Ipilimumab and Pembrolizumab Mixed Response in a 41-Year-Old Patient with SMARCA4-Deficient Thoracic Sarcoma: An Interdisciplinary Case Study

SMARCA4-deficient thoracic sarcoma is a newly described entity of thoracic sarcomas with a poor prognosis, defined by poorly differentiated epithelioid to rhabdoid histomorphology and SMARCA4 gene inactivation. We present a case of a SMARCA4-deficient thoracic sarcoma in a 41-year-old male with a smoking history who presented with an upper anterior mediastinal mass, after seeking medical evaluation for increasing thoracic pain, odynophagia, and dizziness. The biopsy confirmed a large cell tumor with an epithelioid to rhabdoid histomorphology, positive for EMA, CD99, vimentin, TLE1, INI1, PAS-positive cytoplasmic granules, and PD-L1 (100% of tumor cells). High TMB and HRD scores were displayed in the tumor. The histology and immunophenotype of the mass were in line with the diagnosis of SMARCA4-deficient thoracic sarcoma. In the course of his treatment, the patient showcased a partial response to pembrolizumab and the combination of pembrolizumab and ipilimumab. This case report highlights the importance of recognizing SMARCA4-deficient thoracic sarcoma as an individual entity and supports the importance of checkpoint inhibition therapy for SMARCA4-deficient thoracic sarcomas, particularly in cases with a high TMB and PD-L1 expression

Target heterogeneity in oncology : the best predictor for differential response to radioligand therapy in neuroendocrine tumors and prostate cancer

Tumor or target heterogeneity (TH) implies presence of variable cellular populations having different genomic characteristics within the same tumor, or in different tumor sites of the same patient. The challenge is to identify this heterogeneity, as it has emerged as the most common cause of ‘treatment resistance’, to current therapeutic agents. We have focused our discussion on ‘Prostate Cancer’ and ‘Neuroendocrine Tumors’, and looked at the established methods for demonstrating heterogeneity, each with its advantages and drawbacks. Also, the available theranostic radiotracers targeting PSMA and somatostatin receptors combined with targeted systemic agents, have been described. Lu-177 labeled PSMA and DOTATATE are the ‘standard of care’ radionuclide therapeutic tracers for management of progressive treatment-resistant prostate cancer and NET. These approved therapies have shown reasonable benefit in treatment outcome, with improvement in quality of life parameters. Various biomarkers and predictors of response to radionuclide therapies targeting TH which are currently available and those which can be explored have been elaborated in details. Imaging-based features using artificial intelligence (AI) need to be developed to further predict the presence of TH. Also, novel theranostic tools binding to newer targets on surface of cancer cell should be explored to overcome the treatment resistance to current treatment regimens.http://www.mdpi.com/journal/cancerspm2021Nuclear Medicin

Pharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo

Whooping cough is caused by Bordetella pertussis that releases pertussis toxin (PT) which comprises enzyme A-subunit PTS1 and binding/transport B-subunit. After receptor-mediated endocytosis, PT reaches the endoplasmic reticulum from where unfolded PTS1 is transported to the cytosol. PTS1 ADP-ribosylates G-protein alpha -subunits resulting in increased cAMP signaling. Here, a role of target cell chaperones Hsp90, Hsp70, cyclophilins and FK506-binding proteins for cytosolic PTS1-uptake is demonstrated. PTS1 specifically and directly interacts with chaperones in vitro and in cells. Specific pharmacological chaperone inhibition protects CHO-K1, human primary airway basal cells and a fully differentiated airway epithelium from PT-intoxication by reducing intracellular PTS1-amounts without affecting cell binding or enzyme activity. PT is internalized by human airway epithelium secretory but not ciliated cells and leads to increase of apical surface liquid. Cyclophilin-inhibitors reduced leukocytosis in infant mouse model of pertussis, indicating their promising potential for developing novel therapeutic strategies against whooping cough

Interaktion des Pertussistoxins mit dem Chaperon Hsp90 und Peptidyl-prolyl-cis/trans-Isomerasen während seiner Aufnahme in Säugetierzellen

Das Pertussistoxin ist ein AB5-Exotoxin, das von Bordetella pertussis produziert und sezerniert wird und den Auslöser der Infektionskrankheit Pertussis (Keuchhusten) darstellt. Es besteht aus einem A-Protomer, das der S1-Untereinheit entspricht und die Enzymfunktion trägt, und einem B-Oligomer, das aus den Untereinheiten S2, S3, 2 x S4 und S5 besteht und für die Bindung des Toxins an seine Zielzellen und die Translokation des A-Protomers aus dem endoplasmatischen Retikulum in das Zytosol der Zielzellen zuständig ist. Zu seinem Translokationsort gelangt Pertussistoxin als long-trip Toxin nach der Rezeptor-vermittelten Endozytose und dem retrograden Transport durch den Golgi-Apparat. Die Enzymfunktion des A-Protomers besteht in einer Adenosindiphosphat-(ADP)-Ribosyltransferase, welche im Zytosol die kovalente Übertragung von ADP-Ribose-Resten auf die α-Untereinheiten von membrangebundenen inhibitorischen heterotrimeren (Gi/o)-Proteinen katalysiert. Dadurch wird in Zellen die Hemmung der Adenylatzyklase aufgehoben, welche konsekutiv vermehrt zyklisches Adenosinmonophosphat (cAMP) herstellt. Dies führt zu unterschiedlichen Reaktionen auf Pertussistoxin sowohl auf zellulärer als auch auf systemischer Ebene. In der Arbeitsgruppe Barth werden die molekularen Aufnahmemechanismen bakterieller AB-Toxine sowie die Beteiligung von zytosolischen Wirtszellfaktoren an der Translokation der A-Untereinheiten untersucht. Dadurch konnte die Arbeitsgruppe erstmals zeigen, dass das Chaperon Hitzeschockprotein90 (Hsp90) und die Peptidyl-Prolyl-cis/trans-Isomerasen (PPIasen) der Cyclophilin- und der FK506-Bindeprotein-Familien wichtige Rollen bei der Translokation einiger clostridialer Toxine und des Diphtherietoxins spielen, bei denen es sich ebenfalls um ADP-Ribosyltransferasen handelt. Das Ziel der vorliegenden Arbeit war es, die Rolle von Hsp90 und der PPIasen bei der zellulären Aufnahme des Pertussistoxins zu charakterisieren. Dafür wurde die Wirkung der spezifischen pharmakologischen Inhibitoren Radicicol, das Hsp90 hemmt, Cyclosporin A, das Cyclophiline hemmt, und Tacrolimus (FK506), das FK506-Bindeproteine hemmt, auf die Vergiftung von Ovarienzellen des chinesischen Hamsters (CHO-Zellen) durch Pertussistoxin genauer betrachtet, um zu prüfen, ob die Wirtszellfaktoren an der Toxinaufnahme beteiligt sind. In der vorliegenden Arbeit konnte dabei erstmals gezeigt werden, dass Radicicol, Cyclosporin A und FK506 die Vergiftung kultivierter CHO-Zellen durch Pertussistoxin deutlich verzögerten, ebenso das nicht-immunsuppressive Cyclosporin A Derivat VK112. Um die Hypothese, dass dabei die Translokation inhibiert wird, zu bestätigen, wurden weitere Experimente durchgeführt, um die Hemmung genauer zu charakterisieren. Dabei konnte gezeigt werden, dass weder die Bindung des Toxins an zelluläre Rezeptoren noch seine Enzymaktivität durch die Inhibitoren gehemmt wurden. Die Inhibitoren führten dazu, dass in den Zellen weniger Substrat Giα von Pertussistoxin ADP-ribosyliert wurde, da weniger des A-Protomers des Toxins im Zytosol angekommen war. In Zusammenschau mit den vorgenannten Ergebnissen ist dies ist ein sehr starker Hinweis darauf, dass die zytosolischen Faktoren an der Translokation des A-Protomers ins Zytosol beteiligt sind. Somit konnte erstmals die Beteiligung von Hsp90, Cyclophilinen – sehr wahrscheinlich von Cyclophilin A – und FK506-Bindeproteinen an der Aufnahme von Pertussistoxin ins Zytosol aufgezeigt werden, was einen wichtigen Beitrag zum besseren Verständnis seines Aufnahmemechanismus in Säugetierzellen leistet. Überdies haben die Ergebnisse, insbesondere die des nicht-immunsuppressiven Cyclosporin A Derivats VK112, eine medizinisch-klinische Relevanz, da sie zeigen, dass dieser Inhibitor zu einem vielversprechenden Kandidaten für die Entwicklung neuartiger, möglicherweise sogar kausaler, Therapiestrategien zur Behandlung von durch Pertussistoxin verursachten Erkrankungen werden könnte. Die vorliegende Arbeit liefert somit Grundlagen und Anregungen für weitere, vielfältige Versuche zukünftiger Arbeiten, wie die Analyse der Interaktion der einzelnen zytosolischen Faktoren mit Pertussistoxin in vitro und in lebenden Zellen

Nuklearmedizinische Diagnostik und Therapie des Prostatakarzinoms

<jats:title>Zusammenfassung</jats:title><jats:p>Die PSMA-PET/CT hat durch die präzise Darstellung der Tumorausdehnung einen festen Stellenwert in der Diagnostik, insbesondere in der Rezidivsituation, eingenommen und ist bereits in mehreren nationalen und internationalen Leitlinien fest verankert. Sie ermöglicht, in einem Untersuchungsgang Informationen über die Tumorsituation in der Prostataloge und von potenziellen lymphonodalen, viszeralen und ossären Metastasen zu erlangen, die für die zunehmend personalisierten Behandlungsstrategien notwendig sind. Die PSMA-Therapie stellt bereits jetzt – trotz bisher fehlender Zulassung – eine ergänzende nebenwirkungsarme Therapie beim metastasierten kastrationsresistenten Prostatakarzinom dar, die die Lebensqualität der Patienten deutlich verbessern und die Überlebenszeit steigern kann ohne relevante Toxizität, und deren Potenzial für die Zukunft auch durch Kombination mit anderen Therapieverfahren noch lange nicht absehbar ist. Der Beitrag thematisiert die Einsatzgebiete der PSMA-PET-Bildgebung als Grundlage für die erfolgreiche Therapie sowie den aktuellen Stand zur Indikation, Durchführung und Entwicklung der PSMA-Therapie.</jats:p&gt

18F-FDG-PET/MR in Alveolar Echinococcosis: Multiparametric Imaging in a Real-World Setting

Recent improvements in alveolar echinococcosis (AE) therapy can provide long-term disease control, and even allow structured treatment interruption in selected cases. Imaging has a pivotal role in monitoring disease activity, with 18-fluoro-deoxyglucose positron emission and computed tomography (18F-FDG-PET/CT) in particular having proven beneficial for assessing disease activity. Repetitive regular examinations to monitor therapy response, however, can lead to substantial radiation burden. Therefore, by combining metabolic information and excellent tissue contrast in magnetic resonance imaging (MRI), PET/MR appears ideally suited for this task. Here, we retrospectively analyzed 51 AE patients that underwent 18F-FDG-PET/MR. Patients had a ‘confirmed/probable’ diagnosis in 22/29 cases according to the WHO classification. FDG uptake, diffusion restriction, and MRI morphology were evaluated. We found significant differences in FDG uptake between responders to benzimidazole therapy and progressive manifestations (SUVavg 2.7 ± 1.3 vs. 5.4 ± 2.2, p < 0.001) as well as between Kodama Types 1 and 3 (F = 9.9, p < 0.003). No significant differences were detected for ADC values or MRI morphology concerning response and no correlations were present between FDG uptake and ADC values. The mean radiation dose was 5.9–6.5 mSv. We conclude that the combination of metabolic information and MRI morphology at a low radiation dose proposes PET/MR as a suitable imaging modality for AE assessment. Longitudinal studies are needed to define the role of this imaging modality

Imaging in non-bacterial osteomyelitis in children and adolescents: diagnosis, differential diagnosis and follow-up—an educational review based on a literature survey and own clinical experiences

Background!#!Chronic non-bacterial osteomyelitis (CNO) is an autoinflammatory bone disorder affecting children and adolescents. Previously classified as a rare disease, recent studies suggest a higher incidence of the disease. CNO may develop into the clinical presentation of chronic recurrent osteomyelitis (CRMO) with high relapse rate and multifocality.!##!Main body!#!Diagnosis of CNO/CRMO is often delayed, with implications for disease severity and relapse rate. This can be significantly improved by knowledge of the disease entity and its characteristics. Imaging plays a key role in diagnosis, differential diagnosis and therapy monitoring. Magnetic resonance imaging (MRI) has several advantages compared to other imaging methods and is increasingly applied in clinical studies. Recent studies show that a whole-body (WB) coverage (WB-MRI) without contrast agent administration is a rational approach. This educational review is based on a systematic analysis of international peer-reviewed articles and presents our own clinical experiences. It provides an overview of disease entity, incidence and clinical diagnosis. The role of imaging, especially of whole-body MRI, is discussed in detail. Finally, practical advice for imaging, including flowcharts explaining when and how to apply imaging, is provided.!##!Conclusion!#!Knowing the specifics of CNO/CRMO and the importance of MRI/whole-body MRI allows rapid and efficient diagnosis as well as therapy support and helps to avoid irreversible secondary damage

Evaluation of Serological Markers in Alveolar Echinococcosis Emphasizing the Correlation of PET-CTI Tracer Uptake with RecEm18 and Echinococcus-Specific IgG

Human alveolar echinococcosis (AE), which is caused by the cestode Echinococcus (E.) multilocularis, is an epidemiologically relevant issue in modern medicine and still poses a diagnostic and therapeutic challenge. Since diagnosis mainly relies on imaging procedures and serological testing, we retrospectively and comparatively analyzed the performance of an Echinococcus IgG screening ELISA, whole serum IgE, and two specific confirmatory ELISA platforms using the defined E. multilocularis antigens Em2-Em18 (Em2+) and recombinant Em18 (recEm18). With special emphasis on the clinical usefulness of recEm18, we correlated the laboratory results with clinical characteristics and imaging findings in a large and well-characterized cohort of N = 124 AE patients, who were followed over several years after either surgical plus subsequent pharmacological treatment or pharmacotherapy alone. All patients had routinely received PET-CTI every two years. Our data reveal strong correlations for both Echinococcus IgG and recEm18 with tracer uptake in PET-CTI and parasitic lesion size and number, suggesting additional clinical usefulness of recEm18 for certain constellations only, while IgG and Em2+ still appear reasonable and sensitive screening methods for initial diagnosis of AE. With this study, we aim to contribute to further optimizing medical care of AE patients. For instance, it might be reasonable to consider the replacement of some PET-CTI follow-ups by imaging procedures with less radiation exposure or serological means alone. Further studies that clarify the correlation of serological markers with ultrasound criteria might be particularly useful, and further retrospective as well as prospective investigations are justified in this context

Pharmacological Cyclophilin Inhibitors Prevent Intoxication of Mammalian Cells with Bordetella pertussis Toxin

The Bordetella pertussis toxin (PT) is one important virulence factor causing the severe childhood disease whooping cough which still accounted for approximately 63,000 deaths worldwide in children in 2013. PT consists of PTS1, the enzymatically active (A) subunit and a non-covalently linked pentameric binding/transport (B) subunit. After endocytosis, PT takes a retrograde route to the endoplasmic reticulum (ER), where PTS1 is released into the cytosol. In the cytosol, PTS1 ADP-ribosylates inhibitory alpha subunits of trimeric GTP-binding proteins (Giα) leading to increased cAMP levels and disturbed signalling. Here, we show that the cyclophilin (Cyp) isoforms CypA and Cyp40 directly interact with PTS1 in vitro and that Cyp inhibitors cyclosporine A (CsA) and its tailored non-immunosuppressive derivative VK112 both inhibit intoxication of CHO-K1 cells with PT, as analysed in a morphology-based assay. Moreover, in cells treated with PT in the presence of CsA, the amount of ADP-ribosylated Giα was significantly reduced and less PTS1 was detected in the cytosol compared to cells treated with PT only. The results suggest that the uptake of PTS1 into the cytosol requires Cyps. Therefore, CsA/VK112 represent promising candidates for novel therapeutic strategies acting on the toxin level to prevent the severe, life-threatening symptoms caused by PT