Three-dimensional Monte Carlo-based voxel-wise tumor dosimetry in patients with neuroendocrine tumors who underwent 177Lu-DOTATOC therapy

Abstract Background Patients with advanced neuroendocrine tumors (NETs) of the midgut are suitable candidates for 177Lu-DOTATOC therapy. Integrated SPECT/CT systems have the potential to help improve the accuracy of patient-specific tumor dosimetry. Dose estimations to target organs are generally performed using the Medical Internal Radiation Dose scheme. We present a novel Monte Carlo-based voxel-wise dosimetry approach to determine organ- and tumor-specific total tumor doses (TTD). Methods A cohort of 14 patients with histologically confirmed metastasized NETs of the midgut (11 men, 3 women, 62.3 ± 11.0 years of age) underwent a total of 39 cycles of 177Lu-DOTATOC therapy (mean 2.8 cycles, SD ± 1 cycle). After the first cycle of therapy, regions of interest were defined manually on the SPECT/CT images for the kidneys, the spleen, and all 198 tracer-positive tumor lesions in the field of view. Four SPECT images, taken at 4 h, 24 h, 48 h and 72 h after injection of the radiopharmaceutical, were used to determine their effective half-lives in the structures of interest. The absorbed doses were calculated by a three-dimensional dosimetry method based on Monte Carlo simulations. TTD was calculated as the sum of all products of single tumor doses with single tumor volumes divided by the sum of all tumor volumes. Results The average dose values per cycle were 3.41 ± 1.28 Gy (1.91–6.22 Gy) for the kidneys, 4.40 ± 2.90 Gy (1.14–11.22 Gy) for the spleen, and 9.70 ± 8.96 Gy (1.47–39.49 Gy) for all 177Lu-DOTATOC-positive tumor lesions. Low- and intermediate-grade tumors (G 1–2) absorbed a higher TTD compared to high-grade tumors (G 3) (signed-rank test, p =  < 0.05). The pre-therapeutic chromogranin A (CgA) value and the TTD correlated significantly (Pearson correlation:  = 0.67, p = 0.01). Higher TTD resulted in a significant decrease of CgA after therapy. Conclusion These results suggest that Monte Carlo-based voxel-wise dosimetry is a very promising tool for predicting the absorbed TTD based on histological and clinical parameters

Assessment of myocardial fibrosis in patients with systemic sclerosis using [68Ga]Ga-FAPI-04-PET-CT

Purpose Myocardial fibrosis (MF) is a factor of poor prognosis in systemic sclerosis (SSc). Direct in-vivo visualization of fibroblast activation as early readout of MF has not been feasible to date. Here, we characterize 68 Gallium-labeled-Fibroblast-Activation-Inhibitor-04 ([ 68 Ga]Ga-FAPI-04)-PET-CT as a diagnostic tool in SSc-related MF. Methods In this proof-of-concept trial, six SSc patients with and eight without MF of the EUSTAR cohort Erlangen underwent [ 68 Ga]Ga-FAPI-04-PET-CT and cardiac MRI (cMRI) and clinical and serologic investigations just before baseline and during follow-up between January 2020 and December 2020. Myocardial biopsy was performed as clinically indicated. Results [ 68 Ga]Ga-FAPI-04 tracer uptake was increased in SSc-related MF with higher uptake in SSc patients with arrhythmias, elevated serum-NT-pro-BNP, and increased late gadolinium enhancement (LGE) in cMRI. Histologically, myocardial biopsies from cMRI- and [ 68 Ga]Ga-FAPI-04-positive regions confirmed the accumulation of FAP + fibroblasts surrounded by collagen deposits. We observed similar but not equal spatial distributions of [ 68 Ga]Ga-FAPI-04 uptake and quantitative cMRI-based techniques. Using sequential [ 68 Ga]Ga-FAPI-04-PET-CTs, we observed dynamic changes of [ 68 Ga]Ga-FAPI-04 uptake associated with changes in the activity of SSc-related MF, while cMRI parameters remained stable after regression of molecular activity and rather indicated tissue damage. Conclusions We present first in-human evidence that [ 68 Ga]Ga-FAPI-04 uptake visualizes fibroblast activation in SSc-related MF and may be a diagnostic option to monitor cardiac fibroblast activity in situ.Open Access funding enabled and organized by Projekt DEAL.Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659IZKF ErlangenUniversitätsklinikum Erlangen (8546

N-glycosylation regulates intrinsic IFN-γ resistance in colorectal cancer: implications for immunotherapy

Background &amp; Aims: Advanced colorectal carcinoma (CRC) is characterized by a high frequency of primary immune evasion and refractoriness to immunotherapy. Given the importance of interferon (IFN)-γ in CRC immunosurveillance, we investigated whether and how acquired IFN-γ resistance in tumor cells would promote tumor growth, and whether IFN-γ sensitivity could be restored. Methods: Spontaneous and colitis-associated CRC development was induced in mice with a specific IFN-γ pathway inhibition in intestinal epithelial cells. The influence of IFN-γ pathway gene status and expression on survival was assessed in patients with CRC. The mechanisms underlying IFN-γ resistance were investigated in CRC cell lines. Results: The conditional knockout of the IFN-γ receptor in intestinal epithelial cells enhanced spontaneous and colitis-associated colon tumorigenesis in mice, and the loss of IFN-γ receptor α (IFNγRα) expression by tumor cells predicted poor prognosis in patients with CRC. IFNγRα expression was repressed in human CRC cells through changes in N-glycosylation, which decreased protein stability via proteasome-dependent degradation, inhibiting IFNγR-signaling. Downregulation of the bisecting N-acetylglucosaminyltransferase III (MGAT3) expression was associated with IFN-γ resistance in all IFN-γ–resistant cells, and highly correlated with low IFNγRα expression in CRC tissues. Both ectopic and pharmacological reconstitution of MGAT3 expression with all-trans retinoic acid increased bisecting N-glycosylation, as well as IFNγRα protein stability and signaling. Conclusions: Together, our results demonstrated that tumor-associated changes in N-glycosylation destabilize IFNγRα, causing IFN-γ resistance in CRC. IFN-γ sensitivity could be reestablished through the increase in MGAT3 expression, notably via all-trans retinoic acid treatment, providing new prospects for the treatment of immune-resistant CRC

Untersuchungen zur Synthese der extrazellulären Matrix bei physiologischen und pathophysiologischen Prozessen

Prante C. Untersuchungen zur Synthese der extrazellulären Matrix bei physiologischen und pathophysiologischen Prozessen. Bielefeld (Germany): Bielefeld University; 2006.Proteoglykane bilden einen wichtigen Bestandteil der extrazellulären Matrix (ECM). An der Biosynthese der Glykosaminoglykan(GAG)-Ketten sind eine Vielzahl von Glykosyltransferasen beteiligt, wobei die Xylosyltransferase I (XT-I), durch den Transfer von Xylose auf spezifische Serinreste des Proteoglykan-Core-Proteins, die Synthese des Tetrasaccharid-Linkers initiiert. Für das zur XT-I hoch homologe Protein, Xylosyltransferase II (XT-II), konnte bislang keine physiologische Funktion nachgewiesen werden. Im Rahmen dieser Arbeit erfolgte erstmals eine detaillierte Analyse zur Funktion und Regulation der XT-I bei pathophysiologischer Remodellierung der ECM. Anhand von humanen Herzgewebeproben konnte gezeigt werden, dass Patienten mit einer dilatativen Kardiomyopathie (DCM) neben einer gesteigerten Expression des Enzyms auch eine vermehrte Deposition von GAG-Ketten und Proteoglykanen im Myokard aufweisen. Durch die Verwendung eines Modellsystems zur in vitro-Simulation der DCM konnte erstmals nachgewiesen werden, dass eine Hochregulation der XT-I-Expression durch mechanischen Stress erfolgt. Als Induktor der XT-I-Genexpression wurde TGF-[beta]1 identifiziert, welcher bei mechanischer Expansion kardialer Fibroblasten vermehrt sezerniert wird. Durch den Einsatz spezifischer Inhibitoren der TGF-[beta]1-Signalkaskade konnte nachgewiesen werden, dass die Regulation der XT-I-Transkription über den Signalweg der p38-MAP-Kinase reguliert wird. Über eine gezielte siRNA-vermittelte Degradierung der XT-I-mRNA in kardialen Fibroblasten sowie anschließende Quantifizierung des GAG-Gehalts im Zellkulturüberstand konnte zudem erstmals bestätigt werden, dass die XT-I das geschwindigkeitsbestimmende Enzym bei der kardialen GAG-Biosynthese darstellt. Im Rahmen dieser Arbeit wurde eine Vielzahl von Real-Time PCR-Systemen zur relativen Quantifizierung der mRNA-Expression der an der Proteoglykan-Biosynthese beteiligten Enzyme und Core-Proteine etabliert. Unter Verwendung dieser Systeme konnte umfassend die Regulation der Genexpression bei der physiologischen Ausbildung der ECM während der chondrogenen und osteogenen Differenzierung humaner mesenchymaler Stammzellen untersucht werden. Die Expressionsanalyse zeigte, dass sowohl die GAG-bildenden Enzyme als auch die Proteoglykan-Core-Proteine vielfach die gleichen Regulationsmuster aufweisen. Zudem konnte nachgewiesen werden, dass sowohl bei Chondrogenese als auch bei Osteogenese die XT-I, aufgrund einer den anderen Enzymen vorgelagerten Expression, vermutlich eine Schlüsselposition bei der Assemblierung der GAG-Ketten einnimmt. Für die XT-II wurde bei beiden Differenzierungswegen jeweils eine zur XT-I differierende Expressionskinetik detektiert. Zusammenfassend konnte gezeigt werden, dass die Analyse der Expression von Schlüsselenzymen und Core-Proteinen der Proteoglykanbiosynthese eine Möglichkeit darstellt, die unterschiedlichen Entwicklungsstadien der Stammzelldifferenzierung zu kategorisieren. Durch die Verwendung von shRNA und siRNA wurde im Rahmen dieser Arbeit erstmals die mRNA-Expression beider humaner Xylosyltransferasen gezielt in vitro um mehr als 80 Prozent reduziert. Durch die siRNA-vermittelte Reduktion der XT-I- und XT-II-mRNA-Expression in SW1353- und SAOS2-Zellen konnte dadurch erstmals nachgewiesen werden, dass die XT-II eine Xylosyltransferaseaktivität aufweist. Zusätzlich zeigte sich, dass die XT-II in aktiver Form in den Zellkulturüberstand sezerniert wird und dort eine, im Vergleich zur XT-I, abweichende Akzeptorspezifität aufweist. Darüber hinaus wurde bei der Regulation beider Xylosyltransferasen ein Rückkopplungsmechanismus detektiert. So konnte nachgewiesen werden, dass bei einer singulären Reduktion eines der beiden Enzyme eine vermutlich kompensatorische Hochregulation des jeweils anderen Enzyms erfolgt

ConnecTables: Dynamic Coupling of Displays for the Flexible Creation of Shared Workspaces

We present the ConnecTable, a new mobile, networked and context-aware information appliance that provides affordances for pen-based individual and cooperative work as well as for the seamless transition between the two. In order to dynamically enlarge an interaction area for the purpose of shared use, a flexible coupling of displays has been realized that overcomes the restrictions of display sizes and borders. Two ConnecTable displays dynamically form a homogeneous display area when moved close to each other. The appropriate triggering signal comes from built-in sensors allowing users to temporally combine their individual displays to a larger shared one by a simple physical movement in space. Connected ConnecTables allow their users to work in parallel on an ad-hoc created shared workspace as well as exchanging information by simply shuffling objects from one display to the other. We discuss the user interface and related issues as well as the software architecture. We also present the physical realization of the ConnecTables

Roomware - The Second Generation

In this paper, we provide background information on the video shown at UbiComp&apos;02. This video is a revised version of the one shown at CHI&apos;02 [3] and provides an extensive presentation of the second generation of roomware components. Compared to the first generation, the redesign, resp. new design and implementation resulted in a comprehensive environment consisting of several different roomware components and software facilitating new forms of human computer interaction and cooperation. The second generation consisting of: DynaWall, InteracTable, CommChairs, ConnecTable, and the Passage mechanism, together with the corresponding software BEACH, PalmBeach, and MagNets

A portable biosensor for 2,4-dinitrotoluene vapors

Buried explosive material, e.g., landmines, represent a severe issue for human safety all over the world. Most explosives consist of environmentally hazardous chemicals like 2,4,6-trinitrotoluene (TNT), carcinogenic 2,4-dinitrotoluene (2,4-DNT) and related compounds. Vapors leaking from buried landmines offer a detection marker for landmines, presenting an option to detect landmines without relying on metal detection. 2,4-Dinitrotoluene (DNT), an impurity and byproduct of common TNT synthesis, is a feasible detection marker since it is extremely volatile. We report on the construction of a wireless, handy and cost effective 2,4-dinitrotoluene biosensor combining recombinant bioluminescent bacterial cells and a compact, portable optical detection device. This biosensor could serve as a potential alternative to the current detection technique. The influence of temperature, oxygen and different immobilization procedures on bioluminescence were tested. Oxygen penetration depth in agarose gels was investigated, and showed that aeration with molecular oxygen is necessary to maintain bioluminescence activity at higher cell densities. Bioluminescence was low even at high cell densities and 2,4-DNT concentrations, hence optimization of different prototypes was carried out regarding radiation surface of the gels used for immobilization. These findings were applied to sensor construction, and 50 ppb gaseous 2,4-DNT was successfully detected

Three-dimensional Monte Carlo-based voxel-wise tumor dosimetry in patients with neuroendocrine tumors who underwent 177Lu-DOTATOC therapy

Background Patients with advanced neuroendocrine tumors (NETs) of the midgut are suitable candidates for Lu-177-DOTATOC therapy. Integrated SPECT/CT systems have the potential to help improve the accuracy of patient-specific tumor dosimetry. Dose estimations to target organs are generally performed using the Medical Internal Radiation Dose scheme. We present a novel Monte Carlo-based voxel-wise dosimetry approach to determine organ- and tumor-specific total tumor doses (TTD). Methods A cohort of 14 patients with histologically confirmed metastasized NETs of the midgut (11 men, 3 women, 62.3 +/- 11.0 years of age) underwent a total of 39 cycles of Lu-177-DOTATOC therapy (mean 2.8 cycles, SD +/- 1 cycle). After the first cycle of therapy, regions of interest were defined manually on the SPECT/CT images for the kidneys, the spleen, and all 198 tracer-positive tumor lesions in the field of view. Four SPECT images, taken at 4 h, 24 h, 48 h and 72 h after injection of the radiopharmaceutical, were used to determine their effective half-lives in the structures of interest. The absorbed doses were calculated by a three-dimensional dosimetry method based on Monte Carlo simulations. TTD was calculated as the sum of all products of single tumor doses with single tumor volumes divided by the sum of all tumor volumes. Results The average dose values per cycle were 3.41 +/- 1.28 Gy (1.91-6.22 Gy) for the kidneys, 4.40 +/- 2.90 Gy (1.14-11.22 Gy) for the spleen, and 9.70 +/- 8.96 Gy (1.47-39.49 Gy) for all Lu-177-DOTATOC-positive tumor lesions. Low- and intermediate-grade tumors (G 1-2) absorbed a higher TTD compared to high-grade tumors (G 3) (signed-rank test, p = < 0.05). The pre-therapeutic chromogranin A (CgA) value and the TTD correlated significantly (Pearson correlation: = 0.67, p = 0.01). Higher TTD resulted in a significant decrease of CgA after therapy. Conclusion These results suggest that Monte Carlo-based voxel-wise dosimetry is a very promising tool for predicting the absorbed TTD based on histological and clinical parameters