Assessment of attenuation properties for SLA and SLS 3D-printing materials in X-ray imaging and nuclear medicine.

In recent years, access to 3D printers has become increasingly affordable. Alongside industrial and private applications, the significance of 3D printing in the clinical context is also growing. For instance, 3D printing processes enable the production of individual anatomical models that can be used to support patient communication or aid in surgical planning. While filament 3D printing is common, stereolithography (SLA) and selective laser sintering (SLS) printing processes offer higher precision. For the use of 3D printing materials in radiology, understanding their attenuation properties concerning ionizing radiation is crucial. Polymethyl methacrylate (PMMA) serves as an important reference material for radiological applications in this regard. In this research, linear- and mass attenuation coefficients of 38 SLA-/SLS-materials from Formlabs (Somerville, Massachusetts, USA) and PMMA will be determined through intensity measurements in nuclear medicine for the radionuclides technetium-99 m and iodine-131, as well as for X-ray imaging in the range of 60 kVp - 110 kVp tube voltage. Based on the mass attenuation coefficients, correction factors in respect to PMMA will be calculated for each material. A significant number of materials exhibit a deviance within approximately ±5% in respect to PMMA regardless of radiation energy. However, certain materials from the dental and industrial application show deviances up to +500% at the lower end of radiation energy spectrum. In conclusion, most materials can be considered equivalent to PMMA with only minor adjustments required. Materials with high deviances can be utilized as high-contrast materials in custom X-ray phantoms.

Broadening the horizon: potential applications of CAR-T cells beyond current indications.

Engineering immune cells to treat hematological malignancies has been a major focus of research since the first resounding successes of CAR-T-cell therapies in B-ALL. Several diseases can now be treated in highly therapy-refractory or relapsed conditions. Currently, a number of CD19- or BCMA-specific CAR-T-cell therapies are approved for acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), multiple myeloma (MM), and follicular lymphoma (FL). The implementation of these therapies has significantly improved patient outcome and survival even in cases with previously very poor prognosis. In this comprehensive review, we present the current state of research, recent innovations, and the applications of CAR-T-cell therapy in a selected group of hematologic malignancies. We focus on B- and T-cell malignancies, including the entities of cutaneous and peripheral T-cell lymphoma (T-ALL, PTCL, CTCL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), classical Hodgkin-Lymphoma (HL), Burkitt-Lymphoma (BL), hairy cell leukemia (HCL), and Waldenström's macroglobulinemia (WM). While these diseases are highly heterogenous, we highlight several similarly used approaches (combination with established therapeutics, target depletion on healthy cells), targets used in multiple diseases (CD30, CD38, TRBC1/2), and unique features that require individualized approaches. Furthermore, we focus on current limitations of CAR-T-cell therapy in individual diseases and entities such as immunocompromising tumor microenvironment (TME), risk of on-target-off-tumor effects, and differences in the occurrence of adverse events. Finally, we present an outlook into novel innovations in CAR-T-cell engineering like the use of artificial intelligence and the future role of CAR-T cells in therapy regimens in everyday clinical practice.

[Splenic surgery in hematological diseases : Indications and surgical technique]. / Chirurgie der Milz bei hämatologischen Erkrankungen : Indikationen und operative Technik.

BACKGROUND: Splenic surgery in hematological disorders requires a well-weighted decision on the indications because the medical treatment has rapidly changed in recent years due to new pharmaceutical approaches. OBJECTIVE: Summary of the indications, surgical procedures and perioperative management regarding operative interventions on the spleen in hematological disorders. MATERIAL AND METHODS: Selective literature search and summary of reviews and guideline recommendations. RESULTS: In hematological disorders surgical procedures of the spleen (splenectomy and partial splenectomy) are an important part of the repertoire in the treatment. In recent years the indications for surgery have become narrower because of new forms of medicinal treatment. Especially in hereditary spherocytosis, immune thrombocytopenia and symptomatic splenomegaly and hypersplenism it is still of importance. The minimally invasive splenectomy is regarded as the gold standard. The spleen has an important immune and sequestration function, therefore preoperative and postoperative infectious and thromboembolic events have to be anticipated and prevented. A close interdisciplinary cooperation with hematologists is essential for an optimal outcome of patients. CONCLUSION: The minimally invasive splenectomy and partial splenectomy are part of the surgical repertoire in the diagnostics and treatment of hematological disorders. Because of novel medicinal approaches the therapeutic protocols are continuously changing. A close cooperation with hematologists is important for the optimal evaluation of the indications and the perioperative management.

Questionable research practices in competitive grant funding: A survey.

There has been a surge of interest in research integrity over the last decade, with a wide range of studies investigating the prevalence of questionable research practices (QRPs). However, nearly all these studies focus on research design, data collection and analysis, and hardly any empirical research has been done on the occurrence of QRPs in the context of research funding. To fill this gap, we conducted a cross-sectional pre-registered survey of applicants, reviewers and panel members from the Research Foundation-Flanders (FWO), one of the main funding agencies in Belgium. We developed a bespoke survey and further refined it through feedback from experienced researchers and a pilot study. We asked how often respondents had engaged in a series of QRPs over the last ten years. A total of 1748 emails were sent, inviting recipients to participate in the survey, complemented by featuring the survey in the FWO newsletter. This resulted in 704 complete responses. Our results indicate that such QRPs are remarkably prevalent. Of the 496 participants who answered both the applicant and reviewer track, more than 60% responded that they engaged regularly in at least one of such practices, and around 40% indicated that they engaged at least occasionally in half of the QRPs queried. Only 12% reported not to have engaged in any of the QRPs. Contrary to our hypotheses, male respondents did not self-report to engage in the QRPs more often than female respondents, nor was there an association between the prevalence of QRPs and self-reported success rate in grant funding. Furthermore, half of the respondents indicated that they doubted the reliability of the grant peer review process more often than not. These results suggest that preventive action is needed, and provide new reasons to reconsider the practice of allocating research money through grant peer review.

Prognostic factors for the long term outcome after surgical celiac artery decompression in MALS.

BACKGROUND: The median arcuate ligament syndrome (MALS) is a rare disease caused by compression of the celiac artery (ORPHA: 293208). Surgical treatment of MALS aims to restore normal celiac blood flow by laparoscopic celiac artery decompression. However, surgical success rates vary widely between patients, therefore adequate selection of patients is essential to improve surgical outcome. Symptoms of MALS might also overlap with other chronic multi-system disorders such as mast cell activation syndrome (MCAS). So far, no clinical or radiological parameter was found to be predictive of the postoperative outcome. We, therefore, aim to study preclinical parameters in one of the largest MALS cohorts with the focus to identify patients that would benefit from surgical MAL release. RESULTS: By analyzing 20 MALS patients that underwent surgical celiac artery decompression, we found 60% of patients (12/20) had a postoperative relief of their symptoms and a simultaneous decrease of analgetic use. No demographic, radiologic or operative parameter was able to predict postoperative symptom relief. However, mast cell activation syndrome correlated significantly (p = 0.04) with persistent symptoms after the operation. CONCLUSIONS: Overall, laparoscopic MAL release can provide immediate symptomatic relief. Despite the missing predictive value of demographic and imaging data, our data show a correlation between persistent symptoms and a co-existing mast cell activation syndrome. This suggests that MCAS symptoms might be interpreted as MALS symptoms in the presence of celiac artery stenosis and therefore surgical treatment should be evaluated carefully. Overall, the selection of patients who are most likely to respond to surgical MAL release may best be accomplished by an interdisciplinary team of gastroenterologists, radiologists and surgeons.

Targeted hyperactivation of AKT through inhibition of ectopic expressed SHIP1 induces cell death in colon carcinoma cells and derived metastases.

Current therapeutic approaches for colorectal cancer (CRC) focus on the suppression of oncogenic kinase signaling. Here, we test the hypothesis that targeted hyperactivation of the PI3K/AKT-signaling may lead to trigger CRC cell death. Recently we found that hematopoietic SHIP1 is ectopically expressed in CRC cells. Here we show that SHIP1 is more strongly expressed in metastatic cells than in the primary cancer cells, which allows for an increase in AKT signaling in metastatic cells, giving them an advantage from an evolutionary point of view. Mechanistically, the increased SHIP1 expression reduces the activation of the PI3K/ AKT signaling to a value that is below the threshold that leads to cell death. This mechanism gives the cell a selection advantage. We show that genetic hyperactivation of PI3K/AKT-signaling or blocking the activity of the inhibitory phosphatase SHIP1, induces acute cell death in CRC cells, because of excessive accumulation of reactive oxygen species. Our results demonstrate that CRC cells critically depend on mechanisms to fine-tune PI3K/AKT activity and show SHIP1 inhibition as an unexpectedly promising concept for CRC therapy.

Causes or Cures: What makes us think of attention issues as disorders?

Are attention issues disorders or not? Philosophers of medicine have tried to address this question by looking for properties that distinguish disorders from non-disorders. Such properties include deviation of a statistical norm, a loss of function or experienced suffering. However, attempts at such conceptual analysis have not led to a consensus on the necessary and sufficient conditions for the application of the concept of disorder. Recently, philosophers have proposed an experimental approach to investigate in which circumstances people think a specific concept is applicable. Here we present a quantitative vignette study investigating whether disorder attribution depends on the perceived cause and the perceived type of treatment for an attention problem. The results of our study indicate that the attribution of a disorder decreased when the attention problem was understood as caused by bullying (social environmental cause) or by an accident (non-social environmental cause) rather than a genetic cause. When prescribed a pill, attention problems were considered a disorder to a larger extent than when the child was prescribed an environmental treatment. Our study also suggests that whereas successful environmental treatments will not necessarily decrease the disorder attribution, successful pharmacological treatments will decrease the likelihood that a person is thought to still suffer from a disorder after receiving the treatment.

Epidemiology and Characteristics of Gastric Carcinoma in Childhood-An Analysis of Data from Population-Based and Clinical Cancer Registries.

(1) Background: Gastric carcinoma is an exceptionally rare tumor in childhood. Little is known about the etiology, epidemiology, and clinical features of pediatric gastric carcinomas. This analysis aimed to fill this gap by increasing knowledge about the occurrence of gastric carcinoma in childhood. (2) Material and methods: Data from gastric carcinoma cases diagnosed between 2000 and 2017/2018 were retrieved from the Surveillance, Epidemiology, and End Results Program (SEER) and the German Center for Cancer Registry Data. Data from patients <20 years of age were analyzed for patient- and tumor-related characteristics. In addition, clinical data from patients with gastric carcinoma registered in the German Registry for Rare Pediatric Tumors (STEP) were analyzed for diagnostics, therapy, and outcome. (3) Results: Ninety-one cases of gastric carcinoma, mainly in adolescents, were identified in the epidemiologic cancer registries. Among patients with recorded staging data, advanced tumor stages were common (66.7%). Within the follow-up period covered, 63.7% of patients with clinical follow-up data died. Eight pediatric patients with gastric carcinoma were enrolled in the STEP registry, among whom two were patients with hereditary CDH1 mutations and another was a patient with Peutz−Jeghers syndrome. Three patients were found to have distinctly decreased immunoglobulin concentrations. All four patients in whom complete resection was achieved remained in remission. Three of the other four patients died despite multimodal therapy. (4) Conclusions: A combination of Helicobacter pylori infection and tumor predisposition and/or immunodeficiency appears to promote the development of gastric carcinoma in childhood. While patients with localized disease stages have a good chance of achieving durable remission through complete resection, patients with stage IV carcinomas face a dismal prognosis, highlighting the need to develop new strategies such as mutation-guided treatments.

Philosophy of Science Can Prevent Manslaughter.

In September 2020, the surgeon Paulo Macchiarini, who used stem cell technology to enable the transplants of artificial and donor trachea, was charged with aggravated assault in Sweden. In this comment, we argue that the Ethics Council of the Karolinska Institute should have considered issues from philosophy of science when they were brought to their attention, rather than dismiss them as irrelevant to research ethics. We demonstrate how conceptual issues of a philosophy-of-science-kind about clinical research and medical practice should be integral to research ethics.

Tumor cell E-selectin ligands determine partialefficacy of bortezomib on spontaneous lung metastasis formation of solid human tumors in vivo.

Extravasation of circulating tumor cells (CTCs) is critical for metastasis and is initiated by adhesive interactions between glycoligands on CTCs and E-selectin on endothelia. Here, we show that the clinically approved proteasome inhibitor bortezomib (BZM; Velcade) counteracts the cytokine-dependent induction of E-selectin in the lung mediated by the primary tumor, thereby impairing endothelial adhesion and thus spontaneous lung metastasis in vivo. However, the efficacy of BZM crucially depends on the tumor cells' E-selectin ligands, which determine distinct adhesion patterns. The canonical ligands sialyl-Lewis A (sLeA) and sLeX mediate particularly high-affinity E-selectin binding so that the incomplete E-selectin-reducing effect of BZM is not sufficient to disrupt adhesion or metastasis. In contrast, tumor cells lacking sLeA/X nevertheless bind E-selectin, but with low affinity, so that adhesion and lung metastasis are significantly diminished. Such low-affinity E-selectin ligands apparently consist of sialylated MGAT5 products on CD44. BZM no longer has anti-metastatic activity after CD44 knockdown in sLeA/X-negative tumor cells or E-selectin knockout in mice. sLeA/X can be determined by immunohistochemistry in cancer samples, which might aid patient stratification. These data suggest that BZM might act as a drug for inhibiting extravasation and thus distant metastasis formation in malignancies expressing low-affinity E-selectin ligands.

Clinical evaluation of a novel head protection system for interventional radiologists.

PURPOSE: A novel two-part protective system consisting of a modified thyroid collar and a head protection is intended to reduce the radiation dose to the examiners head during fluoroscopy-guided interventions. In this pilot study, we tested this protection system under real-life conditions in general radiological and neuroradiological interventions. METHODS: Two sets of the protection system (set A and B) were equipped with 12 thermoluminiscence detectors (TLD). For simultaneous measurement of radiation exposure and dose-reduction, each six TLDs were fixed to the inner side and on the corresponding outer side of the protection system. Set A was used exclusively for general radiological interventions and set B exclusively for neuroradiological interventions. To compare the staff exposure in general radiology and neuroradiology, dose values were normalized to a DAP of 10 000 µGy∙m2. RESULTS: The sets were tested during 20 general radiological interventions and 32 neuroradiological interventions. In neuroradiology, the mean normalized radiation exposure was 13.44 ± 1.36 µSv/10000 µGy∙m2 at the head protection and 22.27 ± 2.09 µSv/10 000 µGy∙m2 at the thyroid collar. In general radiology, the corresponding results were 29.91 ± 4.19 µSv/10 000 µGy∙m2 (head protection) and 68.07 ± 17.25 µSv/10 000 µGy∙m2 (thyroid collar). Thus, mean dose exposure was 2.5 times higher in general radiological interventions (p = 0.016). The use of the protection system resulted in a mean dose reduction of 81.2 ± 11.1 % (general radiology) and 92.1 ± 4.2 % (neuroradiology; p = 0.016). CONCLUSION: Fluoroscopy-guided interventions lead to significant radiation exposure of the head area for the examiner. The novel protection system tested led to a significant dose reduction of 80-90%, depending on the type of intervention.

What do patients expect? Assessing patient-centredness from the patients' perspective: an interview study.

OBJECTIVE: Although there has been much conceptual work on patient-centredness (PC), patients' perspectives on PC were neglected. In a previous study, participating patients rated the relevance of 16 dimensions of an integrative model of PC as high to very high. However, it remained unclear which specific behaviours described in the dimensions were considered most relevant. Thus, the aim of the current study was to further explore which of the specific behaviours described in the model are especially relevant for the high ratings in the previous study. METHODS AND DESIGN: We conducted semistructured interviews with 20 patients with chronic diseases (16 females, 4 males, mean age: 52 years). Patients answered questions regarding their experiences in the German healthcare system and how optimal healthcare would look like from their perspective. Furthermore, patients were asked to reflect on the most important aspects which they had mentioned in the interview before. Data were analysed via content analysis. RESULTS: Participants addressed many different aspects of PC, but mostly focused on three major themes: (1) time appropriate access to care, (2) competence, empathy and being taken seriously by HCPs, (3) HCPs' individual consideration of each patient's situation (eg, wishes and needs). Minor themes were: (1) taking a holistic perspective of the patient, (2) patient-centred communication, (3) integration of multidisciplinary treatment elements, (4) transparency regarding waiting time and (5) reduction of unequal access to care. CONCLUSION: This study enriches the construct of PC by depicting essential aspects of PC from the patients' perspective. The results allow prioritising strategies to implement patient-centred care. Thus, this study helps to pursue the ultimate goal of fostering patient-centred healthcare delivery in Germany.

Combined Targeting of AKT and mTOR Synergistically Inhibits Formation of Primary Colorectal Carcinoma Tumouroids In Vitro: A 3D Tumour Model for Pre-therapeutic Drug Screening.

BACKGROUND: Pre-therapeutic analysis of three-dimensional spheroid cultures of primary tumour samples is a promising approach of assessing susceptibility to potential treatment. The phosphatidylinositol-3-kinase/AKT serine/threonine kinase/mammalian target of rapamycin (PI3K/AKT/mTOR) signalling pathway is frequently activated in colorectal cancer (CRC). In previous work, we showed combined inhibition of AKT and mTOR to be highly synergistic in cell lines from patients with hepatocellular carcinoma and cholangiocarcinoma in vitro as well as in vivo in murine xenograft tumour models. MATERIALS AND METHODS: Patient-derived xenograft colorectal carcinoma cell lines HROC80 T1 M1, HROC147 T0 M1, HROC147Met, HROC277 T0 M1 and HROC277Met2 were treated with AKT inhibitor MK2206, mTOR inhibitor RAD001 or the combination of both drugs. The sensitivity of these cell lines to inhibition was evaluated by calculation of combinatory indices after bromodeoxyuridine assays and analysis of the respective pathways by western blotting. Furthermore, the dual inhibition of AKT and mTOR was confirmed in vivo in a xenograft mouse model. Additionally, primary CRC samples of four patients were embedded in a three-dimensional matrix and the sensitivity of these samples was analyzed by measurement of the spheroid area. RESULTS: In this study, we demonstrate that combined treatment with MK2206 and RAD001 resulted in strong synergistic effects on growth of several primary CRC cell lines and reduced the growth of a patient-derived CRC xenograft in a xenotransplantation mouse model in vivo. Interestingly, the response to treatment varied between cell lines derived from the primary lesion and a liver metastasis of the same patient. In addition, combined treatment with AKT and mTOR inhibitors resulted in a synergistic inhibition of tumouroid growth in all four of the primary patient samples, analyzed in a three-dimensional spheroid model in vitro. CONCLUSION: Our data demonstrate that combined treatment with AKT and mTOR inhibitors exhibits synergistic effects on proliferation of cell lines and primary tumour cells from patients with CRC and may be a promising approach for the treatment of CRC.

Individual calculation of perfusion activity based on ventilation efficiency for V/P-SPECT.

AIM: Implementation of the individual calculation of perfusion activity to ensure the guideline-compliant ratio of perfusion to ventilation (P/V-ratio) of ≥ 3 in the diagnosis of acute pulmonary embolism (PE) using V/P-SPECT. MATERIAL AND METHODS: 50 consecutive V/P-SPECT examinations, in which a standard activity of 160 MBq was applied for perfusion imaging, are evaluated retrospectively. Based on this patient group an activity factor is determined, which provides a correlation between the applied perfusion activity and the expected perfusion counts of the gamma camera. Using the mean activity factor, the perfusion activity required for a P/V-ratio of four is calculated using the previously acquired ventilation count rate. This is applied prospectively to the 100 subsequent examinations. RESULTS: The mean perfusion activity factor is (54.56 ± 10.13) cps/MBq. The individually calculated perfusion activities range from 80 MBq to 200 MBq with an average value of (146.9 ±â€Š35.3) MBq and a median of 140 MBq. The individual activity calculation thus reduced the mean perfusion activity by 8.2 % and the median by 12.5 %. In addition, the individual calculation reduced the proportion of P/V ratios < 3 from 14 % to 0 % and the proportion of P/V ratios > 5 from 24 % to 19 %. CONCLUSION: The presented method for the individual calculation of perfusion activity offers a simple way to ensure a guideline-compliant P/V-ratio. Furthermore, unnecessarily high perfusion activity as a result of inadequate ventilation can be avoided.

Prenatal radiation exposure in diagnostic and interventional radiology. / Pränatale Strahlenexposition in der diagnostischen und interventionellen Radiologie.

BACKGROUND: The exposure of a pregnant woman to X-rays is an event that can cause uncertainty for all concerned. This review provides guidance on how to assess such a situation and how to determine the dose to the unborn child. In general, the use of X-rays in pregnant women in radiology should be avoided. If possible, alternatives should be used, or examinations postponed to a time after the pregnancy. This review gives a summary of the procedure for determining the radiation exposure of a pregnant woman. METHOD: Based on the previous report of 2002 and the literature on prenatal radiation exposure published thereafter, the DGMP/DRG report on the procedure for the assessment of prenatal radiation exposure was adapted to the current state of science and technology. RESULTS: Typically, only relatively low radiation exposures of less than 20 mSv occur for the unborn child in X-ray diagnostics in the vast majority of cases. At these dose level the additional risk of damage to the embryo or fetus caused by the radiation is low and therefore only a rough conservative estimate using tabulated values are made. Only in a few types of examination (CT and interventional radiology) higher doses values might occur in the uterus. Instead of dose estimates (step 1 in the two-step model) in these cases the calculation of dose (step 2) are required and further action by the physician may be necessary. CONCLUSIONS: During the assessment, it is useful to initially use simple conservative estimation procedures to quickly determine whether a case falls into this large group less than 20 mSv, where there is a very low risk to the unborn child. If this is the case, the pregnant woman should be informed immediately by the doctor who performed the examination/treatment. This avoids a psychological burden on the patient. The DGMP/DRG report suggests a relatively simple, clearly structured procedure with advantages for all parties involved (physician, medical physics experts, MTRA and patient). KEY POINTS: · The DGMP/DRG report on prenatal radiation exposure describes the procedure for calculating radiation exposures and the associated risks for the unborn child.. · Using the two-step model, only a simple assessment based on the first step is necessary for most prenatal radiation exposures.. · With the given tables it is possible to estimate individual risks for the unborn child taking into account the radiation exposure.. · Only in the rare case that the first estimate results in a uterine dose larger 20 mSv a more accurate calculation is necessary.. CITATION FORMAT: · Fiebich M, Block A, Borowski M et al. Prenatal radiation exposure in diagnostic and interventional radiology. Fortschr Röntgenstr 2021; 193: 778 - 786.

Grant writing and grant peer review as questionable research practices.

A large part of governmental research funding is currently distributed through the peer review of project proposals. In this paper, we argue that such funding systems incentivize and even force researchers to violate five moral values, each of which is central to commonly used scientific codes of conduct. Our argument complements existing epistemic arguments against peer-review project funding systems and, accordingly, strengthens the mounting calls for reform of these systems.

Case report: acute abdominal pain in a 37-year-old patient and the consequences for his family.

BACKGROUND: Hereditary diffuse gastric cancer is a rare condition that accounts for approximately 1-3% of all gastric cancer cases. Due to its rapid and invasive growth pattern, it is associated with a very poor prognosis. As a result, comprehensive genetic testing is imperative in patients who meet the current testing criteria in order to identify relatives at risk. This case report illustrates the substantial benefit of genetic testing in the family of a patient diagnosed with hereditary diffuse gastric cancer. CASE PRESENTATION: A 37-year-old patient was admitted to the emergency department with acute abdominal pain. Following explorative laparoscopy, locally advanced diffuse gastric cancer was diagnosed. The indication for genetic testing of CDH1 was given due to the patient's young age. A germline mutation in CDH1 was identified in the index patient. As a result, several family members underwent genetic testing. The patient's father, brother and one aunt were identified as carriers of the familial CDH1 mutation and subsequently received gastrectomy. In both the father and the aunt, histology of the surgical specimen revealed a diffuse growing adenocarcinoma after an unremarkable preoperative gastroscopy. CONCLUSION: Awareness and recognition of a potential hereditary diffuse gastric cancer can provide a substantial health benefit not only for the patient but especially for affected family members.