Publications by authors named "Michael Mohr"

49 Publications

Systemic Bevacizumab for Treatment of Respiratory Papillomatosis: International Consensus Statement.

Laryngoscope 2021 Jan 6. Epub 2021 Jan 6.

Department of Otolaryngology-Head and Neck Surgery, Eastern Virginia Medical School, Children's Hospital of the King's Daughters, Norfolk, Virginia, U.S.A.

Objectives/hypothesis: The purpose of this study is to develop consensus on key points that would support the use of systemic bevacizumab for the treatment of recurrent respiratory papillomatosis (RRP), and to provide preliminary guidance surrounding the use of this treatment modality.

Study Design: Delphi method-based survey series.

Methods: A multidisciplinary, multi-institutional panel of physicians with experience using systemic bevacizumab for the treatment of RRP was established. The Delphi method was used to identify and obtain consensus on characteristics associated with systemic bevacizumab use across five domains: 1) patient characteristics; 2) disease characteristics; 3) treating center characteristics; 4) prior treatment characteristics; and 5) prior work-up.

Results: The international panel was composed of 70 experts from 12 countries, representing pediatric and adult otolaryngology, hematology/oncology, infectious diseases, pediatric surgery, family medicine, and epidemiology. A total of 189 items were identified, of which consensus was achieved on Patient Characteristics (9), Disease Characteristics (10), Treatment Center Characteristics (22), and Prior Workup Characteristics (18).

Conclusion: This consensus statement provides a useful starting point for clinicians and centers hoping to offer systemic bevacizumab for RRP and may serve as a framework to assess the components of practices and centers currently using this therapy. We hope to provide a strategy to offer the treatment and also to provide a springboard for bevacizumab's use in combination with other RRP treatment protocols. Standardized delivery systems may facilitate research efforts and provide dosing regimens to help shape best-practice applications of systemic bevacizumab for patients with early-onset or less-severe disease phenotypes.

Level Of Evidence: 5. Laryngoscope, 2021.
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http://dx.doi.org/10.1002/lary.29343DOI Listing
January 2021

Long-Term Follow-Up on Systemic Bevacizumab Treatment in Recurrent Respiratory Papillomatosis.

Laryngoscope 2020 Dec 31. Epub 2020 Dec 31.

Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany.

Objectives/hypothesis: Recurrent respiratory papillomatosis (RRP) is a primarily benign disease affecting the entire respiratory tract. Treatment is challenging and usually involves surgical interventions and adjuvant medications. Previously, promising results on systemic administration of bevacizumab have been reported. However, experience on long-term systemic use in patients with RRP is not yet available. Here, we present our long-term follow-up on RRP patients undergoing systemic bevacizumab treatment.

Study Design: Case series.

Methods: To describe experience on long-term systemic bevacizumab administration, we performed the underlying investigation. Clinical, radiological, and bronchoscopy data were collected.

Results: To date, a total of n = 5 patients has been treated with systemic bevacizumab at Muenster University Hospital. With a median follow-up since first systemic bevacizumab administration of 95.5 months long-term follow-up is illustrated. Following bevacizumab treatment partial remission or very good partial remission were achieved in all patients. After papilloma recurrence/progression due to bevacizumab discontinuation, further response was documented in all patients in whom bevacizumab was started again. In one patient, bevacizumab was discontinued due to loss of efficacy. Lung cancer developed in one patient with pulmonary papillomatosis prior to bevacizumab administration whereas three patients suffered from malignant transformation during bevacizumab treatment. Systemic bevacizumab led to long-term reduction in surgical interventions in all patients. Except from mild proteinuria and hypertension in two patients therapy was well tolerated.

Conclusions: Systemic bevacizumab represents a promising long-term treatment option for aggressive forms of papillomatosis. Rate of malignant transformation under bevacizumab treatment, optimal treatment schedule, and influence on survival should be further evaluated in clinical trials.

Level Of Evidence: 4 Laryngoscope, 2020.
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http://dx.doi.org/10.1002/lary.29351DOI Listing
December 2020

Effects of nasal high flow on sympathovagal balance, sleep, and sleep-related breathing in patients with precapillary pulmonary hypertension.

Sleep Breath 2020 Aug 22. Epub 2020 Aug 22.

Institute of Life Sciences, Scuola Superiore Sant'Anna, Piazza Martiri della Libertà, 33, 56127, Pisa, PI, Italy.

Background: In precapillary pulmonary hypertension (PH), nasal high flow therapy (NHF) may favorably alter sympathovagal balance (SVB) and sleep-related breathing through washout of anatomical dead space and alleviation of obstructive sleep apnea (OSA) due to generation of positive airway pressure.

Objectives: To investigate the effects of NHF on SVB, sleep, and OSA in patients with PH, and compare them with those of positive airway pressure therapy (PAP).

Methods: Twelve patients with PH (Nice class I or IV) and confirmed OSA underwent full polysomnography, and noninvasive monitoring of SVB parameters (spectral analysis of heart rate, diastolic blood pressure variability). Study nights were randomly split into four 2-h segments with no treatment, PAP, NHF 20 L/min, or NHF 50 L/min. In-depth SVB analysis was conducted on 10-min epochs during daytime and stable N2 sleep at nighttime.

Results: At daytime and compared with no treatment, NHF20 and NHF50 were associated with a flow-dependent increase in peripheral oxygen saturation but a shift in SVB towards increased sympathetic drive. At nighttime, NHF20 was associated with increased parasympathetic drive and improvements in sleep efficiency, but did not alter OSA severity. NHF50 was poorly tolerated. PAP therapy improved OSA but had heterogenous effects on SVB and neutral effects on sleep outcomes. Hemodynamic effects were neutral for all interventions.

Conclusions: In sleeping PH patients with OSA NHF20 but not NHF50 leads to decreased sympathetic drive likely due to washout of anatomical dead space. NHF was not effective in lowering the apnea-hypopnoea index and NHF50 was poorly tolerated.
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http://dx.doi.org/10.1007/s11325-020-02159-1DOI Listing
August 2020

Tumor infiltrating T cells influence prognosis in stage I-III non-small cell lung cancer.

J Thorac Dis 2020 May;12(5):1824-1842

Gerhard Domagk Institute of Pathology, University Hospital Muenster, Muenster, Germany.

Background: T cell infiltration in non-small cell lung cancer (NSCLC) is essential for the immunological response to malignant tissue, especially in the era of immune-checkpoint inhibition. To investigate the prognostic impact of CD4 T helper cells (T), CD8 cytotoxic (T) and FOXP3 regulatory T (T) cells in NSCLC, we performed this analysis.

Methods: By counterstaining of CD4, CD8 and FOXP3 we used immunohistochemistry on tissue microarrays (TMA) to evaluate peritumoral T cells, T cells and T cells in n=294 NSCLC patients with pTNM stage I-III disease.

Results: Strong CD4 infiltration was associated with higher tumor stages and lymphonodal spread. However, strong CD4 infiltration yielded improved overall survival (OS) (P=0.014) in adenocarcinoma (ADC) and large cell carcinoma (LCC) but not in squamous cell carcinoma (SCC). A CD4/CD8 ratio <1 was associated with high grade NSCLC tumors (P=0.020). High CD8 T cell infiltration was an independent prognostic factor for OS (P=0.040) and progression-free survival (PFS) (P=0.012) in the entire study collective. The OS benefit of high CD8 infiltration was especially prominent in PD-L1 negative NSCLC (P=0.001) but not in PD-L1 positive tissue (P=0.335). Moreover, positive FOXP3 expression in tumor infiltrating lymphocytes was associated with increased OS (P=0.007) and PFS (P=0.014) in SCC but not in ADC and LCC (all P>0.05). Here, prognostic effects were prominent in PD-L1 positive SCC (P=0.023) but not in PD-L1 negative SCC (P=0.236).

Conclusions: High proportion of CD8 T cells correlated with improved prognostic outcome in stage I-III NSCLC. T cells and T cells have implications on outcome with respect to tumor histology and biology.
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http://dx.doi.org/10.21037/jtd-19-3414aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330340PMC
May 2020

Alpha-1 Antitrypsin Deficiency and Pulmonary Morbidity in Patients with Primary Immunodeficiency Disease: A Single-Center Experience.

Can Respir J 2020 27;2020:4019608. Epub 2020 May 27.

Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany.

Background: Alpha-1 antitrypsin deficiency (AATD) is of importance in the pathogenesis of pulmonary emphysema, chronic obstructive pulmonary diseases (COPD), and bronchiectasis. Various pulmonary disorders are a typical feature of primary immunodeficiency disease (PID). This includes recurrent pulmonary infections, immunodysregulation, and autoinflammatory diseases. As a result, incidence of acute and chronic pulmonary diseases is higher. Interestingly, pulmonary morbidity in PID and AATD share similar features. To study the coexistence of AATD in patients suffering from PID, we performed the underlying investigation.

Methods: We evaluated a study group of 149 patients ( = 149) with PID. In total, serum AAT concentrations were available for 110 patients ( = 110). For the identified patients, we analyzed both clinical associations and interactions.

Results: Among the investigated patients, reduced serum AAT levels were detected in 7 patients. With regard to the genotype, PI∗ZZ was found in 2 patients, whereas PI∗MZ was observed in 5 patients. Independent of the underlying phenotype, obstructive lung diseases were found in 2 patients with PI∗ZZ and 2 patients with PI∗MZ.

Conclusions: In Germany, the estimated percentage for PI∗ZZ and PI∗MZ is 0.01% and 1.9%, respectively. As demonstrated, the ratio in our study group was even higher. We identified seven patients with AATD. Since AATD contributes to pulmonary morbidity in PID patients, systematic underdiagnosis of the coexistence might yield a strong clinical impact. Hence, AAT analysis should be offered to all patients with confirmed PID diagnoses. To strengthen this finding, we suggest the investigation of larger databases.
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http://dx.doi.org/10.1155/2020/4019608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273390PMC
May 2020

Correction to: Validity of transit time-based blood pressure measurements in patients with and without heart failure or pulmonary arterial hypertension across different breathing maneuvers.

Sleep Breath 2020 09;24(3):1257-1258

Cardiovascular Medicine Division, Fondazione Toscana Gabriele Monasterio, National Research Council, CNR-Regione Toscana, Scuola Superiore San't Anna, Pisa, Italy.

After the publication of the original manuscript we found that the calculation of the supplemental data regarding the capacity of PTT-based blood pressure (BP) recordings to detect changes in systolic and diastolic BP in different cohorts of patients was incorrect. These errors occured when data were transformed from MS Excel to Sigma-Plot tables. In this correction, the affected data and the respective figures were now revised.
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http://dx.doi.org/10.1007/s11325-020-02120-2DOI Listing
September 2020

Respiratory Muscle and Lung Function in Lung Allograft Recipients: Association with Exercise Intolerance.

Respiration 2020;99(5):398-408. Epub 2020 May 13.

Respiratory Physiology Laboratory, Department of Neurology with Institute for Translational Neurology, University Hospital Münster, Münster, Germany.

Background: In lung transplant recipients (LTRs), restrictive ventilation disorder may be present due to respiratory muscle dysfunction that may reduce exercise capacity. This might be mediated by pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6).

Objective: We investigated lung respiratory muscle function as well as circulating pro-inflammatory cytokines and exercise capacity in LTRs.

Methods: Fifteen LTRs (6 female, age 56 ± 14 years, 63 ± 45 months post-transplantation) and 15 healthy controls matched for age, sex, and body mass index underwent spirometry, measurement of mouth occlusion pressures, diaphragm ultrasound, and recording of twitch transdiaphragmatic (twPdi) and gastric pressures (twPgas) following magnetic stimulation of the phrenic nerves and the lower thoracic nerve roots. Exercise capacity was quantified using the 6-min walking distance (6MWD). Plasma IL-6 and TNF-α were measured using enzyme-linked immunosorbent assays.

Results: Compared with controls, patients had lower values for forced vital capacity (FVC; 81 ± 30 vs.109 ± 18% predicted, p = 0.01), maximum expiratory pressure (100 ± 21 vs.127 ± 17 cm H2O, p = 0.04), diaphragm thickening ratio (2.2 ± 0.4 vs. 3.0 ± 1.1, p = 0.01), and twPdi (10.4 ± 3.5 vs. 17.6 ± 6.7 cm H2O, p = 0.01). In LTRs, elevation of TNF-α was related to lung function (13 ± 3 vs. 11 ± 2 pg/mL in patients with FVC ≤80 vs. >80% predicted; p < 0.05), and lung function (forced expiratory volume after 1 s) was closely associated with diaphragm thickening ratio (r = 0.81; p < 0.01) and 6MWD (r = 0.63; p = 0.02).

Conclusion: There is marked restrictive ventilation disorder and respiratory muscle weakness in LTRs, especially inspiratory muscle weakness with diaphragm dysfunction. Lung function impairment relates to elevated levels of circulating TNF-α and diaphragm dysfunction and is associated with exercise intolerance.
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http://dx.doi.org/10.1159/000507264DOI Listing
May 2020

Prognostic impact of CD34 and SMA in cancer-associated fibroblasts in stage I-III NSCLC.

Thorac Cancer 2020 01 24;11(1):120-129. Epub 2019 Nov 24.

Department of Medicine A, Hematology, Oncology and Pulmonary Medicine, University Hospital Muenster, Muenster, Germany.

Background: Epithelial-to-mesenchymal transition (EMT) is a crucial step in lung cancer pathogenesis. Among others, cancer-associated fibroblasts (CAFs) are reported to regulate this process.

Objectives: To investigate the prognostic and clinical impact, we analyzed CD34+ and SMA+ CAFs in non-small cell lung cancer (NSCLC).

Methods: Retrospectively, immunohistochemistry was performed to study stromal protein expression of both CD34 and SMA in 304 NSCLC patients with pTNM stage I-III disease. All tissue samples were embedded on tissue microarrays (TMAs).

Results: Our analysis revealed an association for CD34+ CAFs with G1/2 tumors and adenocarcinoma histology. Moreover CD34+ CAFs were identified as an independent prognostic factor (both for progression free survival [PFS] and overall survival [OS] in stage I-III NSCLC). Besides, SMA+ expression correlated with higher pTNM-tumor stages and lymphatic spread (pN stage). In turn, SMA-negativity was associated with improved PFS, but no prognostic impact was found on OS. Of interest, neither CD34+ CAFs nor SMA+ CAFs were associated with the primary tumor size, localization and depth of infiltration (pT stage).

Conclusions: CD34 was identified as an independent prognostic marker in pTNM stage I-III NSCLC. Moreover, loss of CD34+ CAFs might influence the dedifferentiation of the NSCLC tumor from its cell origin. Finally, SMA+ CAFs are more prevalent in NSCLC tumors of higher stages and lymphonodal positive NSCLC.

Key Points: Expression of CD34 on cancer associated fibroblasts (CAFs) is an independent prognostic factor in stage I-III NSCLC. SMA+ cancer associated fibroblasts are associated with higher tumor stages in NSCLC and might contribute to tumor progression in NSCLC.
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http://dx.doi.org/10.1111/1759-7714.13248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938745PMC
January 2020

Blood clot removal by cryoextraction in critically ill patients with pulmonary hemorrhage.

J Thorac Dis 2019 Oct;11(10):4319-4327

Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany.

Background: Severe pulmonary hemorrhage is a life-threatening complication in critically ill patients. Due to tracheobronchial obstruction, ventilation is often impaired. Traditionally, rigid bronchoscopy is an option for recanalization. However, in comparison to flexible bronchoscopy, the application of rigid bronchoscopy is more complex. Against this background we evaluated the use of flexible cryo-probes for blood clot removal in critically ill patients.

Methods: Retrospectively, we identified 16 patients (median age: 60 years, 69% male patients), who suffered from severe airway obstruction due to blood clots. All patients required invasive ventilation and 11 patients depended on extracorporeal membrane oxygenation (ECMO). To remove blood clots, flexible bronchoscopic cryoextraction was performed in n=27 cases, whereas rigid bronchoscopy was only needed in two cases.

Results: Whereas in 9 cases single flexible cryoextraction was successful immediately, the procedure had to be repeated again in 7 patients. In all cases, tracheobronchial obstruction was treated with success and conditions of invasive ventilation were improved. In no case severe complications were observed.

Conclusions: In consideration of the underlying evaluation, we highly recommend flexible cryoextraction as both a safe and less complex technique for blood clot removal in critically ill patients.
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http://dx.doi.org/10.21037/jtd.2019.09.46DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6837984PMC
October 2019

Impact of Simulated Hyperventilation and Periodic Breathing on Sympatho-Vagal Balance and Hemodynamics in Patients with and without Heart Failure.

Respiration 2019;98(6):482-494. Epub 2019 Aug 28.

Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy.

Background: The effects of hyperventilation and hyperventilation in the context of periodic breathing (PB) on sympatho-vagal balance (SVB) and hemodynamics in conditions of decreased cardiac output and feedback resetting, such as heart failure (HF) or pulmonary arterial hypertension (PAH), are not completely understood.

Objectives: To investigate the effects of voluntary hyperventilation and simulated PB on hemodynamics and SVB in healthy subjects, in patients with systolic HF and reduced or mid-range ejection fraction (HFrEF and HFmrEF) and in patients with PAH.

Methods: Study participants (n = 20 per group) underwent non-invasive recording of diastolic blood pressure, heart rate variability (HRV), baroreceptor-reflex sensitivity (BRS), total peripheral resistance index (TPRI) and cardiac index (CI). All measurements were performed at baseline, during voluntary hyperventilation and during simulated PB with different length of the hyperventilation phase.

Results: In healthy subjects, voluntary hyperventilation led to a 50% decrease in the mean BRS slope and a 29% increase in CI compared to baseline values (p < 0.01 and p < 0.05). Simulated PB did not alter TPRI or CI and showed heterogeneous effects on BRS, but analysis of dPBV revealed decreased sympathetic drive in healthy volunteers depending on PB cycle length (p < 0.05). In HF patients, hyperventilation did not affect BRS and TPRI but increased the CI by 10% (p < 0.05). In HF patients, simulated PB left all of these parameters unaffected. In PAH patients, voluntary hyperventilation led to a 15% decrease in the high-frequency component of HRV (p < 0.05) and a 5% increase in CI (p < 0.05). Simulated PB exerted neutral effects on both SVB and hemodynamic parameters.

Conclusions: Voluntary hyperventilation was associated with sympathetic predominance and CI increase in healthy volunteers, but only with minor hemodynamic and SVB effects in patients with HF and PAH. Simulated PB had positive effects on SVB in healthy volunteers but neutral effects on SVB and hemodynamics in patients with HF or PAH.
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http://dx.doi.org/10.1159/000502155DOI Listing
September 2020

Diaphragm function does not independently predict exercise intolerance in patients with precapillary pulmonary hypertension after adjustment for right ventricular function.

Biosci Rep 2019 09 3;39(9). Epub 2019 Sep 3.

Cardiology and Cardiovascular Medicine Division, Fondazione Toscana Gabriele Monasterio, CNR-Regione Toscana, Pisa, Italy.

Several determinants of exercise intolerance in patients with precapillary pulmonary hypertension (PH) due to pulmonary arterial hypertension and/or chronic thromboembolic PH (CTEPH) have been suggested, including diaphragm dysfunction. However, these have rarely been evaluated in a multimodal manner. Forty-three patients with PH (age 58 ± 17 years, 30% male) and 43 age- and gender-matched controls (age 54 ± 13 years, 30% male) underwent diaphragm function (excursion and thickening) assessment by ultrasound, standard spirometry, arterial blood gas analysis, echocardiographic assessment of pulmonary artery pressure (PAP), assay of amino-terminal pro-brain natriuretic peptide (NT-proBNP) levels, and cardiac magnetic resonance (CMR) imaging to evaluate right ventricular systolic ejection fraction (RVEF). Exercise capacity was determined using the 6-min walk distance (6MWD). Excursion velocity during a sniff maneuver (SniffV, 4.5 ± 1.7 vs. 6.8 ± 2.3 cm/s, <0.01) and diaphragm thickening ratio (DTR, 1.7 ± 0.5 vs. 2.8 ± 0.8, <0.01) were significantly lower in PH patients versus controls. PH patients with worse exercise tolerance (6MWD <377 vs. ≥377 m) were characterized by worse SniffV, worse DTR, and higher NT-pro-BNP levels as well as by lower arterial carbon dioxide levels and RVEF, which were all univariate predictors of exercise limitation. On multivariate analysis, the only independent predictors of exercise limitation were RVEF (r = 0.47, =0.001) and NT-proBNP (r = -0.27, =0.047). Patients with PH showed diaphragm dysfunction, especially as exercise intolerance progressed. However, diaphragm dysfunction does not independently contribute to exercise intolerance, beyond what can be explained from right heart failure.
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http://dx.doi.org/10.1042/BSR20190392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723707PMC
September 2019

The German National Registry of Primary Immunodeficiencies (2012-2017).

Authors:
Sabine M El-Helou Anika-Kerstin Biegner Sebastian Bode Stephan R Ehl Maximilian Heeg Maria E Maccari Henrike Ritterbusch Carsten Speckmann Stephan Rusch Raphael Scheible Klaus Warnatz Faranaz Atschekzei Renata Beider Diana Ernst Stev Gerschmann Alexandra Jablonka Gudrun Mielke Reinhold E Schmidt Gesine Schürmann Georgios Sogkas Ulrich H Baumann Christian Klemann Dorothee Viemann Horst von Bernuth Renate Krüger Leif G Hanitsch Carmen M Scheibenbogen Kirsten Wittke Michael H Albert Anna Eichinger Fabian Hauck Christoph Klein Anita Rack-Hoch Franz M Sollinger Anne Avila Michael Borte Stephan Borte Maria Fasshauer Anja Hauenherm Nils Kellner Anna H Müller Anett Ülzen Peter Bader Shahrzad Bakhtiar Jae-Yun Lee Ursula Heß Ralf Schubert Sandra Wölke Stefan Zielen Sujal Ghosh Hans-Juergen Laws Jennifer Neubert Prasad T Oommen Manfred Hönig Ansgar Schulz Sandra Steinmann Klaus Schwarz Gregor Dückers Beate Lamers Vanessa Langemeyer Tim Niehues Sonu Shai Dagmar Graf Carmen Müglich Marc T Schmalzing Eva C Schwaneck Hans-Peter Tony Johannes Dirks Gabriele Haase Johannes G Liese Henner Morbach Dirk Foell Antje Hellige Helmut Wittkowski Katja Masjosthusmann Michael Mohr Linda Geberzahn Christian M Hedrich Christiane Müller Angela Rösen-Wolff Joachim Roesler Antje Zimmermann Uta Behrends Nikolaus Rieber Uwe Schauer Rupert Handgretinger Ursula Holzer Jörg Henes Lothar Kanz Christoph Boesecke Jürgen K Rockstroh Carolynne Schwarze-Zander Jan-Christian Wasmuth Dagmar Dilloo Brigitte Hülsmann Stefan Schönberger Stefan Schreiber Rainald Zeuner Tobias Ankermann Philipp von Bismarck Hans-Iko Huppertz Petra Kaiser-Labusch Johann Greil Donate Jakoby Andreas E Kulozik Markus Metzler Nora Naumann-Bartsch Bettina Sobik Norbert Graf Sabine Heine Robin Kobbe Kai Lehmberg Ingo Müller Friedrich Herrmann Gerd Horneff Ariane Klein Joachim Peitz Nadine Schmidt Stefan Bielack Ute Groß-Wieltsch Carl F Classen Jessica Klasen Peter Deutz Dirk Kamitz Lisa Lassay Klaus Tenbrock Norbert Wagner Benedikt Bernbeck Bastian Brummel Eusebia Lara-Villacanas Esther Münstermann Dominik T Schneider Nadine Tietsch Marco Westkemper Michael Weiß Christof Kramm Ingrid Kühnle Silke Kullmann Hermann Girschick Christof Specker Elisabeth Vinnemeier-Laubenthal Henriette Haenicke Claudia Schulz Lothar Schweigerer Thomas G Müller Martina Stiefel Bernd H Belohradsky Veronika Soetedjo Gerhard Kindle Bodo Grimbacher

Front Immunol 2019 19;10:1272. Epub 2019 Jul 19.

Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1-25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0-88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%-subcutaneous; 29%-intravenous; 1%-unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.
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http://dx.doi.org/10.3389/fimmu.2019.01272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659583PMC
October 2020

Future Options of Molecular-Targeted Therapy in Small Cell Lung Cancer.

Cancers (Basel) 2019 May 17;11(5). Epub 2019 May 17.

Department of Medicine A, Hematology, Oncology and Pulmonary Medicine, University Hospital Muenster, 48149 Muenster, Germany.

Lung cancer is the leading cause of cancer-related deaths worldwide. With a focus on histology, there are two major subtypes: Non-small cell lung cancer (NSCLC) (the more frequent subtype), and small cell lung cancer (SCLC) (the more aggressive one). Even though SCLC, in general, is a chemosensitive malignancy, relapses following induction therapy are frequent. The standard of care treatment of SCLC consists of platinum-based chemotherapy in combination with etoposide that is subsequently enhanced by PD-L1-inhibiting atezolizumab in the extensive-stage disease, as the addition of immune-checkpoint inhibition yielded improved overall survival. Although there are promising molecular pathways with potential therapeutic impacts, targeted therapies are still not an integral part of routine treatment. Against this background, we evaluated current literature for potential new molecular candidates such as surface markers (e.g., DLL3, TROP-2 or CD56), apoptotic factors (e.g., BCL-2, BET), genetic alterations (e.g., CREBBP, NOTCH or PTEN) or vascular markers (e.g., VEGF, FGFR1 or CD13). Apart from these factors, the application of so-called 'poly-(ADP)-ribose polymerases' (PARP) inhibitors can influence tumor repair mechanisms and thus offer new perspectives for future treatment. Another promising therapeutic concept is the inhibition of 'enhancer of zeste homolog 2' (EZH2) in the loss of function of tumor suppressors or amplification of (proto-) oncogenes. Considering the poor prognosis of SCLC patients, new molecular pathways require further investigation to augment our therapeutic armamentarium in the future.
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http://dx.doi.org/10.3390/cancers11050690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562929PMC
May 2019

Noncaseating granulomatous diseases in germ cell cancer patients-A single-center experience.

Urol Oncol 2019 08 30;37(8):531.e17-531.e25. Epub 2019 Apr 30.

Department of Medicine A, Hematology, Oncology and Pulmonary Medicine, University Hospital Muenster, Muenster, Germany.

Objectives: In patients with testicular Germ Cell Tumors (GCT) noncaseating granulomatous diseases such as Sarcoid Like Lesions (SLL) or Sarcoidosis can mimic metastasis due to hilar or mediastinal lymphadenopathy. Due to the clinical and prognostic impact, exclusion of malignant diseases is mandatory.

Material And Methods: Retrospectively, data from 636 GCT patients, who were seen in the course of tumor surveillance/follow-up were collected. Focus was put on the detection of tumor relapse vs. noncaseating granulomatous reactions. For the differential diagnosis of thoracic lymphadenopathy or pulmonary infiltrates either bronchoscopy (e.g., endobronchial ultrasound-guided transbronchial needle aspiration, endobronchial ultrasound-guided transbronchial needle aspiration) or thoracic surgery was performed. Both GCT patients with either tumor relapse or coexisting SLL were compared to GCT patients without SLL and tumor relapse.

Results: Twenty-nine patients suffered from suspected tumor relapse. Whereas thoracic relapses were suspected in 15 patients on chest computed tomography, thoracic relapse was confirmed in 5 cases by open surgery. In 2 cases open surgery yielded reactive lymphadenitis, and in 8 cases SLL was diagnosed either via EBUS-TBNA (n = 7) or thoracoscopic wedge resection plus lymphadenectomy (n = 1). With focus on overall survival, no relevant difference was found between all tested subgroups (P = 0.265; logrank test).

Conclusions: In GCT patients, the coexistence of noncaseating granulomatous disease is common. Minimal invasive bronchoscopic techniques can serve for the cytopathologic exclusion of malignant thoracic manifestations. In our monocenter patient group the coexistence of SLL did not have any prognostic impact on overall survival.
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http://dx.doi.org/10.1016/j.urolonc.2019.03.010DOI Listing
August 2019

Validity of transit time-based blood pressure measurements in patients with and without heart failure or pulmonary arterial hypertension across different breathing maneuvers.

Sleep Breath 2020 Mar 2;24(1):221-230. Epub 2019 May 2.

Cardiovascular Medicine Division, Fondazione Toscana Gabriele Monasterio, National Research Council, CNR-Regione Toscana, Scuola Superiore San't Anna, Pisa, Italy.

Purpose: Pulse transit time (PTT) derived by ECG and plethysmographic signal can be a promising alternative to invasive or oscillometry-based blood pressure (BP) monitoring in sleep laboratories because it does not cause arousals from sleep. Therefore, this study assessed the validity of PTT for BP monitoring under sleep laboratory-like conditions.

Methods: Ten volunteers (55.8 ± 19.6 years), 12 patients with heart failure with reduced ejection fraction (HFrEF; 67.3 ± 8.6 years), and 14 patients with Nizza class I pulmonary arterial hypertension (PAH; 59.5 ± 13.4 years) performed different breathing patterns to simulate nocturnal sleep-disordered breathing (SDB). BP was measured at least every 15 min over 1 h using oscillometry (Task Force Monitor™) and PTT (SOMNOscreen™) devices in free breathing conditions and during SDB simulation (alternating phases of hyperventilation and apneas).

Results: One hundred forty-two points of measurements were collected. No difference was found in both mean systolic BP (SBP) and diastolic BP (DBP) between oscillometric PTT-based BP measurements in the whole population and throughout the whole recording (SBP 111.3 ± 15.1 mmHg versus 110.0 ± 14.7 mmHg, p = 0.051; DBP 69.9 ± 12.2 versus 69.9 ± 14.2 mmHg, p = 0.701). Likewise, no significant difference in SBP and DBP was found between the two methods in the subgroups of healthy subjects, HFrEF patients and PAH patients, both in free breathing conditions (p > 0.05) and during SDB simulation (p > 0.05).

Conclusions: When monitoring BP in healthy subjects, and in patients with HFrEF or PAH, PTT provides a BP estimation comparable with oscillometric measurement, though slightly inaccurate, both in the condition of regular and unstable breathing.
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http://dx.doi.org/10.1007/s11325-019-01848-wDOI Listing
March 2020

Cyclophosphamide pulse therapy as treatment for severe interstitial lung diseases.

Sarcoidosis Vasc Diffuse Lung Dis 2019 1;36(2):157-166. Epub 2019 May 1.

Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany.

Introduction: Besides invasive or non-invasive ventilation, treatment of severe forms of interstitial lung diseases (ILD) includes immunosuppressive medication. In case of refractory organ- or life-threatening courses of disease, cyclophosphamide pulse therapy can serve as a rescue treatment option.

Objectives: To investigate therapeutic and prognostic effects of cyclophosphamide for the treatment of severe forms of ILD on intensive care unit (ICU) we performed this analysis.

Methods: Between 2009 and 2017 we identified 14 patients, who were treated on intensive care unit (ICU) with severe forms of ILD. Retrospectively, clinical, radiologic and prognostic data were collected and evaluated.

Results: Our analysis demonstrated a prognostic impact of cyclophosphamide on the ILD in general. Whereas pulmonary manifestations of both systemic sclerosis (SSc) and ANCA-associated vasculitis had an improved outcome, a reduced overall survival was found for Goodpasture syndrome (GPS), dermatomyositis (DM), cryptogenic organizing pneumonia (COP) and drug reaction with eosinophilia and systemic symptoms (DRESS; p=0.040, logrank test). Besides, additional plasmapheresis and initiation of cyclophosphamide within ten days following initial diagnosis of ILD were associated with improved prognosis.

Conclusion: Positive prognostic effects of cyclophosphamide pulse therapy in ICU treated patients suffering from severe respiratory failure due to pulmonary manifestations of both SSc and ANCA-associated-vasculitis were observed. Further prognostic and therapeutic data are needed for cyclophosphamide for this indication in order to prevent patients from its toxic side-effects, who most likely will not benefit from its application.
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http://dx.doi.org/10.36141/svdld.v36i2.7636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247101PMC
July 2020

Several Polyphosphate Kinase 2 Enzymes Catalyse the Production of Adenosine 5'-Polyphosphates.

Chembiochem 2019 04 28;20(8):1019-1022. Epub 2019 Feb 28.

Institute of Pharmaceutical Sciences, University of Freiburg, Albertstrasse 25, 79104, Freiburg, Germany.

Polyphosphate kinases (PPKs) are involved in many metabolic processes; enzymes of the second family (PPK2) are responsible for nucleotide synthesis fuelled by the consumption of inorganic polyphosphate. They catalyse the phosphorylation of nucleotides with various numbers of phosphate residues, such as monophosphates or diphosphates. Hence, these enzymes are promising candidates for cofactor regeneration systems. Besides adenosine 5'-triphosphate, PPK2s also catalyse the synthesis of highly phosphorylated nucleotides in vitro, as shown here for adenosine 5'-tetraphosphate and adenosine 5'-pentaphosphate. These unusually phosphorylated adenosine 5'-polyphosphates add up to 50 % of the whole adenosine nucleotides in the assay. The two new products were chemically synthesised to serve as standards and compared with the two enzymatically produced compounds by high-performance ion chromatography and P NMR analysis. This study shows that PPK2s are highly suitable for biocatalytic synthesis of different phosphorylated nucleotides.
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http://dx.doi.org/10.1002/cbic.201800704DOI Listing
April 2019

CD13 as target for tissue factor induced tumor vascular infarction in small cell lung cancer.

Lung Cancer 2017 11 22;113:121-127. Epub 2017 Sep 22.

Gerhard-Domagk-Institute of Pathology, University of Muenster, 48149 Muenster, Germany.

Objectives: Zinc-binding protease aminopeptidase N (CD13) is expressed on tumor vascular cells and tumor cells. It represents a potential candidate for molecular targeted therapy, e.g. employing truncated tissue factor (tTF)-NGR, which can bind CD13 and thereby induce tumor vascular infarction. We performed a comprehensive analysis of CD13 expression in a clinically well characterized cohort of patients with small cell lung cancer (SCLC) to evaluate its potential use for targeted therapies in this disease.

Material And Methods: CD13 expression was analyzed immunohistochemically in 27 SCLC patients and correlated with clinical course and outcome. In CD-1 nude mice bearing human HTB119 SCLC xenotransplants, the systemic effects of the CD13-targeting fusion protein tTF-NGR on tumor growth were tested.

Results And Conclusion: In 52% of the investigated SCLC tissue samples, CD13 was expressed in tumor stroma cells, while the tumor cells were negative for CD13. No prognostic effect was found in the investigated SCLC study collective with regard to overall survival (p>0.05). In CD-1 nude mice, xenografts of CD13 negative HTB119 SCLC cells showed CD13 expression in the intratumoral vascular and perivascular cells, and the systemic application of CD13-targeted tissue factor tTF-NGR led to a significant reduction of tumor growth. We here present first data on the expression of CD13 in SCLC tumor samples. Our results strongly recommend the further investigation of tTF-NGR and other molecules targeted by NGR-peptides in SCLC patients. Considering the differential expression of CD13 in SCLC samples pre-therapeutic CD13 analysis is proposed for testing as investigational predictive biomarker for patient selection.
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http://dx.doi.org/10.1016/j.lungcan.2017.09.013DOI Listing
November 2017

Prostate specific membrane antigen (PSMA) expression in non-small cell lung cancer.

PLoS One 2017 27;12(10):e0186280. Epub 2017 Oct 27.

Gerhard Domagk Institute of Pathology, University of Münster, Münster, Germany.

Objectives: PSMA (prostate-specific membrane antigen) is overexpressed in prostate cancer cells and is reported to be a promising target for antibody-based radioligand therapy in patients with metastasized prostate cancer. Since PSMA expression is not restricted to prostate cancer, the underlying study investigates PSMA expression in non-small cell lung cancer (NSCLC).

Material And Methods: Immunohistochemistry was used to identify PSMA expression in n = 275 samples of NSCLC tissue specimens. By means of CD34 co-expression, the level of PSMA expression in tumor associated neovasculature was investigated. The impact of PSMA expression on clinicopathologic parameters and prognosis was evaluated.

Results: PSMA tumor cell expression in NSCLC is as low as 6% and was predominantly found in squamous cell carcinoma (p = 0.002). Neovascular PSMA expression was found in 49% of NSCLC. High neovascular PSMA expression was associated with higher tumor grading (G3/G4) (p < 0.001). Neither for PSMA tumor cell expression, nor for PSMA neovascular cell expression prognostic effects were found for the investigated NSCLC cases.

Conclusion: Here, we report on the expression of PSMA in NSCLC tissue samples. Against the background of a potential treatment with radiolabeled PSMA ligands, our data might serve for the future identification of patients who could benefit from this therapeutic option.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0186280PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5659610PMC
November 2017

[Not Available].

Dtsch Med Wochenschr 2017 Oct 10;142(20):1531-1534. Epub 2017 Oct 10.

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http://dx.doi.org/10.1055/s-0043-103471DOI Listing
October 2017

Temporary Tracheal Stenting After Pulmonary Artery Sling Repair in a Newborn.

World J Pediatr Congenit Heart Surg 2020 Jul 21;11(4):NP69-NP71. Epub 2017 Sep 21.

Division of Pediatric Cardiac Surgery, Department of Cardiothoracic Surgery, University Hospital Muenster, Muenster, Germany.

Pulmonary artery sling (PAS) is a rare disease frequently associated with severe malacia and stenosis of the trachea. We present a two-day-old newborn that underwent urgent surgery for PAS and needed prolonged respiratory support afterward. Temporary airway stenting above the level of the tracheal bifurcation was performed five days after surgery to overcome severe airway obstruction caused by tracheomalacia and laceration of the tracheal mucosa after diagnostic bronchoscopy. Two days after the procedure, the child could be extubated and after two weeks the stent was removed without complications. Temporary tracheal stenting after PAS repair can be an effective therapeutic strategy in newborns with tracheal obstruction and allows timely weaning from ventilator support.
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http://dx.doi.org/10.1177/2150135117713740DOI Listing
July 2020

Systemic bevacizumab for recurrent respiratory papillomatosis: A national survey.

Laryngoscope 2017 10 28;127(10):2225-2229. Epub 2017 Jun 28.

Pediatric Otolaryngology, The Children's Hospital of Philadelphia, The University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.

Objectives/hypothesis: Aggressive laryngeal, tracheal, and pulmonary papilloma is an extremely challenging clinical problem without proven treatment options. A recent German report documented promising results with systemic bevacizumab. The objective of this study is to report the initial experience of this novel treatment in the United States for recurrent respiratory papillomatosis (RRP).

Study Design: Cases series.

Methods: Electronic survey of the RRP Task Force of the American Society of Pediatric Otolaryngology, American Broncho-Esophagological Association, and physicians known to the authors to have used systemic bevacizumab for RRP.

Results: Eleven completed surveys were obtained. In three cases, systemic bevacizumab was considered clinically but not administered. Eight patients were treated with systemic bevacizumab, all for aggressive papillomatosis uncontrolled by surgical and adjuvant therapy, including seven of eight with pulmonary disease. Treatment dosing ranged from 5 to 10 mg/kg every 2 to 4 weeks, with all patients responding (7/8 partial response, 1/8 complete response). In four patients who had postbevacizumab chest imaging, three demonstrated improvement of disease and one stabilization. Treatment interval could be lengthened in seven patients and clinical response maintained. One patient with long-standing pulmonary disease (>10 years) was diagnosed with malignant transformation while on treatment, and bevacizumab was discontinued in lieu of other chemotherapeutic agents. All other patients continue on systemic bevacizumab with minimal complications (hemoptysis n = 1, proteinuria n = 1).

Conclusions: Systemic bevacizumab appears to have significant promise in the most treatment-resistant and aggressive forms of papillomatosis with a low complication profile. These results suggest bevacizumab should be studied in a formal clinical trial for RRP.

Level Of Evidence: 4. Laryngoscope, 127:2225-2229, 2017.
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http://dx.doi.org/10.1002/lary.26662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607082PMC
October 2017

Potential therapeutic impact of CD13 expression in non-small cell lung cancer.

PLoS One 2017 12;12(6):e0177146. Epub 2017 Jun 12.

Gerhard-Domagk-Institute of Pathology, University of Muenster, Muenster, Germany.

Background: Aminopeptidase N (CD13) is a zinc-binding protease that has functional effects on both cancerogenesis and tumor angiogenesis. Since CD13 is an antigen suitable for molecular targeted therapies (e.g. tTF-NGR induced tumor vascular infarction), we evaluated its impact in NSCLC patients, and tested the effects of the CD13-targeted fusion protein tTF-NGR (truncated tissue factor (tTF) containing the NGR motif: asparagine-glycine-arginine) in vivo in nude mice.

Methods: Expression of both CD13 and CD31 was studied in 270 NSCLC patients by immunohistochemistry. Clinical correlations and prognostic effects of the expression profiles were analyzed using univariate and multivariate analyses. In addition, a microarray-based analysis on the basis of the KM plotter database was performed. The in vivo effects of the CD13-targeted fusion protein tTF-NGR on tumor growth were tested in CD1 nude mice carrying A549 lung carcinoma xenotransplants.

Results: CD13 expression in tumor endothelial and vessel associated stromal cells was found in 15% of the investigated samples, while expression in tumor cells was observed in 7%. Although no significant prognostic impact was observed in the full NSCLC study cohort, both univariate and multivariate models identified vascular CD13 protein expression to correlate with poor overall survival in stage III and pN2+ NSCLC patients. Microarray-based mRNA analysis for either adenocarcinomas or squamous cell carcinomas did not reveal any significant effect. However, the analysis of CD13 mRNA expression for all lung cancer histologies demonstrated a positive prognostic effect. In vivo, systemic application of CD13-targeted tissue factor tTF-NGR significantly reduced CD13+ A549 tumor growth in nude mice.

Conclusions: Our results contribute a data basis for prioritizing clinical testing of tTF-NGR and other antitumor molecules targeted by NGR-peptides in NSCLC. Because CD13 expression in NSCLC tissues was found only in a specific subset of NSCLC patients, rigorous pre-therapeutic testing will help to select patients for these studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0177146PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5467809PMC
September 2017

Progressive histoplasmosis with hemophagocytic lymphohistiocytosis and epithelioid cell granulomatosis: A case report and review of the literature.

Eur J Haematol 2017 Jul 11;99(1):91-100. Epub 2017 May 11.

Department of Medicine A, University Hospital Muenster, Muenster, Germany.

Histoplasmosis in central Europe is a rare fungal disease with diverse clinical presentations. Apart from acute pulmonary histoplasmosis and involvement of the central nervous system, the most serious clinical presentation is progressive disseminated histoplasmosis which is generally associated with severe immunodeficiency and, in particular, advanced human immunodeficiency virus infection. Here, we report on an immunocompetent female residing in a non-endemic area, presenting with progressive disseminated histoplasmosis after a remote travel history to Thailand and Costa Rica. Diagnosis was delayed by several months due to misinterpretation of epithelioid cell granulomatosis of the intestine as Crohn's disease and of similar lung lesions as acute sarcoidosis. Prompted by clinical deterioration with signs and symptoms consistent with hemophagocytic lymphohistiocytosis, a bone marrow aspiration was performed that documented hemophagocytosis and intracellular organisms interpreted as Leishmania sp., but later identified by molecular methods as Histoplasma capsulatum. Treatment with liposomal amphotericin B followed by posaconazole led to prompt clinical improvement and ultimately cure.
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http://dx.doi.org/10.1111/ejh.12886DOI Listing
July 2017

Management of destructive Candida albicans spondylodiscitis of the cervical spine: a systematic analysis of literature illustrated by an unusual case.

Eur Spine J 2017 04 5;26(4):1009-1018. Epub 2016 Nov 5.

Department of Trauma, Hand and Reconstructive Surgery, University Hospital Münster, Waldeyerstraße 1, 48149, Münster, Germany.

Purpose: Candida induced spondylodiscitis of the cervical spine in immunocompetent patients is an extremely rare infectious complication. Since clinical symptoms might be nonspecific, therapeutic latency can lead to permanent spinal cord damage, sepsis and fatal complications. Surgical debridement is strongly recommended but there is no standard antimycotic regime for postsurgical treatment. This paper summarizes available data and demonstrates another successfully treated case.

Methods: The systematic analysis was performed according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. PubMed and Web of Science were scanned to identify English language articles. Additionally, the authors describe the case of a 60-year-old male patient who presented with a Candida albicans induced cervical spondylodiscitis after an edematous pancreatitis and C. albicans sepsis. Anterior cervical corpectomy and fusion of C4-C6, additional anterior plating, as well as posterior stabilization C3-Th1 was followed by a 6-month antimycotic therapy. There was neither funding nor conflict of interests.

Results: A systematic literature analysis was conducted and 4599 articles on spondylodiscitis were scanned. Only four cases were found reporting about a C. albicans spondylodiscitis in a non-immunocompromised patient. So far, our patient was followed up for 2 years. Until now, he shows free of symptoms and infection parameters. Standard testing for immunodeficiency showed no positive results.

Conclusion: Candida albicans spondylodiscitis of the cervical spine presents a potentially life-threatening disease. To our knowledge, this is the fifth case in literature that describes the treatment of C. albicans spondylodiscitis in an immunocompetent patient. Surgical debridement has to be considered, following antimycotic regime recommendations vary in pharmaceutical agents and treatment duration.
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http://dx.doi.org/10.1007/s00586-016-4827-3DOI Listing
April 2017

Thoracic Malignancies and Pulmonary Nodules in Patients under Evaluation for Transcatheter Aortic Valve Implantation (TAVI): Incidence, Follow Up and Possible Impact on Treatment Decision.

PLoS One 2016 12;11(5):e0155398. Epub 2016 May 12.

Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany.

Background: Transcatheter aortic valve implantation (TAVI) has become the treatment of choice in patients with severe aortic valve stenosis who are not eligible for operative replacement and an alternative for those with high surgical risk. Due to high age and smoking history in a high proportion of TAVI patients, suspicious findings are frequently observed in pre-procedural chest computer tomography (CCT).

Methods: CCT scans of 484 consecutive patients undergoing TAVI were evaluated for incidentally discovered solitary pulmonary nodules (SPN).

Results: In the entire study population, SPN ≥ 5 mm were found in 87 patients (18%). These patients were compared to 150 patients who were incidentally collected from the 397 patients without SPN or with SPN < 5 mm (control group). After a median follow-up of 455 days, lung cancer was diagnosed in only two patients. Neither SPN ≥ 5 mm (p = 0.579) nor SPN > 8 mm (p = 0.328) were significant predictors of overall survival.

Conclusions: Despite the high prevalence of SPNs in this single center TAVI cohort lung cancer incidence at midterm follow-up seems to be low. Thus, aggressive diagnostic approaches for incidentally discovered SPN during TAVI evaluation should not delay the treatment of aortic stenosis. Unless advanced thoracic malignancy is obvious, the well documented reduction of morbidity and mortality by TAVI outweighs potentially harmful delays regarding further diagnostics. Standard guideline-approved procedure for SPN can be safely performed after TAVI.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0155398PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4865104PMC
July 2017

PD-1 and PD-L1 Expression in NSCLC Indicate a Favorable Prognosis in Defined Subgroups.

PLoS One 2015 27;10(8):e0136023. Epub 2015 Aug 27.

Gerhard-Domagk-Institute of Pathology, University of Münster, Münster, Germany.

Background: Immunotherapy can become a crucial therapeutic option to improve prognosis for lung cancer patients. First clinical trials with therapies targeting the programmed cell death receptor PD-1 and its ligand PD-L1 have shown promising results in several solid tumors. However, in lung cancer the diagnostic, prognostic and predictive value of these immunologic factors remains unclear.

Method: The impact of both factors was evaluated in a study collective of 321 clinically well-annotated patients with non-small lung cancer (NSCLC) using immunohistochemistry.

Results: PD-1 expression by tumor infiltrating lymphocytes (TILs) was found in 22%, whereas tumor cell associated PD-L1 expression was observed in 24% of the NSCLC tumors. In Fisher's exact test a positive correlation was found for PD-L1 and Bcl-xl protein expression (p = 0.013). Interestingly, PD-L1 expression on tumor cells was associated with improved overall survival in pulmonary squamous cell carcinomas (SCC, p = 0.042, log rank test), with adjuvant therapy (p = 0.017), with increased tumor size (pT2-4, p = 0.039) and with positive lymph node status (pN1-3, p = 0.010). These observations were confirmed by multivariate cox regression models.

Conclusion: One major finding of our study is the identification of a prognostic implication of PD-L1 in subsets of NSCLC patients with pulmonary SCC, with increased tumor size, with a positive lymph node status and NSCLC patients who received adjuvant therapies. This study provides first data for immune-context related risk stratification of NSCLC patients. Further studies are necessary both to confirm this observation and to evaluate the predictive value of PD-1 and PD-L1 in NSCLC in the context of PD-1 inhibition.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0136023PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4552388PMC
May 2016

Evaluation of hydrogen peroxide vapor for the inactivation of nosocomial pathogens on porous and nonporous surfaces.

Am J Infect Control 2015 Jan;43(1):82-5

Bioquell UK Ltd, Andover, Hampshire, UK; Centre for Clinical Infection and Diagnostics Research, Department of Infectious Diseases, King's College London and Guy's and St. Thomas' National Health Service (NHS) Foundation Trust, London, UK.

Background: Clostridium difficile spores and multidrug-resistant (MDR) organisms, such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), and MDR Acinetobacter baumannii, are important nosocomial pathogens that are difficult to eliminate from the hospital environment. We evaluated the efficacy of hydrogen peroxide vapor (HPV), a no-touch automated room decontamination system, for the inactivation of a range of pathogens dried onto hard nonporous and porous surfaces in an operating room (OR).

Methods: Stainless steel and cotton carriers containing >4 log10 viable MRSA, VRE, or MDR A baumannii were placed at 4 locations in the OR along with 7 pouched 6 log10Geobacillus stearothermophilus spore biologic indicators (BIs). HPV was then used to decontaminate the OR. The experiment was repeated 3 times.

Results: HPV inactivated all spore BIs (>6 log10 reduction), and no MRSA, VRE, or MDR A baumannii were recovered from the stainless steel and cotton carriers (>4-5 log10 reduction, depending on the starting inoculum). HPV was equally effective at all carrier locations. We did not identify any difference in efficacy for microbes dried onto stainless steel or cotton surfaces, indicating that HPV may have a role in the decontamination of both porous and nonporous surfaces.

Conclusion: HPV is an effective way to decontaminate clinical areas where contamination with bacterial spores and MDR organisms is suspected.
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http://dx.doi.org/10.1016/j.ajic.2014.10.007DOI Listing
January 2015

Rapid response to systemic bevacizumab therapy in recurrent respiratory papillomatosis.

Oncol Lett 2014 Nov 28;8(5):1912-1918. Epub 2014 Aug 28.

Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany.

Recurrent respiratory papillomatosis (RRP) is a primary benign disease, which is characterized by papillomatous growth in the respiratory tract. Malignant transformation occurs in only 3-5% of cases, however, local growth of the benign papillomas is interpreted as clinically malignant in a markedly higher proportion of patients. Local surgical or endoscopic interventional debulking or excision is currently the commonly selected treatment method and antiviral therapy is a potential adjuvant approach. However, the long-term management of RRP patients, who commonly require multiple procedures over numerous years, is challenging and the overall therapeutic armamentarium remains unsatisfactory. The administration of systemic bevacizumab treatment in a series of five patients with long histories of RRP, who required repeated local interventions to control papilloma growth is evaluated. Treatment with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab was administered at a dose of 5 mg/kg (n=1), 10 mg/kg (n=3) or 15 mg/kg (n=1) intravenously to the five RRP patients, who were clinically classified as exhibiting progressive disease. Endoscopic evaluations were performed prior to the first infusion of bevacizumab and intermittently at variable time points during the course of therapy. Histopathological analyses were performed using pre- and post-treatment papilloma biopsies, including immunohistochemical analyses of VEGF and phosphorylated VEGF receptor (VEGFR)-2 expression. The patients received between three and 16 courses of bevacizumab (median, six courses). The first course was initiated when progression following the previous intervention was observed. An immediate response to bevacizumab treatment was demonstrated in all five RRP patients. While the cumulative number of interventions in the five patients was 18 throughout the 12 months prior to the initiation of bevacizumab treatment, only one patient required interventional treatment due to a malignant transformation during the 12 months following treatment with bevacizumab (18 vs. 1 interventions, P=0.042). Histopathological analyses revealed regressive perivascular edema and normalization of the vascular structure, however, immunohistochemical analyses of the VEGF and phosphorylated VEGFR-2 expression did not demonstrate any changes following therapy. Due to the limited number of alternative treatments, VEGF-targeted therapies may represent a promising novel strategy in the treatment of RRP, which may have the potential to modify the current treatment standards, particularly in patients with poorly accessible papilloma lesions, however, this requires further investigation in clinical trials.
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http://dx.doi.org/10.3892/ol.2014.2486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4186578PMC
November 2014