (
= 150). All immunoglobulins were analyzed by a luminometric assay using Chinese hamster ovary (CHO) cells overexpressing the mAChR3 and cholangiocytes (TFK-1-cells) expressing the receptor constitutively. Cell proliferation was measured by
H-thymidine assay. PBC patients were also analyzed in the follow-up.
Antibodies inhibiting the mAChR3 were found in 49 and 79% of PBC patients using CHO-cells or TFK-1-cells, respectively, but only in up to 26% of controls (
< 0.01). Stimulatory antibodies were hardly detected. Antibody reactivity only marginally changed during the course of the disease, independently of the choice of treatment (ursodeoxycholic acid, immunosuppressive therapy, or no medication). There was no correlation with laboratory, clinical or histological parameters, but the antibodies were more frequently found in PBC patients with a benign course (96%) than in patients with active disease progressing to late stages within 10 years (57%;
< 0.01). Proliferation of cells was not influenced by immunoglobulins from PBC-patients.
Sera from patients with PBC contain inhibitory antibodies to the mAChR3 on cholangiocytes (TFK-1 cells) without influencing TFK-1-cell proliferation. These antibodies were predominantly observed in patients with non-progressing PBC.
To assess the spectrum of different etiologies, the intrauterine course, outcome and possible prognostic markers in prenatally detected fetal growth restriction (FGR) combined with polyhydramnios. ...Retrospective study of 153 cases with FGR combined with Polyhydramnios diagnosed by prenatal ultrasound over a period of 17 years. Charts were reviewed for ultrasound findings, prenatal and postnatal outcome. All cases were categorized into etiological groups and examined for differences. Five etiological groups were identified: chromosomal anomalies (n = 64, 41.8%), complex malformation syndromes (n = 37, 24.1%), isolated malformations (n = 24, 15.7%), musculoskeletal disorders (n = 14, 9.2%) and prenatal non-anomalous fetuses (n = 14, 9.2%). Subgroups showed significant disparities in initial diagnosis of combination of both pathologies, Ratio AFI/ gestational weeks and Doppler ultrasound examinations. Overall mortality rate was 64.7%. Fetuses prenatally assigned to be non-anomalous, showed further complications in 42.9% (n = 6). Fetuses prenatally diagnosed with FGR combined with polyhydramnios are affected by a high morbidity and mortality. Five etiologic groups can be differentiated, showing significant disparities in prenatal and postnatal outcome. Even without recognizable patterns prenatally, long-term-follow up is necessary, as neurodevelopmental or growth delay may occur.
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Data on the prevalence of resistance‐associated substitutions (RASs) and their implications for treatment with direct‐acting antivirals (DAAs) are sparse in European patients with HCV genotype 4. ...This study investigated RASs before and after DAA failure in different genotype 4 subtypes and evaluated retreatment efficacies. Samples of 195 genotype 4‐infected patients were collected in the European Resistance Database and investigated for NS3, NS5A and NS5B RASs. Retreatment efficacies in DAA failure patients were analysed retrospectively. After NS5A inhibitor (NS5Ai) failure, subtype 4r was frequent (30%) compared to DAA‐naïve patients (5%) and the number of NS5A RASs was significantly higher in subtype 4r compared to 4a or 4d (median three RASs vs no or one RAS, respectively, P < .0001). RASsL28V, L30R and M31L pre‐existed in subtype 4r and were maintained after NS5Ai failure. Typical subtype 4r RASs were located in subdomain 1a of NS5A, close to membrane interaction and protein‐protein interaction sites that are responsible for multimerization and hence viral replication. Retreatment of 37 DAA failure patients was highly effective with 100% SVR in prior SOF/RBV, PI/SOF and PI/NS5Ai failures. Secondary virologic failures were rare (n = 2; subtype 4d and 4r) and only observed in prior NS5Ai/SOF failures (SVR 90%). In conclusion, subtype 4r harboured considerably more RASs compared to other subtypes. A resistance‐tailored retreatment using first‐ and second‐generation DAAs was highly effective with SVR rates ≥90% across all subtypes and first‐line treatment regimens.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Herpes simplex virus 1 (HSV‐1) is a frequently unrecognized, yet deadly cause of acute liver failure (ALF). We, therefore, analysed three cases of fatal HSV‐1‐induced ALF. All patients shared ...clinical (extremely elevated transaminases, LDH and AST/LDH ratio < 1) and virological characteristics (ratio of viral load in plasma versus throat swabs: 60–700‐fold, lack of anti‐HSV‐1‐IgG antibodies or low IgG‐avidity during primary infection), which may help to identify patients at risk. Additionally, in vitro chemosusceptibility assays revealed high efficacy of the helicase‐primase inhibitors (HPI), pritelivir and drug‐candidate IM‐250 compared to acyclovir (ACV) using HSV‐1‐isolates from two patients; hence, ACV/HPI‐combinations might offer new therapeutic options for HSV‐induced ALF.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Amniotic fluid (AF) is the first fluid to enter the gastrointestinal tract. Preterm birth is leading to a sudden interruption of AF swallowing. Understanding the composition of amniotic fluid is ...crucial to implement strategies preventing intestinal injury in preterm infants. We hypothesized that the fetal gastrointestinal tract (GIT) is exposed to melatonin and antioxidant enzymes via amniotic fluid throughout prenatal development. Amniotic fluid samples from 76 pregnant women with a median (range) gestational age of 38.0 (14.3–40.1) weeks have been collected. Immediately after birth blood samples were collected from the umbilical vein (n = 53). Median (Interquartile range) melatonin concentration was 30.5 pg/ml (12.7–118.3) and superoxide dismutase 1 (SOD1) concentration was 84 ng/ml (59–123). Extracellular glutathione peroxidase concentration was either not detectable or exceptionally low. We found a positive correlation between melatonin concentration in amniotic fluid and gestational age (Spearman’s correlation coefficient, r = 0.570, p<0.001), while SOD1 concentration in amniotic fluid was inversely correlated with gestational age (r = −0.246, p = 0.032). Compared to serum samples, melatonin concentration was statistically significantly higher in amniotic fluid (p<0.001). Our results indicate that the fetal gastrointestinal system is continuously exposed to melatonin and SOD1 via the amniotic fluid throughout prenatal development.
New therapeutic principles in clinical oncology require the adjustment of response criteria to govern therapy decisions. For advanced hepatocellular carcinoma (HCC) a new era has recently begun by ...the approval of the multikinase inhibitor sorafenib. As a unique feature, HCC usually develops in a diseased liver and current imaging technologies employing classical response criteria have not been prospectively evaluated for this new treatment.
MRI signal patterns were assessed in 21 advanced HCC patients receiving sorafenib. MRI was performed at baseline and in short-term intervals thereafter. Signal changes under therapy on T1WI, T2WI and post-gadolinium images including necrosis volume and its ratio to the entire tumor volume were compared to baseline imaging. To assess the association between the categorical variables, Fisher's exact tests were applied for a statistical analysis. Survey time ranged from 2-65 weeks, and a total of 39 target lesions were evaluated.
Signal abnormalities during sorafenib therapy were disclosed by T1WI and T2WI in 15/21 patients. The predominant tumor signal change was hyperintensity on both T1WI and T2WI. Interestingly, most patients developed MRI signal changes within 4 weeks of therapy; in contrast, two non-responders did not show any signal alteration at follow-up. Under therapy, 16/21 patients presented with new or progressive necrosis, whereas 7 patients achieved temporarily >75% tumor necrosis under sorafenib. Significantly associated MRI variables were increase in T1WI signal and tumor necrosis (p = 0.017) as well as increase of tumor necrosis with an elevated ratio of necrotic to vital tumor areas (p = 0.002). Remarkably, some (3/13) of the patients developing necrotic tumor areas showed a relevant (>20%) increase in tumor volume, which should be considered in the assessment of imaging studies.
As sorafenib induces early intralesional necrosis with profound changes in T1WI/T2WI MRI signal intensities and measurable necrotic tumor areas in most HCC patients, early MRI-based evaluation could pave the way for its rationale and cost-effective application.
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