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Wenzel, Mike ; Collà Ruvolo, Claudia ; Würnschimmel, Christoph ; Nocera, Luigi ; Tian, Zhe ; Saad, Fred ; Briganti, Alberto ; Tilki, Derya ; Graefen, Markus ; Becker, Andreas ; Roos, Frederik ; Mandel, Philipp ; Chun, Felix ; Karakiewicz, Pierre I.
Background: The survival benefit of primary external beam radiation therapy (EBRT) has never been formally tested in elderly men who were newly diagnosed with metastatic prostate cancer (mPCa). We hypothesized that elderly patients may not benefit of EBRT to the extent as younger newly diagnosed mPCa patients, due to shorter life expectancy.
Methods: We relied on Surveillance, Epidemiology and End Results (2004–2016) to identify elderly newly diagnosed mPCa patients, aged >75 years. Kaplan–Meier, univariable and multivariable Cox regression models, as well as Competing Risks Regression models tested the effect of EBRT versus no EBRT on overall mortality (OM) and cancer-specific mortality (CSM).
Results: Of 6556 patients, 1105 received EBRT (16.9%). M1b stage was predominant in both EBRT (n = 823; 74.5%) and no EBRT (n = 3908; 71.7%, p = 0.06) groups, followed by M1c (n = 211; 19.1% vs. n = 1042; 19.1%, p = 1) and M1a (n = 29; 2.6% vs. n = 268; 4.9%, p < 0.01). Median overall survival (OS) was 23 months for EBRT and 23 months for no EBRT (hazard ratio [HR]: 0.97, p = 0.6). Similarly, median cancer-specific survival (CSS) was 29 months for EBRT versus 30 months for no EBRT (HR: 1.04, p = 0.4). After additional multivariable adjustment, EBRT was not associated with lower OM or lower CSM in the entire cohort, as well as after stratification for M1b and M1c substages.
Conclusions: In elderly men who were newly diagnosed with mPCa, EBRT does not affect OS or CSS. In consequence, our findings question the added value of local EBRT in elderly newly diagnosed mPCa patients.
Maurer-Grubinger, Christian ; Adjami, Frederic ; Avaniadi, Ioanna ; Christian, Wolfgang ; Doerry, Charlotte ; Fay, Viola Nathalie ; Fisch, Vanessa ; Gerez, Ali ; Goecke, Julian ; Kaya, Ugur ; Keller, Julia ; Krüger, Kai-Dominik ; Pflaum, Julia ; Porsch, Laurin ; Wischnewski, Christina ; Scharnweber, Benjamin ; Sosnov, Polyna ; Oremek, Gerhard ; Groneberg, Jan David Alexander ; Ohlendorf, Daniela Maren
Objectives: Symmetrical dental occlusion blocking is used in dentistry as a quick diagnostic tool to test for potential influences of the craniomandibular system on body sway and weight distribution. This study presents the changes of body sway and pressure distribution in healthy subjects, free of a temporomandibular dysfunction (TMD). Immediate effects between occlusal blocking and rest position on body sway and body weight distribution in general, as well as for both genders and for four age decades will be evaluated.
Materials and methods: 725 (396f/329 m) subjects (neither subjective signs of TMD nor acute/chronic complaints in the musculoskeletal system) volunteered (21 to 60 years) while both genders were divided into four age groups according to decades. A pressure measuring platform was used. Body sway and weight distribution were recorded in two dental occlusion conditions (a) in rest position and (b) symmetrical blocking (bicuspid region) by cotton rolls.
Results: Both, the frontal sway and the sagittal sway reduced by 0.67 mm (t(724) = − 3.9 (p < 0.001)) and by 0.33 mm (t(724) = − 3.4 (p < 0.001)). The relative pressure under the left forefoot increased by 0.33% (t(724) = 2.88 (p < 0.001)) and the relative pressure overall under the forefoot increased by 0.67% (t(724) = − 3.4 (p < 0.001)). Gender-specific, age-specific and BMI-specific reactions could not be identified.
Conclusions: Subjects, free of any TMD and with no complaints of the musculoskeletal system, show small changes of the body sway and weight distribution when biting symmetrically on a cotton roll. These changes are independent of age, gender or body mass index (BMI). Due to the relative large sample size, the presented results can also be seen as norm values when body sway is used as an additional assessment of a TMD.
Maurer-Grubinger, Christian ; Avaniadi, Ioanna ; Adjami, Frederic ; Christian, Wolfgang ; Doerry, Charlotte ; Fay, Viola Nathalie ; Fisch, Vanessa ; Gerez, Ali ; Goecke, Julian ; Kaya, Ugur ; Keller, Julia ; Krüger, Kai-Dominik ; Pflaum, Julia ; Porsch, Laurin ; Wischnewski, Christina ; Scharnweber, Benjamin ; Sosnov, Polyna ; Oremek, Gerhard ; Groneberg, Jan David Alexander ; Ohlendorf, Daniela Maren
Background: Temporary occlusal changes and their influence on the upper body statics are still controversially discussed. Furthermore, concrete statements on whether age- or gender-specific differences in neurophysiological reactions exist are missing. Therefore, it is the aim of this study to evaluate the immediate effects of a symmetrical occlusion blocking on the upper body posture. These effects shall be investigated for both genders and for a larger age range.
Methods: In this study, 800 (407f/393 m) subjects volunteered aged from 21 to 60 years. Both genders were divided into four age groups according to decades. The three-dimensional upper body posture was measured by using the rasterstereography (ABW-Bodymapper). The habitual static posture was measured in two dental occlusion conditions (a) in rest position and (b) symmetrical blocking in the bicuspid region by cotton rolls.
Results: A significant reduction of the trunk length (0.72 mm; p < 0.001), an increase of the lumbar (0.30°; p < 0.001) and the thoracic bending angle (0.14°; p = 0.001), a reduction of the spinal forward decline (0.16°; p < 0.001) and a reduction of the scapular distance (0.36 mm; p = 0.001) was found. Gender-specific reactions can only be recorded in scapular distance, in that regard men reduce this distance while over all age groups women did not show a significant change.
Discussion: Slight gender- and age-independent reactions due to a symmetric occlusion blockade are shown: A gender independent reaction of the spinal related variables in the sagittal plane (thoracic and lumbar flexion angle, trunk length, spinal forward decline). In addition, a gender specific change of the shoulder blade distance could be observed, where men reduced the distance while female did not show a change. However, since these reactions are of a minimum amount, it can be concluded that neurophysiological compensation mechanisms work equally well regardless of age and sex, and the upper body posture of healthy people changes only very slightly due to a temporarily symmetrical altered bite position.
Koch, Vitali ; Abt, Julia Anna Walburga ; Grünewald, Leon David ; Eichler, Katrin ; D'Angelo, Tommaso ; Martin, Simon S. ; Albrecht, Moritz Hans Ernst ; Thalhammer, Axel ; Booz, Christian ; Yel, Ibrahim ; Bernatz, Simon ; Mahmoudi, Scherwin ; Harth, Marc ; Derwich, Wojciech ; Vogl, Thomas J. ; Gray, Daphne ; Gruber-Rouh, Tatjana ; Jung, Georg
Highlights
• MRI and ultrasound provided significant correlations between findings suggestive of vasculitis and the final diagnosis.
• Careful selection of available imaging techniques is warranted considering the time course, location, and clinical history.
• Considering its moderate diagnostic power to distinguish tracer uptake, a holistic view of PET/CT findings is essential.
Abstract
Purpose: To assess the diagnostic value of different imaging modalities in distinguishing systemic vasculitis from other internal and immunological diseases.
Methods: This retrospective study included 134 patients with suspected vasculitis who underwent ultrasound, magnetic resonance imaging (MRI), or 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) between 01/2010 and 01/2019, finally consisting of 70 individuals with vasculitis. The main study parameter was the confirmation of the diagnosis using one of the three different imaging modalities, with the adjudicated clinical and histopathological diagnosis as the gold standard. A secondary parameter was the morphological appearance of the vessel affected by vasculitis.
Results: Patients with systemic vasculitis had myriad clinical manifestations with joint pain as the most common symptom. We found significant correlations between different imaging findings suggestive of vasculitis and the final adjudicated clinical diagnosis. In this context, on MRI, vessel wall thickening, edema, and diameter differed significantly between vasculitis and non-vasculitis groups (p < 0.05). Ultrasound revealed different findings that may serve as red flags in identifying patients with vasculitis, such as vascular occlusion or halo sign (p = 0.02 vs. non-vasculitis group). Interestingly, comparing maximal standardized uptake values from PET/CT examinations with vessel wall thickening or vessel diameter did not result in significant differences (p > 0.05).
Conclusions: We observed significant correlations between different imaging findings suggestive of vasculitis on ultrasound or MRI and the final adjudicated diagnosis. While ultrasound and MRI were considered suitable imaging methods for detecting and discriminating typical vascular changes, 18F-FDG PET/CT requires careful timing and patient selection given its moderate diagnostic accuracy.
Die Sepsis ist mit einer hohen Letalität im Krankenhaus verbunden. Ein wesentlicher Auslöser der Sepsis ist das Endotoxin. Es führt zu Entzündungsreaktionen im Organismus mit Ausbildung eines septischen Schocks bis hin zum Multiorganversagen. Zudem führt es zu Veränderungen im Gerinnungssystem mit unterschiedlich schweren Ausprägungen. Das Endotoxin wird physiologisch im menschlichen Körper durch IgM neutralisiert. In dieser Studie wurde der Effekt von IgM angereichertem intravenösen Immunglobulin auf die Endotoxinaktivität untersucht. Zusätzlich wurden die Auswirkungen einer IgM-IVIg-Therapie auf Entzündungsparameter und auf viskoelastische und konventionelle Gerinnungsparameter betrachtet. Patienten mit schwerer Sepsis und septischem Schock auf einer anästhesiologisch-chirurgischen Intensivstation wurden rekrutiert. Nach dem Studieneinschluss von 15 Patienten erfolgte die Implementierung einer neuen SOP, in der die Anwendung von IgM-IVIg (5g/kg/d für 3 Tage) integriert wurde. Daraus bildeten sich eine Kontroll- und eine IgM-IVIg Gruppe. Der Beobachtungszeitraum umfasste 4 Tage. Es wurde der Endotoxin Activity Assay® (EAA®) zur Messung der Endotoxinaktivität an Vollblutproben durchgeführt. Die durchgeführte Rotationsthrombelastometrie ROTEM® diente neben der Messung der Gerinnungszeiten auch zur Erfassung der mechanischen und zeitlichen Stabilität eines Blutgerinnsels. Als Maß für die Aggregation von Thrombozyten diente die Impedanzaggregometrie Multiplate®. Die Routinelaborparameter wurden nach allgemeinem Standard erhoben. Eingeschlossen wurden die Daten von 26 Patienten. Die IgM-IVIg-Gruppe zeigte am ersten Tag, 6 und 12 Stunden nach Behandlungsbeginn, eine Reduktion der Endotoxinaktivität (0,51±0,06 vs. 0,26±0,07, p<0,05) und unterschied sich signifikant im Vergleich zur Kontrollgruppe 6 Stunden nach Behandlungsbeginn (0,26±0,07 vs. 0,43±0,07, p<0,05). Die Thrombozytenzahl war signifikant höher in der IgM-IVIg- Gruppe im Beobachtungszeitraum (200/nl±43 vs. 87/nl±20, p<0,05). Die Fibrinogenkonzentration war in der Kontrollgruppe am zweiten (311mg/dl±37 vs. 475mg/dl±47 (p=0,015)) und am vierten Tag (307mg/dl±35 vs. 420mg/dl±16 (p=0,017)) signifikant niedriger. Es konnten keine Unterschiede in den thromboelastometrischen oder aggregometrischen Untersuchungen, oder bei den Entzündungsparametern beobachtet werden. Die präsentierten Ergebnisse müssen aufgrund der geringen Stichprobengröße sorgsam interpretiert werden. Dennoch könnten die Ergebnisse die Basis für weitere Studien in der Zukunft sein, die auf IgM-IVIg als eine therapeutische Option bei Patienten mit einer hohen Endotoxinaktivität abzielen. In der vorliegenden Studie fanden wir Hinweise, dass eine IgM-IVIg-Therapie bei Patienten mit schwerer Sepsis und septischem Schock die Endotoxinaktivität vermindert. Zudem scheint IgM-IVIg bei o.g. Patienten eine pathognomonische Thrombozytopenie positiv zu modelieren.
T Helper Cell Lineage-Defining Transcription Factors: Potent Targets for Specific GVHD Therapy?
(2022)
Allogenic hematopoietic stem cell transplantation (allo-HSCT) represents a potent and potentially curative treatment for many hematopoietic malignancies and hematologic disorders in adults and children. The donor-derived immunity, elicited by the stem cell transplant, can prevent disease relapse but is also responsible for the induction of graft-versus-host disease (GVHD). The pathophysiology of acute GVHD is not completely understood yet. In general, acute GVHD is driven by the inflammatory and cytotoxic effect of alloreactive donor T cells. Since several experimental approaches indicate that CD4 T cells play an important role in initiation and progression of acute GVHD, the contribution of the different CD4 T helper (Th) cell subtypes in the pathomechanism and regulation of the disease is a central point of current research. Th lineages derive from naïve CD4 T cell progenitors and lineage commitment is initiated by the surrounding cytokine milieu and subsequent changes in the transcription factor (TF) profile. Each T cell subtype has its own effector characteristics, immunologic function, and lineage specific cytokine profile, leading to the association with different immune responses and diseases. Acute GVHD is thought to be mainly driven by the Th1/Th17 axis, whereas Treg cells are attributed to attenuate GVHD effects. As the differentiation of each Th subset highly depends on the specific composition of activating and repressing TFs, these present a potent target to alter the Th cell landscape towards a GVHD-ameliorating direction, e.g. by inhibiting Th1 and Th17 differentiation. The finding, that targeting of Th1 and Th17 differentiation appears more effective for GVHD-prevention than a strategy to inhibit Th1 and Th17 cytokines supports this concept. In this review, we shed light on the current advances of potent TF inhibitors to alter Th cell differentiation and consecutively attenuate GVHD. We will focus especially on preclinical studies and outcomes of TF inhibition in murine GVHD models. Finally, we will point out the possible impact of a Th cell subset-specific immune modulation in context of GVHD.
Bein, Julia ; Flinner, Nadine ; Häupl, Björn ; Mathur, Aastha ; Schneider, Olga ; Abu-Ayyad, Marwa ; Hansmann, Martin-Leo ; Piel, Matthieu ; Oellerich, Thomas ; Hartmann, Sylvia
Classic Hodgkin lymphoma (cHL) is usually characterized by a low tumour cell content, derived from crippled germinal centre B cells. Rare cases have been described in which the tumour cells show clonal T-cell receptor rearrangements. From a clinicopathological perspective, it is unclear if these cases should be classified as cHL or anaplastic large T-cell lymphoma (ALCL). Since we recently observed differences in the motility of ALCL and cHL tumour cells, here, we aimed to obtain a better understanding of T-cell-derived cHL by investigating their global proteomic profiles and their motility. In a proteomics analysis, when only motility-associated proteins were regarded, T-cell-derived cHL cell lines showed the highest similarity to ALK− ALCL cell lines. In contrast, T-cell-derived cHL cell lines presented a very low overall motility, similar to that observed in conventional cHL. Whereas all ALCL cell lines, as well as T-cell-derived cHL, predominantly presented an amoeboid migration pattern with uropod at the rear, conventional cHL never presented with uropods. The migration of ALCL cell lines was strongly impaired upon application of different inhibitors. This effect was less pronounced in cHL cell lines and almost invisible in T-cell-derived cHL. In summary, our cell line-derived data suggest that based on proteomics and migration behaviour, T-cell-derived cHL is a neoplasm that shares features with both cHL and ALCL and is not an ALCL with low tumour cell content. Complementary clinical studies on this lymphoma are warranted.
El-Hindi, Khadija ; Brachtendorf, Sebastian ; Hartel, Jennifer ; Oertel, Stephanie ; Birod, Kerstin ; Merz, Nadine ; Trautmann, Sandra ; Thomas, Dominique ; Weigert, Andreas ; Schäufele, Tim J. ; Scholich, Klaus ; Schiffmann, Susanne ; Ulshöfer, Thomas ; Utermöhlen, Olaf ; Grösch, Sabine
To better understand the role of sphingolipids in the multifactorial process of inflammatory bowel disease (IBD), we elucidated the role of CerS4 in colitis and colitis-associated cancer (CAC). For this, we utilized the azoxymethane/dextran sodium sulphate (AOM/DSS)-induced colitis model in global CerS4 knockout (CerS4 KO), intestinal epithelial (CerS4 Vil/Cre), or T-cell restricted knockout (CerS4 LCK/Cre) mice. CerS4 KO mice were highly sensitive to the toxic effect of AOM/DSS, leading to a high mortality rate. CerS4 Vil/Cre mice had smaller tumors than WT mice. In contrast, CerS4 LCK/Cre mice frequently suffered from pancolitis and developed more colon tumors. In vitro, CerS4-depleted CD8+ T-cells isolated from the thymi of CerS4 LCK/Cre mice showed impaired proliferation and prolonged cytokine production after stimulation in comparison with T-cells from WT mice. Depletion of CerS4 in human Jurkat T-cells led to a constitutively activated T-cell receptor and NF-κB signaling pathway. In conclusion, the deficiency of CerS4 in T-cells led to an enduring active status of these cells and prevents the resolution of inflammation, leading to a higher tumor burden in the CAC mouse model. In contrast, CerS4 deficiency in epithelial cells resulted in smaller colon tumors and seemed to be beneficial. The higher tumor incidence in CerS4 LCK/Cre mice and the toxic effect of AOM/DSS in CerS4 KO mice exhibited the importance of CerS4 in other tissues and revealed the complexity of general targeting CerS4.
Macrophages not only represent an integral part of innate immunity but also critically contribute to tissue and organ homeostasis. Moreover, disease progression is accompanied by macrophage accumulation in many cancer types and is often associated with poor prognosis and therapy resistance. Given their critical role in modulating tumor immunity in primary and metastatic brain cancers, macrophages are emerging as promising therapeutic targets. Different types of macrophages infiltrate brain cancers, including (i) CNS resident macrophages that comprise microglia (TAM-MG) as well as border-associated macrophages and (ii) monocyte-derived macrophages (TAM-MDM) that are recruited from the periphery. Controversy remained about their disease-associated functions since classical approaches did not reliably distinguish between macrophage subpopulations. Recent conceptual and technological advances, such as large-scale omic approaches, provided new insight into molecular profiles of TAMs based on their cellular origin. In this review, we summarize insight from recent studies highlighting similarities and differences of TAM-MG and TAM-MDM at the molecular level. We will focus on data obtained from RNA sequencing and mass cytometry approaches. Together, this knowledge significantly contributes to our understanding of transcriptional and translational programs that define disease-associated TAM functions. Cross-species meta-analyses will further help to evaluate the translational significance of preclinical findings as part of the effort to identify candidates for macrophage-targeted therapy against brain metastasis.