University Medical Center Freiburg Research Articles

Longitudinal cardiac dimensions in patients undergoing LVAD implantation.

In conventional left ventricular assist devices (LVAD), a separate outflow graft is sutured to the ascending aorta. Novel device designs may include a transventricular outflow cannula crossing the aortic valve (AV). While transversal ventricular dimensions are well investigated in patients with severe heart failure, little is known about the longitudinal dimensions. These dimensions are, however, particularly critical for the design and development of mechanical circulatory support (MCS) devices with transaortic outflow cannula. In an explorative retrospective cohort study at the University Medical Center Freiburg, Germany, the longitudinal cardiac dimensions of patients undergoing computed tomography angiography (CTA) before and, if available, after LVAD implantation were analyzed. Among others, the following dimensions were assessed: (a) apex to AV, (b) apex to mitral valve, (c) AV to sinotubular junction (STJ), (d) apex to STJ, (e) apex to brachiocephalic artery (BCA), and (f) AV to BCA. In total, 44 LVAD patients (36 male, age 55.8 years, height 1.75 m) were included. The longitudinal cardiac dimensions were (a) 114.5 ± 12.1 mm, (b) 108.0 ± 12.4 mm, (c) 20.9 ± 2.9, (d) 135.4 ± 13.4 mm, (e) 206.0 ± 18.3, and (f) 91.5 ± 9.8 mm. Postoperatively, (a) and (b) decreased by 31.5% and 39.5%, respectively (N = 14). Longitudinal cardiac dimensions may be reduced by up to 40% after LVAD implantation. A better knowledge of these dimensions and their postoperative alterations in LVAD patients may improve surgical planning and help to design MCS devices with transventricular outflow cannula.

Investigation of Maximum Monosyllabic Word Recognition as a Predictor of Speech Understanding with Cochlear Implant

Background: The cochlear implant (CI) is an established treatment option for patients with inadequate speech understanding and insufficient aided scores. Nevertheless, reliable predictive models and specific therapy goals regarding achievable speech understanding are still lacking. Method: In this retrospective study, 601 cases of CI fittings between 2005 and 2021 at the University Medical Center Freiburg were analyzed. We investigated the preoperative unaided maximum word recognition score (mWRS) as a minimum predictor for post-interventional scores at 65 dB SPL, WRS65(CI). The WRS65(CI) was compared with the preoperative-aided WRS, and a previously published prediction model for the WRS65(CI) was reviewed. Furthermore, the effect of duration of hearing loss, duration of HA fitting, and etiology on WRS65(CI) were investigated. Results: In 95.5% of the cases, a significant improvement in word recognition was observed after CI. WRS65(CI) achieved or exceeded mWRS in 97% of cases. Etiology had a significant impact on WRS65(CI). The predicted score was missed by more than 20 percentage points in 12.8% of cases. Discussion: Our results confirmed the minimum prediction via mWRS. A more precise prediction of the expected WRS65(CI) is possible. The etiology of hearing loss should be considered in the indication and postoperative care to achieve optimal results.

Clinical phenotype and outcome of persistent SARS-CoV-2 replication in immunocompromised hosts: a retrospective observational study in the Omicron era

PurposeThis study aims to describe clinical, virological and radiological characteristics as well as treatment strategies and outcomes of immunocompromised patients with persistent SARS-CoV-2 replication.MethodsWe performed a retrospective cohort study of immunocompromised patients at the University Medical Center Freiburg between 01/2022 and 05/2023. Patients with substantial immunosuppression and persistent SARS-CoV-2 detection (Ct-value < 30 after 14 days) were included.Results36 patients in our cohort reported mainly fever, dyspnoea or continuous cough. Viral load was significantly higher in concurrent samples taken from the lower respiratory tract (Ct-value = 26) than from the upper respiratory tract (Ct-value = 34). Time of detectable viral RNA after start of antiviral treatment was shorter in patients receiving two antivirals (median 15 days vs. 31 days with one antiviral agent). Short-course antiviral therapy (≤ 5 days) was less efficient in reduction of symptoms and viral load than prolonged therapy > 10 days. In 30% (8/27) of patients with repeated CT scans, we found the emergence of chronic pulmonary changes, which were more frequently in patients with B cell depletion (37%, 7/19) compared to patients with organ transplantation (12%, 2/17).ConclusionOngoing SARS-CoV-2 replication in the lower respiratory tract is a relevant differential diagnosis in patients with severe immunosuppression and continuous cough, fever or dyspnoea even if nasopharyngeal swabs test negative for SARS-CoV-2. Especially in B cell-depleted patients, this may lead to inflammatory or fibrotic-like pulmonary changes, which are partially reversible after inhibition of viral replication. Antiviral therapy seems to be most effective in combination and over a prolonged period of time of > 10 days.Trial registration numberDRKS 00027299.

Early Prediction of Treatment Response By Circulating Tumor DNA Profiling in Patients with Diffuse Large B-Cell Lymphoma Receiving CAR T-Cell Therapy

Introduction Patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) are characterized by a particularly poor prognosis. Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has improved outcomes of patients with r/r DLBCL, yet a substantial proportion of patients still experiences relapse or progression after CAR T-cell treatment. Identifying patients at high risk of CAR T-cell therapy resistance or future lymphoma progression remains challenging. Here, we explored the value of circulating tumor DNA (ctDNA) as a prognostic biomarker at baseline and early into treatment in DLBCL patients undergoing standard-of-care CAR T-cell therapy, without the need for matched tumor genotypes. We further investigated associations between ctDNA and other known clinical risk factors. Methods We applied targeted next-generation sequencing (NGS) to a total of 53 samples from r/r DLBCL patients receiving CAR T-cell therapy (axicabtagene ciloleucel and tisagenlecleucel, n=16) at the University Medical Center Freiburg (Germany), using a modified version of the AVENIO ctDNA analysis workflow (Roche; Research Use Only) that covered ~314kb and targeted 466 distinct genes recurrently mutated in DLBCL (based on the CAPP-Seq workflow, Kurtz DM et al. J Clin Oncol 2018). Tumor genotypes were assessed noninvasively from plasma samples obtained at baseline before lymphodepletion with matched germline controls. Concentrations of ctDNA were quantified at baseline and early after CAR T-cell therapy at day 7-10. Initial treatment response was assessed by conventional PET-CT obtained 4-6 weeks after treatment based on the Lugano criteria. Results At baseline prior to lymphodepletion, we detected somatic mutations in 100% of plasma samples by noninvasive genotyping, with a median of 19.5 mutations per patient (range: 3-97). The most frequently mutated genes were IGHV, IGLL5, BCL2, MYC, BTG1, CREBBP, and TP53. Patients with high baseline ctDNA concentrations (mean allele frequency [AF] &amp;gt;= 1%) showed shorter progression-free survivial (PFS) and overall survival (OS) than patients with ctDNA levels below this threshold (median PFS: 86.5 days vs. not reached, p=0.04, HR: 6.3, 95% CI: 1.7-23.6; median OS: 219 days vs. not reached, p=0.048, HR: 4.1, 95% CI 1.0-16.6, Figure 1). Pretreatment ctDNA levels were significantly correlated with LDH concentrations ( p=0.049, r=0.5). We further found significantly higher ctDNA concentrations in patients with transformed DLBCL (vs. non-transformed, p=0.008) and in those with 3 or more prior treatment lines (vs. 1-2, p=0.04). At day 7-10 after CAR T-cell therapy, ctDNA levels dropped a median of 10-fold compared to the pretreatment time point ( p=0.008). Patients achieving a complete (CMR) or partial metabolic response (PMR) by PET-CT after 4-6 weeks showed a significant decrease of ctDNA ( p=0.001), while those with a stable (SD) or progressive disease (PD) had no significant ctDNA reduction at day 7-10 after CAR T-cell infusion. Vice versa, while 100% of patients with a &amp;gt;1.5-log-fold drop of ctDNA level between the pretreatment and interim time point revealed a CMR or PMR in early PET-CT scans, only 62% of patients with a smaller ctDNA decline responded to treatment according to PET-CT. Conclusions Our data suggests, together with previously published studies (Sworder BJ et al., Cancer Cell, 2023; Frank MJ et al. J Clin Oncol, 2021), that ctDNA profiling may allow robust noninvasive genotyping, accurate risk-stratification, and early prediction of clinical outcomes in r/r DLBCL patients undergoing CAR T-cell therapy. Although limited by small sample size, this pilot study highlights a potential future role of ctDNA measurements for personalized treatment selection and guidance in clinical trials.

Impact of a Multidisciplinary Head and Neck Tumor Board on Treatment and Survival in Laryngeal Carcinoma.

Pretherapeutic discussion in the head and neck tumor board (HNT) has been mandatory at the University Medical Center Freiburg since 01/2015, and it is intended to contribute to a survival benefit through interdisciplinary decision making. Prior to 2015, an optional HNT existed in which mainly advanced tumor stages were discussed. The aim of this study was to determine the effect of a pretherapeutic HNT on treatment and survival in laryngeal cancer. A retrospective data analysis of 412 laryngeal carcinoma patients treated at the Head and Neck Cancer Center of the University Medical Center Freiburg between 01/2010 and 12/2020 was conducted. Differences regarding TNM status, UICC classification, tumor localization, gender and age at initial diagnosis, recurrence, secondary tumors, therapy, 5-year survival, and 5-year recurrence-free survival (5YSR/5Y-RFS) were assessed for therapy initiation with or without a pretherapeutic HNT. In total, 314 patients underwent a pretherapeutic HNT, and 98 received therapy initiation without an HNT. The HNT group showed significantly more advanced T stages and UICC classifications (p < 0.001; p = 0.003) and more frequent primary chemo/radiotherapy (p < 0.001). There was no significant difference regarding 5YSR (43 vs. 47 months, p = 0.96) or 5Y-RFS (48 vs. 52 months, p = 0.16). The time between initial diagnosis and therapy initiation was significantly longer when an HNT was performed (38 vs. 20 days, p = 0.008). The HNT group showed significantly more advanced tumor stages, suggesting that even before it became mandatory, it was frequently used for interdisciplinary case discussion in more complex cases. Due to the small number of T3/4 patients in the non-HNT group, a survival advantage of an HNT cannot be validly demonstrated in our study. However, the HNT led to broader patient counselling regarding their therapy options. At the same time, a significant delay in therapy initiation could be seen, suggesting that workflows between diagnosis, HNT presentation, and therapy initiation should be optimized.

Long-Term Follow-up of AML Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation after Primary Induction Failure

Introduction Allogeneic hematopoietic stem cell transplantation (HCT) is the standard consolidation treatment for most patients with adverse-risk acute myeloid leukemia (AML). Achieving complete remission (CR) before HCT has been associated with improved clinical outcomes. Thus, AML patients with primary induction failure (PIF) are often not considered for immediate allogeneic HCT, despite being the only curative option. Most recently, Stelljes et al. reported similar survival rates after a median follow-up of 37 months for relapsed/refractory AML patients who either proceeded directly to allogeneic HCT or underwent intensive remission induction prior to HCT within the ASAP trial (Stelljes et al., ASHAnnual Meeting 2022). Yet, the effect of immediate allogeneic HCT in this clinical setting for long-term prognosis is still largely unclear. Thus, we explored long-term clinical outcomes of AML patients with PIF undergoing allogeneic HCT with active disease at our institution over a period of 30 years between 1989 and 2019, and investigated associations with molecular and clinical features. Methods We retrospectively analyzed AML patients undergoing allogeneic HCT after PIF at the University Medical Center Freiburg (Germany) between 1989 and 2019. PIF was defined as never achieving CR during induction or re-induction, assessed either by cytomorphology or molecular measurable residual disease as defined by the NCI (Version 23.06d, Code C70622). All clinical examinations and laboratory analyses were performed as part of standard clinical care. Statistical analyses were performed considering the entire cohort as well as distinct transplant periods: i) 1989-2000, ii) 2001-2010, and iii) 2011-2019. Primary endpoints were disease-free survival (DFS) and overall survival (OS). Other endpoints were time to relapse and time to non-relapse mortality (NRM). Results We included 220 patients in this retrospective single-center study, with a median follow-up of 8.5 years (range: 0.06-25.4). Median age of patients was 55 years (range: 20-75), increasing over time as reduced toxicity conditioning became more established (1989-2000: 13.9%; 2011-2019: 61.8%). Patients received in median two lines of treatment before HCT (range: 1-6). Blast count in bone marrow before initiation of allogeneic HCT was in median 36% (range: 0-95%). Molecular risk was assessed in 63.2% of patients, while genetic information was missing in 36.8% of AML cases. 39.8% of AML patients were disease-free after 1 year, 25.2% after 5 and 18.7% after 10 years from allogeneic HCT (Fig. 1A). 206 patients (93.6%) were alive at day 30 after HCT and 59 patients (26.8%) were alive at the time of the analysis. Median OS was 1.05 years, with 1-year, 5-year, and 10-year OS rates being 50.4%, 29.8%, and 21.6%, respectively (Fig. 1A). Survival rates were largely stable over time. 5-year OS in patients treated between 1989-2000 was 28.7%, in those receiving HCT between 2001 and 2010 28.7%, and 30.3% in patients transplanted between 2011 and 2019 (Fig. 1A). NRM was 29.3% after 5 years and 32.5% after 10 years (Fig. 1A). Over time, relapse rates decreased, with 5-year relapse rates of 45.7% between 1989 and 2000 and 33.3% between 2011 and 2019 (Fig. 1A). The main cause of death after HCT was AML progression/relapse (57.8%), while infections (19.3%), GvHD (11.2%), and treatment-related toxicity (8.4%) were leading causes of NRM. In Cox regression analyses incorporating known molecular and clinical risk factors, poor performance status (ECOG &amp;gt; 1 vs. 0-1; DFS: p=0.001, HR 2.26, 95% CI 1.37-3.73; OS: p=8*10 -5, HR 2.76, 95% CI 1.66-4.58,), adverse genetic risk at AML diagnosis (vs. intermediate/favorable risk; DFS: p=0.03, HR 1.6, 95% CI 1.1-2.4; OS: p=0.01, HR 1.7, 95% CI 1.1-2.6), and long diagnosis-to-HCT interval (DFS: p=0.01, HR 2.7, 95% CI 1.2-6.1; OS: p=0.005, HR 3.1, 95% CI 1.4-6.8) were strongly and independently associated with unfavorable DFS and OS (Fig. 1B). Conclusion We here demonstrated that immediate allogeneic HCT in AML patients with active disease represents a valid alternative to intensive remission induction prior to HCT and provides long-term survival and cure in a significant proportion of patients, suggesting to proceed with allogeneic HCT in patients with refractory disease as soon as a donor is available. The benefit of hypomethylating agents and venetoclax therapy prior to allogeneic HCT remains to be elucidated.

App-Controlled Treatment Monitoring and Support for Patients With Head and Neck Cancer Undergoing Radiotherapy: Results From a Prospective Randomized Controlled Trial.

Head and neck cancers (HNCs) are very common malignancies, and treatment often requires multimodal approaches, including radiotherapy and chemotherapy. Patients with HNC often display a high symptom burden, both due to the disease itself and the adverse effects of the multimodal therapy. Close telemonitoring of symptoms and quality of life during the course of treatment may help to identify those patients requiring early medical support. The App-Controlled Treatment Monitoring and Support for Patients With Head and Neck Cancer (APCOT) trial aimed to investigate the feasibility of integrating electronic patient-reported outcomes (ePROs) in the treatment surveillance pathway of patients with HNC during the course of their radiotherapy. Additionally, the influence of app-based ePRO monitoring on global and disease-specific quality of life and patient satisfaction with treatment was assessed. Patients undergoing radiotherapy for histologically proven HNCs at the Department of Radiation Oncology, University Medical Center Freiburg, Germany, were enrolled in this trial and monitored by weekly physician appointments. Patients were randomized between additional ePRO monitoring on each treatment day or standard-of-care monitoring. Feasibility of ePRO monitoring was defined as ≥80% of enrolled patients answering ≥80% of their daily app-based questions. Quality of life and patient satisfaction were assessed by the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ-C30), the head and neck cancer module (H&N35), and the validated Patient Satisfaction Questionnaire Short Form (PSQ-18) at the completion of treatment and compared between trial arms. A total of 100 patients were enrolled in this trial, and 93 patients were evaluable. All patients (100%) in the experimental arm answered ≥80% of the ePRO questions during treatment, reaching the predefined threshold for the feasibility of ePRO monitoring (P<.001 in the binomial test). No clinical or patient-specific factor was found to influence feasibility. Global health and most domains of the general quality of life were comparable between trial arms, but an increased HNC-specific symptom burden was reported by patients undergoing ePRO surveillance. ePRO monitoring resulted in improved patient satisfaction regarding interpersonal manners (P=.01), financial aspects (P=.01), and time spent with a doctor (P=.01). This trial demonstrated the feasibility of incorporating daily app-based ePRO surveillance for patients with HNC undergoing radiotherapy. Our data, for the first time, demonstrate that telemonitoring in this setting led to increased reporting of HNC-specific symptom burden and significantly improved several domains of patient satisfaction. Further analyses are needed to assess whether our findings hold true outside the context of a clinical trial. German Clinical Trials Register DRKS00020491; https://drks.de/search/en/trial/DRKS00020491.

CARC6: Longitudinal Cardiac Dimensions in Patients Undergoing Left Ventricular Assist Device Implantation

Background: In conventional left ventricular assist devices (LVADs) a separate outflow graft is sutured to the aorta. Novel device designs may include intracardiac outflow grafts crossing the aortic valve. While transversal ventricular dimensions are well investigated in patients undergoing LVAD implantation, little is known about the longitudinal cardiac dimensions. These dimensions are, however, particularly critical for the design of LVADs with transaortic outflow graft. We characterized the longitudinal dimensions in patients with dilated cardiomyopathy prior to LVAD implantation. Methods: In an explorative retrospective cohort study at the University Medical Center Freiburg, Germany, the longitudinal cardiac dimensions in patients undergoing computed tomography angiography (CTA) between 06/2002 and 06/2021 prior to LVAD implantation were analyzed. In 14 patients, a postoperative CTA was performed. Figure A and B show the measured dimensions: (a) apex to aortic valve (AV), (b) apex to mitral valve, (c) aortic valve to sinotubular junction (STJ), (d) apex to sinotubular junction, (e) apex to brachiocephalic artery (BCA) and (f) aortic valve to brachiocephalic artery. Correlation between these dimensions and body height was calculated (R, Austria). Results: In total, 44 patients (36 male, age 55.8 years, height 1.75 m) were included. The longitudinal cardiac dimensions measured were (a) 114.5 ± 11.9 mm, (b) 108.0 ± 12.3 mm, (c) 20.9 ± 2.8, (d) 135.4 ± 13.2 mm, (e) 206.0 ± 18.1 and (f) 91.5 ± 9.7 mm. Among LVAD patients these dimensions varied by 12 mm (c) to 72 mm (e). As shown in Figure C, a moderate correlation was found between the selected dimensions and body height. Postoperatively, the distances (a) and (b) decreased by 31.5 and 39.5 %, respectively (n = 14). Conclusions: The analysis presents data about the preoperative longitudinal cardiac dimensions in patients with dilated cardiomyopathy undergoing LVAD implantation, and provides an estimate about changes after LVAD support. A better knowledge of these dimensions and their postoperative alterations may improve surgical planning of patients undergoing LVAD implantation, and helps to design assist devices with transaortic outflow graft.

Low-dose AtropIne for Myopia Control in Children (AIM): protocol for a randomised, controlled, double-blind, multicentre, clinical trial with two parallel arms

IntroductionMyopia is a major cause of degenerative eye disease and increases the risk of secondary visual impairment. Mitigating its progression therefore has great potential of clinically relevant benefit as shown...

Early SARS-CoV-2 infection: Platelet-neutrophil complexes and platelet function

BackgroundConflicting results have been reported on platelet activity ex vivo and responsiveness in vitro among patients with COVID-19 with or without thromboembolic complications. ObjectivesTo assess platelet reactivity in patients with moderate disease at early stages of COVID-19. MethodsWe performed a prospective, descriptive analysis of 100 consecutive patients presenting with suspected SARS-CoV-2 infection at University Medical Center Freiburg during the first or second wave of the pandemic. Following polymerase chain reaction testing and compliance with study inclusion criteria, 20 SARS-CoV-2–positive and 55 SARS-CoV-2–negative patients (serving as patient controls) were enrolled. In addition, 15 healthy subjects were included. Platelet reactivity was assessed using whole-blood impedance aggregometry and flow cytometry in response to various agonists. ResultsPlatelet aggregation was significantly impaired in the patients with COVID-19 compared with that in the patient controls or healthy subjects. The reduced platelet responsiveness in the patients with COVID-19 was associated with impaired activation of GPIIb/IIIa (αIIbβ3). In contrast, low expression of P-selectin at baseline and intact secretion upon stimulation in vitro suggest that no preactivation in vivo, leading to “exhausted” platelets, had occurred. The proportion of circulating platelet-neutrophil complexes was significantly higher in the patients with COVID-19 (mean ± SD, 41% ± 13%) than in the patient controls (18% ± 7%; 95% CI, 11.1-34.1; P = .0002) or healthy subjects (17% ± 4%; 95% CI, 13.8-33.8; P < .0001). An analysis of neutrophil adhesion receptors revealed upregulation of CD11b (α-subunit of αMβ2) and CD66b (CEACAM8) but not of CD162 (PSGL-1) in the patients with COVID-19. ConclusionDespite reduced platelet responsiveness, platelet-neutrophil complexes are increased at early stages of moderate disease. Thus, this cellular interaction may occur during COVID-19 without preceding platelet activation.

Need for Further Training for Function Holders of Cancer Self-Help Organizations

As part of the Center for Competence Development in Cancer Self-Help at the University Medical Center Freiburg, an analysis of the need for training and education was conducted among the member organizations of the House of the Cancer Patient Support Associations of Germany (HKSH). The online survey took place from February to April 2021 and was completed by functionaries at various organization levels and group members. In a questionnaire developed together with self-help representatives 19 potential training topics were ranked in terms of importance. In addition, it was indicated whether the respective topic was perceived as sufficiently covered by already existing qualification offers. Using a forced-choice approach, respondents finally named the five most important topics for them. The topics that a particularly high proportion of the N=293 respondents identified as "very important" and which at the same time were perceived as inadequately addressed by existing qualification offers were dealing with stressful issues (e. g. relapse, metastases, dying), recruiting new members and successors for association tasks, socio-legal aspects, as well as conversational and communication skills. In the prioritization of the five most important topics, the first three topics were named again, with dealing with excessive demands and assistance for self-care/burnout prevention following in fourth place and in the fifth place the topics of knowledge in dealing with complementary medicine and knowledge of professional care structures in oncology, each with the same number of votes. There was a clear need for a broad range of training topics that goes beyond the existing offers of the cancer self-help organizations. Through the needs analysis, the topics could be identified which are prioritized as training topics across all ten member organizations of the HKSH. Based on this needs assessment, the respective training courses can be prioritized and implemented in cooperation with the patient representatives of the HKSH.

Complaints and clinical findings six months after COVID-19: outpatient follow-up at the University Medical Center Freiburg

Increasing evidence suggests that some patients suffer from persistent symptoms for months after recovery from acute COVID-19. However, the clinical phenotype and its pathogenesis remain unclear. We here present data on complaints and results of a diagnostic workup of patients presenting to the post-COVID clinic at the University Medical Center Freiburg. Retrospective data analysis of persistently symptomatic patients presenting to our clinic at least 6 months after onset of acute COVID-19. All patients were assessed by a doctor and routine laboratory analysis was carried out. Quality of life was assessed using SF-36 questionnaire. In case of specific persisting symptoms, further organ-specific diagnostic evaluation was performed, and patients were referred to respective departments/specialists. 132 Patients (58 male, 74 female; mean age 53.8 years) presented to our clinic at least 6 months after COVID-19. 79 (60 %) had been treated as outpatients and 53 (40 %) as inpatients. Most common complaints were persistent fatigue (82 %) and dyspnea on exertion (61 %). Further common complaints were impairments of concentration (54 %), insomnia (43 %), and impairments of smell or taste (35 %). Quality of life was reduced in all sections of the SF-36 questionnaire, yielding a reduced working capacity. Significant pathological findings in laboratory, echocardiographic and radiological work-up were rare. Impairments in lung function tests were more common in previously hospitalized patients. Patients presenting 6 months after onset of acute COVID-19 suffer from a diverse spectrum of symptoms with impaired quality of life, also referred to as Long COVID or Post-Acute Sequelae of SARS-CoV-2 infection (PASC). Further research is needed to determine the frequency of these post-COVID syndromes and their pathogenesis, natural course and treatment options. Evaluation and management should be multi-disciplinary.

247.5: Magnetic Resonance Imaging of Renal Oxygen Metabolism by Means of 17-O Administration During Ex Vivo Organ Perfusion

Background: Renal normothermic machine perfusion (NMP) is a method studied for pre-transplant evaluation of kidney graft quality. This technique creates an isolated near-physiological environment by circulating a perfusion solution at body temperature with oxygen and nutrients. However, reliable ex vivo organ viability markers are still lacking. Magnetic resonance imaging (MRI) has recently been applied as a new rapid non-invasive technique to study renal viability ex vivo. Oxygen-17 (17O) offers a novel sensitive assessment of oxidative metabolism. In our MRI compatible perfusion setup, we aimed to study oxygen metabolism during NMP. Methods: Three viable porcine kidneys were retrieved at a slaughterhouse and preserved by oxygenated hypothermic machine perfusion. In addition, one discarded human kidney was shipped to our center in static cold storage. Subsequently each kidney was perfused for 4 hours at 37°C inside a clinical 3T MRI scanner. Blood gas, glucose, and electrolytes were periodically monitored. Anatomical T2-weighted images and T2* maps were obtained using a 1H 18Ch-bodyflex coil and dynamic radial 17O MR images were acquired using a 17O Tx/Rx loop coil and a 17O 3D-UTE sequence. The 17O perfusion protocol consisted of 4 minutes of deoxygenation with nitrogen gas, 8 minutes of 70%-enriched 17O2 gas infusion at 0.1L/min, and 20 minutes of subsequent carbogen (95% O2/ 5% CO2) oxygenation. 17O-magnitude data was analyzed dynamically over time. To study the 17O-related global signal change, a region of interest was defined in the anatomical T2-weighted images and co-registered to the dynamic 17O-magnitude data. Results: Porcine kidneys showed homogenous perfusion with increased H217O-concentration in the medulla and decreased concentration in the cortex. The discarded human kidney demonstrated a focused concentration in the medial side of the lower pole with little to no signal intensity in the upper pole and the majority of the cortex, which was consistent with its reason for discard (wide cist in the lateral pole). Six minutes after administration of 17O2-gas, a rapid H217O signal increase was observed until minute 20 of the dynamic acquisition, where saturation was reached and the signal plateaued. Overall, an enhancement of 16% between the first and last data point was measured. Conclusion: In these pilot experiments, we were able to quantify the regional production of H217O in time, both in porcine and human kidneys. The slope of occurrence of H217O may be an interesting ex vivo organ viability biomarker, immediately related to the rate of oxidative metabolism in the organ and hence organ quality. As the kidney is in an ex vivo setting, any increase in H217O-concentration must be the direct result of metabolism within the organ. The current setup has great potential for investigating renal oxygen metabolism ex vivo. NUKEM Isotopes GmbH, Alzenau, Germany. Department of Radiology, University Medical Center Freiburg, Freiburg, Germany.

Severe hyperlactatemia in unselected surgical patients: retrospective analysis of prognostic outcome factors

BackgroundEtiology of hyperlactatemia in ICU patients is heterogeneous—septic, cardiogenic or hemorrhagic shock seem to be predominant reasons. Multiple studies show hyperlactatemia as an independent predictor for ICU mortality. Only limited data exists about the etiology of hyperlactatemia and lactate clearance and their influence on mortality. The goal of this single-center retrospective study, was to evaluate the effect of severe hyperlactatemia and reduced lactate clearance rate on the outcome of unselected ICU surgical patients.MethodsOverall, 239 surgical patients with severe hyperlactatemia (> 10 mmol/L) who were treated in the surgical ICU at the University Medical Center Freiburg between June 2011 and August 2017, were included in this study. The cause of the hyperlactatemia as well as the postoperative course and the patient morbidity and mortality were retrospectively analyzed. Lactate clearance was calculated by comparing lactate level 12 h after first measurement of > 10 mmol/L.ResultsThe overall mortality rate in our cohort was 82.4%. Severe hyperlactatemia was associated with death in the ICU (p < 0.001). The main etiologic factor was sepsis (51.9%), followed by mesenteric ischemia (15.1%), hemorrhagic shock (13.8%) and liver failure (9.6%). Higher lactate levels at ICU admission were associated with increased mortality (p < 0.001). Lactate clearance after 12 h was found to predict ICU mortality (ANOVA p < 0.001) with an overall clearance of under 50% within 12 h. The median percentage of clearance was 60.3% within 12 h for the survivor and 29.1% for the non-survivor group (p < 0.001).ConclusionLactate levels appropriately reflect disease severity and are associated with short-term mortality in critically ill patients. The main etiologic factor for surgical patients is sepsis. When elevated lactate levels persist more than 12 h, survival chances are low and the benefit of continued maximum therapy should be evaluated.

Perceived professional development of Chinese psychotherapy trainees: a pilot study

For more than 30 years counselling and psychotherapy services in China have progressed rapidly. Currently, various Chinese universities, hospitals, official mental health centres, and private mental health service organizations provide psychotherapy training programs. However, little is known about Chinese psychotherapy trainees and their development. This pilot study investigated the characteristics and perceived professional development of 20 Chinese trainees during and after an advanced training program for psychosomatic medicine and psychotherapy, which is a collaboration project between Peking Union Medical College Hospital and the Department of Psychosomatic Medicine and Psychotherapy from the University Medical Center Freiburg in Germany. Trainees completed questionnaires from the SPRISTAD (Society for Psychotherapy Research Interest Section on Therapist Training and Development) study at the beginning (T1), at the end (T2), and one year after finishing the program (T3). Seventeen of the twenty participants were clinicians. Trainees reported a prominent rise of Currently Experienced Growth throughout the training period, which nearly dropped to the baseline level after the training, although Retrospective Career Development showed a trend of an overall increase. Both ‘experience in therapy with patients’ and ‘participation in courses or seminars’ were the most important positively perceived sources of influence on trainees’ development. This implies the importance of continuous psychotherapy training for the development of therapists during their career. Future research with a larger sample size should also assess trainees’ development from the viewpoint of trainers, supervisors, and patients.

Valerian and postoperative sleep: a retrospective cohort analysis of gynecological, urologic, and general surgical patients.

Postoperative sleep disturbances appear to be a common complication after surgery being treated with sleep-promoting medication such as valerian, but robust data and evidence of medicinal approaches are lacking. We performed a retrospective cohort analysis of all 21 168 urological, gynecological, and general surgical patients of the University Medical Center Freiburg, Germany, who underwent surgery between 2015 and 2020. Target parameters were the usage of sleep-promoting medication to estimate the occurrence of postoperative sleep disturbances as well as the kind of sleep medication with a special focus on herbal medication such as valerian. Drug-treated sleep disturbances occurred in 15% (n = 3083) of the patients. Valerian was the second most applied drug (n = 814, 26.4%) after classic benzodiazepines (n = 1 138, 36.9%). The majority of patients got valerian as monotherapy. Age, length of stay, and comorbidities were associated with demand for sleep medication in general (p < .001). Valerian monotherapy was more common in women (OR 1.53, 95% CI: 1.33-1.77, p < .001), elderly patients (OR 1.50, 95% CI: 1.29-1.75, p < .001), and patients with prolonged hospital stay (OR 2.23, 95% CI: 1.91-2.61, p < .001). Valerian plays an important role in the treatment of postoperative sleep disturbances clinically, and it appears to be a promising therapeutic approach especially in women, older and sicker patients, and those with prolonged hospital stay. Further research has to clarify the efficacy of valerian postoperatively. DRKS00027903, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00027903.

Cytokine adsorption in patients with post-cardiac arrest syndrome after extracorporeal cardiopulmonary resuscitation (CYTER) – A single-centre, open-label, randomised, controlled trial

AimTo investigate the effect of cytokine adsorption in patients receiving extracorporeal cardiopulmonary resuscitation (ECPR) after cardiac arrest. MethodsCYTER was a single-centre, open-label, randomised, controlled trial. Patients selected for ECPR at the University Medical Center Freiburg (Freiburg, Germany) were assigned to extracorporeal membrane oxygenation (ECMO) support with or without cytokine adsorption (1:1) using the CytoSorb adsorber, incorporated into the ECMO, replaced every 24 hours, and removed after 72 hours. The primary endpoint was serum interleukin (IL)-6 concentration at 72 hours (intention-to-treat analysis). Secondary endpoints included 30-day survival, vasopressor support and biomarkers of end-organ injury. ResultsOf 50 patients enrolled in the trial, 26 (52%) were treated with cytokine adsorption and 24 (48%) without. Nine patients were excluded (informed consent could not be obtained); 41 patients were therefore included in the primary analysis. Median IL-6 levels (IQR) decreased from 408.0(93.4–906.5) to 324.0 (134.3–4617.3) pg/mL and increased from 133.0 (56.2–528.5) to 241.0 (132.8–718.0) pg/mL in the cytokine adsorption and control group, respectively (linear regression for treatment [cytokine adsorption vs control]: p = 0.48). Three (14%) of 22 patients treated with cytokine adsorption and 8 (42%) of 19 patients treated without cytokine adsorption survived to day 30 (HR = 1.85, 95% CI 0.86–4.01; p = 0.10). Vasopressor support and NSE, S100b, troponin T, CRP and PCT levels were similar between groups. ConclusionCytokine adsorption in patients receiving ECPR did not reduce serum IL–6 and had no significant effect on survival, vasopressor support, or biomarkers of injury. Clinical trial registrationClinicalTrials.gov: NCT03685383.

Implementation of an acute palliative care unit for COVID-19 patients in a tertiary hospital: Qualitative data on clinician perspectives

Background: During the COVID-19 pandemic, it has become apparent that palliative care has dynamically adapted to the care of dying patients with and without COVID-19 and has developed new forms of collaboration. Evaluation is needed to assess which innovations should be integrated into future pandemic management. Aim: To explore the experiences of stakeholders and staff in implementing and operating an ad hoc unit delivering acute palliative care. What lessons were learned? Design: Qualitative interview study (German Clinical Trials Register; identifier 22,473) with qualitative content analysis. Setting/participants: During the first wave of the pandemic, the University Medical Center Freiburg (Germany) established an ad hoc unit delivering acute palliative care for COVID-19 patients likely to die. Nurses from non-palliative areas and the specialist palliative care team formed a new team working together there. Twenty-nine individuals from management and staff of this unit were interviewed. Results: Patient care and teamwork were rated positively. Joint familiarization, bedside teaching, and team/management support were evaluated as core elements for success. Challenges for the nurses from non-palliative settings included adapting to palliative care routines and culture of care. The palliative care team had to adjust the high standards of palliative care to pandemic conditions. Due to sufficient hospital-wide capacity, only three COVID-19 patients were treated, significantly fewer than anticipated at planning. Conclusions: Results show the feasibility of an ad hoc COVID-19 acute palliative care unit. In the event of capacity constraints, such a unit can be a viable part of future pandemic management.

Complaints and clinical findings six months after COVID-19: outpatient follow-up at the University Medical Center Freiburg

Increasing evidence suggests that some patients suffer from persistent symptoms for months after recovery from acute COVID-19. However, the clinical phenotype and its pathogenesis remain unclear. We here present data on complaints and results of a diagnostic workup of patients presenting to the post-COVID clinic at the University Medical Center Freiburg. Retrospective data analysis of persistently symptomatic patients presenting to our clinic at least 6 months after onset of acute COVID-19. All patients were assessed by a doctor and routine laboratory analysis was carried out. Quality of life was assessed using SF-36 questionnaire. In case of specific persisting symptoms, further organ-specific diagnostic evaluation was performed, and patients were referred to respective departments/specialists. 132 Patients (58 male, 74 female; mean age 53.8years) presented to our clinic at least 6 months after COVID-19. 79 (60 %) had been treated as outpatients and 53 (40 %) as inpatients. Most common complaints were persistent fatigue (82 %) and dyspnea on exertion (61 %). Further common complaints were impairments of concentration (54 %), insomnia (43 %), and impairments of smell or taste (35 %). Quality of life was reduced in all sections of the SF-36 questionnaire, yielding a reduced working capacity. Significant pathological findings in laboratory, echocardiographic and radiological work-up were rare. Impairments in lung function tests were more common in previously hospitalized patients. Patients presenting 6 months after onset of acute COVID-19 suffer from a diverse spectrum of symptoms with impaired quality of life, also referred to as Long COVID or Post-Acute Sequelae of SARS-CoV-2 infection (PASC). Further research is needed to determine the frequency of these post-COVID syndromes and their pathogenesis, natural course and treatment options. Evaluation and management should be multi-disciplinary.

Cytokine adsorption in patients with severe COVID-19 pneumonia requiring extracorporeal membrane oxygenation (CYCOV): a single centre, open-label, randomised, controlled trial

BackgroundWe sought to clarify the benefit of cytokine adsorption in patients with COVID-19 supported with venovenous extracorporeal membrane oxygenation (ECMO).MethodsWe did a single-centre, open-label, randomised, controlled trial to investigate cytokine adsorption in adult patients with severe COVID-19 pneumonia requiring ECMO. Patients with COVID-19 selected for ECMO at the Freiburg University Medical Center (Freiburg, Germany) were randomly assigned (1:1) to receive cytokine adsorption using the CytoSorb device or not. Randomisation was computer-generated, allocation was concealed by opaque, sequentially numbered sealed envelopes. The CytoSorb device was incorporated into the ECMO circuit before connection to the patient circuit, replaced every 24 h, and removed after 72 h. The primary endpoint was serum interleukin-6 (IL-6) concentration 72 h after initiation of ECMO analysed by intention to treat. Secondary endpoints included 30-day survival. The trial is registered with ClinicalTrials.gov (NCT04324528) and the German Clinical Trials Register (DRKS00021300) and is closed.FindingsFrom March 29, 2020, to Dec 29, 2020, of 34 patients assessed for eligibility, 17 (50%) were treated with cytokine adsorption and 17 (50%) without. Median IL-6 decreased from 357·0 pg/mL to 98·6 pg/mL in patients randomly assigned to cytokine adsorption and from 289·0 pg/mL to 112·0 pg/mL in the control group after 72 h. One patient in each group died before 72 h. Adjusted mean log IL-6 concentrations after 72 h were 0·30 higher in the cytokine adsorption group (95% CI −0·70 to 1·30, p=0·54). Survival after 30 days was three (18%) of 17 with cytokine adsorption and 13 (76%) of 17 without cytokine adsorption (p=0·0016).InterpretationEarly initiation of cytokine adsorption in patients with severe COVID-19 and venovenous ECMO did not reduce serum IL-6 and had a negative effect on survival. Cytokine adsorption should not be used during the first days of ECMO support in COVID-19.FundingNone.