The SBRT database initiative of the German Society for Radiation Oncology (DEGRO): patterns of care and outcome analysis of stereotactic body radiotherapy (SBRT) for liver oligometastases in 474 patients with 623 metastases

Background: The intent of this pooled analysis as part of the German society for radiation oncology (DEGRO)stereotactic body radiotherapy (SBRT) initiative was to analyze the patterns of care of SBRT for liver oligometastases and to derive factors influencing treated metastases control and overall survival in a large patient cohort. Methods: From 17 German and Swiss centers, data on all patients treated for liver oligometastases with SBRT since its introduction in 1997 has been collected and entered into a centralized database. In addition to patient and tumor characteristics, data on immobilization, image guidance and motion management as well as dose prescription and fractionation has been gathered. Besides dose response and survival statistics, time trends of the aforementioned variables have been investigated. Results: In total, 474 patients with 623 liver oligometastases (median 1 lesion/patient; range 1–4) have been collected from 1997 until 2015. Predominant histologies were colorectal cancer (n= 213 pts.; 300 lesions) and breast cancer (n= 57; 81 lesions). All centers employed an SBRT specific setup. Initially, stereotactic coordinates and CT simulation were used for treatment set-up (55%), but eventually were replaced by CBCT guidance (28%) or more recently robotic tracking (17%). High variance in fraction (fx) number (median 1 fx; range 1–13) and dose per fraction (median: 18.5 Gy; range 3–37.5 Gy) was observed, although median BED remained consistently high after an initial learning curve. Median follow-up time was 15 months; median overall survival after SBRT was 24 months. One- and 2-year treated metastases control rate of treated lesions was 77% and 64%; if maximum isocenter biological equivalent dose (BED) was greater than 150 Gy EQD2Gy, it increased to 83% and 70%, respectively. Besides radiation dose colorectal and breast histology and motion management methods were associated with improved treated metastases control

ИССЛЕДОВАНИЕ И ОПИСАНИЕ БЫТОВЫХ ГАЗОВЫХ СЧЕТЧИКОВ

В работе описывается исследование бытовых газовых счетчиков, их разновидности по принципу действия, основные преимущества и их метрологические характеристики. А также рассмотрены характеристики природного газа

Dendritic cell-specific delivery of Flt3L by coronavirus vectors secures induction of therapeutic antitumor immunity

Efficacy of antitumor vaccination depends to a large extent on antigen targeting to dendritic cells (DCs). Here, we assessed antitumor immunity induced by attenuated coronavirus vectors which exclusively target DCs in vivo and express either lymphocyte- or DC-activating cytokines in combination with a GFP-tagged model antigen. Tracking of in vivo transduced DCs revealed that vectors encoding for Fms-like tyrosine kinase 3 ligand (Flt3L) exhibited a higher capacity to induce DC maturation compared to vectors delivering IL-2 or IL-15. Moreover, Flt3L vectors more efficiently induced tumor-specific CD8(+) T cells, expanded the epitope repertoire, and provided both prophylactic and therapeutic tumor immunity. In contrast, IL-2- or IL-15-encoding vectors showed a substantially lower efficacy in CD8(+) T cell priming and failed to protect the host once tumors had been established. Thus, specific in vivo targeting of DCs with coronavirus vectors in conjunction with appropriate conditioning of the microenvironment through Flt3L represents an efficient strategy for the generation of therapeutic antitumor immunity

A Key Role for E-cadherin in Intestinal Homeostasis and Paneth Cell Maturation

E-cadherin is a major component of adherens junctions. Impaired expression of E-cadherin in the small intestine and colon has been linked to a disturbed intestinal homeostasis and barrier function. Down-regulation of E-cadherin is associated with the pathogenesis of infections with enteropathogenic bacteria and Crohn's disease. To genetically clarify the function of E-cadherin in intestinal homeostasis and maintenance of the epithelial defense line, the Cdh1 gene was conditionally inactivated in the mouse intestinal epithelium. Inactivation of the Cdh1 gene in the small intestine and colon resulted in bloody diarrhea associated with enhanced apoptosis and cell shedding, causing life-threatening disease within 6 days. Loss of E-cadherin led cells migrate faster along the crypt-villus axis and perturbed cellular differentiation. Maturation and positioning of goblet cells and Paneth cells, the main cell lineage of the intestinal innate immune system, was severely disturbed. The expression of anti-bacterial cryptidins was reduced and mice showed a deficiency in clearing enteropathogenic bacteria from the intestinal lumen. These results highlight the central function of E-cadherin in the maintenance of two components of the intestinal epithelial defense: E-cadherin is required for the proper function of the intestinal epithelial lining by providing mechanical integrity and is a prerequisite for the proper maturation of Paneth and goblet cells

Голодомор 1932 –– 1933 рр. в Україні як геноцид

Given its fundamental role in development and cancer, the Wnt-beta-catenin signaling pathway is tightly controlled at multiple levels. RING finger protein 43 (RNF43) is an E3 ubiquitin ligase originally found in stem cells and proposed to inhibit Wnt signaling by interacting with the Wnt receptors of the Frizzled family. We detected endogenous RNF43 in the nucleus of human intestinal crypt and colon cancer cells. We found that RNF43 physically interacted with T cell factor 4 (TCF4) in cells and tethered TCF4 to the nuclear membrane, thus silencing TCF4 transcriptional activity even in the presence of constitutively active mutants of beta-catenin. This inhibitory mechanism was disrupted by the expression of RNF43 bearing mutations found in human gastrointestinal tumors, and transactivation of the Wnt pathway was observed in various cells and in Xenopus embryos when the RING domain of RNF43 was mutated. Our findings indicate that RNF43 inhibits the Wnt pathway downstream of oncogenic mutations that activate the pathway. Mimicking or enhancing this inhibitory activity of RNF43 may be useful to treat cancers arising from aberrant activation of the Wnt pathwa

Relationship between the Clinical Frailty Scale and short-term mortality in patients ≥ 80 years old acutely admitted to the ICU: a prospective cohort study.

BACKGROUND: The Clinical Frailty Scale (CFS) is frequently used to measure frailty in critically ill adults. There is wide variation in the approach to analysing the relationship between the CFS score and mortality after admission to the ICU. This study aimed to evaluate the influence of modelling approach on the association between the CFS score and short-term mortality and quantify the prognostic value of frailty in this context. METHODS: We analysed data from two multicentre prospective cohort studies which enrolled intensive care unit patients ≥ 80 years old in 26 countries. The primary outcome was mortality within 30-days from admission to the ICU. Logistic regression models for both ICU and 30-day mortality included the CFS score as either a categorical, continuous or dichotomous variable and were adjusted for patient's age, sex, reason for admission to the ICU, and admission Sequential Organ Failure Assessment score. RESULTS: The median age in the sample of 7487 consecutive patients was 84 years (IQR 81-87). The highest fraction of new prognostic information from frailty in the context of 30-day mortality was observed when the CFS score was treated as either a categorical variable using all original levels of frailty or a nonlinear continuous variable and was equal to 9% using these modelling approaches (p < 0.001). The relationship between the CFS score and mortality was nonlinear (p < 0.01). CONCLUSION: Knowledge about a patient's frailty status adds a substantial amount of new prognostic information at the moment of admission to the ICU. Arbitrary simplification of the CFS score into fewer groups than originally intended leads to a loss of information and should be avoided. Trial registration NCT03134807 (VIP1), NCT03370692 (VIP2)

Niedrig dosierte thorako-abdominelle Bestrahlung (TAI) zur Behandlung der chronischen Graft-versus-Host-Disease (GvHD): ein Fallbericht

Einleitung: Die chron. GvHD ist eine der häufigsten Komplikationen nach allogener Knochenmarktransplantation (KMT) und peripherer Blutstammzelltransplantation (PBSZT). Sie ist der wichtigste Grund für die späte Mortalität nach Transplantation. Haut, Schleimhäute, Leber und Augen sind am häufigsten betroffen. Die Therapie besteht in einer Suppression des Immunsystem mittels hoch dosiertem Kortikosteroid, Cyclosporin, Antikörpertherapie oder/und extrakorporaler Photochemotherapie. Die Ganzkörperbestrahlung (TBI) wird zur Induktion vor allogener Transplantation mit dem Ziel der Ausschaltung des patienteneigenen Immunsystems durchgeführt. Es wurde die These entwickelt, dass eine im Vergleich zur TBI niedrig dosierte weitflächige Ganzkörperbestrahlung (TAI) mit 1-2Gy das transplantierte Immunsystem soweit supprimieren kann, dass die chron. GvHD damit abgemildert wird (Robin et al., 2005). Methode: 12/2006 stellte sich ein 40jähriger Patient mit Zustand nach allogener PBSZT vom HLA-identen Spender 2002 (Konditionierung TBI 8 Gy)/2004 sowie einmalig vom Fremdspender 2005 bei akuter Myelofibrose vor. Nach der dritten Transplantation entwickelte der Patient trotz medikamentöser Intensivierung der immunsuppressiven Therapie eine chron. GvHD (extensive disease) mit Ausbildung eines ulzerierten makulopapulösen Exanthems im Bereich des gesamten Integuments sowie einer Fasciitis mit starken Schmerzen und notwendiger Hospitalisierung. Daraus folgte eine depressiv-aggressive Grundstimmung mit Suizidgedanken. Bestrahlungstechnik: Aufgrund der Schmerzen war nur die Rückenlage möglich. Nach Durchführung einer Planungs-CT von Kehlkopf bis Unterrand Symphyse wurde das Bestrahlungsvolumen (thorako-abdominal ohne Extremitäten und Haupt) im Planungssystem Oncentra MasterPlan (Nucletron) definiert. Zur Anwendung kam eine opponierende Gegenfeldtechnik aus 0 (VD)/180 (DV) Grad mit zwei Isozentren (kranial/kaudal) mit einer Gesamtdosis von 1Gy und Lagerung auf der Beschleunigerliege. Ein divergenzfreier Feldanschluss wurde durch Gantrykippung realisiert. Der FokusHautAbstand betrug 130 cm bei 15MV-Photonen mit einer Dosisleistung von weniger als 50 cGy/min. Ergebnisse: Die Behandlung wurde ohne Übelkeit oder andere Nebenwirkungen toleriert. Es zeigte sich ein langsamer Abfall der Leukozyten, Thrombozyten sowie des Hb um 3 g/dl bis Tag 22 mit Substitutionsnotwendigkeit. An Tag 28 nach TAI waren die Werte für den Hb 9,4 g/dl, Leukozyten 1,92/nl und Thrombozyten 19/nl ohne Blutungszeichen. Es zeigte sich ein sehr gutes Ansprechen auf die Therapie mit Rückbildung aller ulzerierten Befunde, weitestgehender Rückbildung des makulopapulösen Exanthems sowie der Schmerzen mit täglicher Besserung bis Tag 28. Der Patient befindet sich in ambulanter Betreuung. Zusammenfassung: Die TAI zeigt sich bis auf den Blutbildabfall als komplikationsarme und effektive Therapiemaßnahme in der Behandlung einer therapierefraktären chron. GvHD