Conservative Versus Operative Treatment of Proximal Humerus Fractures in Older Individuals­an Analysis of Insurance Data.

BACKGROUND: Little is known about the frequency and results of conservative treatment of proximal humerus fractures in older individuals. METHODS: Billing data of the BARMER health insurance carrier for all patients of age 65 and above with proximal humerus fractures in the years 2005-2021 were retrospectively analyzed with multivariable Cox regression models, taking account of the patients' age, sex, and comorbidity profiles. The defined primary endpoints were overall survival (OS), major adverse events (MAE), thromboembolic events (TE), and complications of surgery or of trauma. Multivariable p values for the effect of treatment on all primary endpoints were jointly adjusted with the Bonferroni-Holm method. RESULTS: 54% of 81 909 patients were treated conservatively. Conservative treatment was more common in those who received their diagnosis as outpatients (79.5%, vs. 37.2% for inpatients). Operative treatment was associated with significantly longer overall survival (long-term HR 0.89, 95% confidence interval [0,86; 0,91]) and fewer MAE (0.90; [0.88; 0.92]) and TE (0.89; [0.87; 0.92]), but more complications due to surgery or trauma (1.66; [1,.4; 1.78]; all p < 0.001). 3.1% of the patients who had been initially treated conservatively underwent surgery within 6 months of their diagnosis. Risk factors for the failure of conservative treatment included alcohol abuse, obesity, cancer, diabetes mellitus, Parkinson disease, and osteoporosis. CONCLUSION: The conservative treatment of proximal humerus fracture is associated with a lower overall rate of complications due to surgery or trauma, but also with more MAE and TE and higher overall mortality. These findings underline the need for individualized and risk-adjusted treatment recommendations.

Quality of Life and Pain after Proximal Humeral Fractures in the Elderly: A Systematic Review.

Background and Objectives: The proximal humeral fracture (PHF) is one of the most common fractures in elderly patients. A PHF might influence the quality of life (QoL) on several different levels, especially in elderly patients, but it is unclear which treatment option results in a better QoL outcome. Therefore, we aimed to systematically review the current literature for studies that have analyzed the QoL and pain of elderly patients treated either surgically or non-operatively for PHF. Materials and Methods: A comprehensive search of the literature was performed in the PubMed database from January to April 2023. Studies describing the QoL or the level of pain of patients older than 60 years with the EuroQoL-5 Dimension (EQ-5D) score or the visual analogue scale (VAS) after the treatment of PHF, either non-operatively (non-OP), with open-reduction and internal fixation using a locking plate (LPF), or with reverse total shoulder arthroplasty (RTSA) were included. Twelve studies were analyzed descriptively and the individual risk of bias was assessed using the ROB2 and ROBINS-I tools. Results: A total of 12 studies with 712 patients at baseline were included (78% female sex, mean age 75.2 years). The reported VAS scores at 12-month follow-up (FU) ranged from 0.7 to 2.5. The calculated overall mean VAS score across all studies showed a decreasing tendency for all treatments, with an increasing FU time up to 12 months after PHF. None of the studies reported any significant differences of the EQ-5D across the groups. The overall calculated EQ-5D indices showed an increasing trend after 6-8 weeks FU, but did not differ significantly between the three treatments. Conclusions: In conclusion, the current literature suggests that there are no clinically important differences between the QoL or pain in elderly patients with PHF after non-operative treatment or surgical treatment with LPF or RTSA. However, the number of studies and level of evidence is rather low and further trials are urgently needed.

Administration Routes for SSTR-/PSMA- and FAP-Directed Theranostic Radioligands in Mice.

The NETTER-1, VISION, and TheraP trials proved the efficacy of repeat intravenous application of small radioligands. Application by subcutaneous, intraperitoneal, or oral routes is an important alternative and may yield comparable or favorable organ and tumor radioligand uptake. Here, we assessed organ and tumor biodistribution for various radioligand application routes in healthy mice and models of cancer expressing somatostatin receptor (SSTR), prostate-specific membrane antigen (PSMA), and fibroblast activation protein (FAP). Methods: Healthy and tumor-bearing male C57BL/6 or NOD SCID γ-mice, respectively, were administered a mean of 6.0 ± 0.5 MBq of 68Ga-DOTATOC (RM1-SSTR allograft), 5.3 ± 0.3 MBq of 68Ga-PSMA11 (RM1-PSMA allograft), or 4.8 ± 0.2 MBq of 68Ga-FAPI46 (HT1080-FAP xenograft) by intravenous, intraperitoneal, subcutaneous, or oral routes. In vivo PET images and ex vivo biodistribution in tumor, organs, and the injection site were assessed up to 5 h after injection. Healthy mice were monitored for up to 7 d after the last scan for signs of stress or adverse reactions. Results: After intravenous, intraperitoneal, and subcutaneous radioligand administration, average residual activity at the injection site was less than 17 percentage injected activity per gram (%IA/g) at 1 h after injection, less than 10 %IA/g at 2 h after injection, and no more than 4 %IA/g at 4 h after injection for all radioligands. After oral administration, at least 50 %IA/g remained within the intestines until 4 h after injection. Biodistribution in organs of healthy mice was nearly equivalent after intravenous, intraperitoneal, and subcutaneous application at 1 h after injection and all subsequent time points (≤1 %IA/g for liver, blood, and bone marrow; 11.2 ± 1.4 %IA/g for kidneys). In models for SSTR-, PSMA- and FAP-expressing cancer, tumor uptake was increased or equivalent for intraperitoneal/subcutaneous versus intravenous injection at 5 h after injection (ex vivo): SSTR, 7.2 ± 1.0 %IA/g (P = 0.0197)/6.5 ± 1.3 %IA/g (P = 0.0827) versus 2.9 ± 0.3 %IA/g, respectively; PSMA, 3.4 ± 0.8 %IA/g (P = 0.9954)/3.9 ± 0.8 %IA/g (P = 0.8343) versus 3.3 ± 0.7% IA/g, respectively; FAP, 1.1 ± 0.1 %IA/g (P = 0.9805)/1.1 ± 0.1 %IA/g (P = 0.7446) versus 1.0 ± 0.2 %IA/g, respectively. Conclusion: In healthy mice, biodistribution of small theranostic ligands after intraperitoneal/subcutaneous application is nearly equivalent to that after intravenous injection. Subcutaneous administration resulted in the highest absolute SSTR tumor and tumor-to-organ uptake as compared with the intravenous route, warranting further clinical assessment.

Enzalutamide Enhances PSMA Expression of PSMA-Low Prostate Cancer.

Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) prolongs overall survival in men with metastatic castration-resistant prostate cancer (mCRPC). However, men with low PSMA expression are excluded from RLT. We explored the effect of androgen receptor blockade with enzalutamide on PSMA expression. Assessment of PSMA and androgen receptor (AR) expression on the human PC cell lines 22Rv1, C4-2, and LNCaP by immunohistochemistry and flow cytometry revealed low (22Rv1) and high (C4-2 and LNCaP) PSMA expression, and high, comparable AR positivity. Treatment with enzalutamide increased PSMA levels in 22Rv1, C4-2, and LNCaP (2.2/2.3/2.6-fold, p = 0.0005/0.03/0.046) after one week compared to DMSO-treated controls as assessed by flow cytometry. NOD/Scid mice bearing 22Rv1 tumors were treated with enzalutamide for two weeks. Positron emission tomography/computed tomography (PET/CT) demonstrated higher tumor uptake of 68Ga-PSMA after enzalutamide treatment (p = 0.004). Similarly, a clinical case with low baseline PSMA avidity demonstrated increased uptake of 68Ga-PSMA after enzalutamide on PET/CT and post-therapeutic 177Lu-PSMA scintigraphy in a patient with mCRPC. Enzalutamide induced PSMA expression in the 22Rv1 xenograft model and in an mCRPC patient, both with low baseline tumoral PSMA levels. Therefore, enzalutamide pre-treatment might render patients with low PSMA expression eligible for 177Lu-PSMA RLT.

Drug and molecular radiotherapy combinations for metastatic castration resistant prostate cancer.

Metastatic castration resistant prostate cancer (mCRPC) is a highly lethal disease. Several novel therapies have been assessed in the past years. Targeting DNA damage response (DDR) pathways in prostate cancer became a promising treatment strategy and olaparib and rucaparib, Poly(ADP-ribose) polymerase (PARP) inhibitors, have been approved for patients carrying mutations in homologous recombination (HR) repair pathways. Other DDR inhibitor targets, such as ATM, ATR, CHK1, CHK2, and WEE1 are under extensive investigation. Additionally, molecular radiotherapy (MRT) including [177Lu]Lu-PSMA, [225Ac]Ac-PSMA, [223Ra]Ra-dichloride, [153Sm]-EDTMP, [188Re]Re-HDMP and GRPR-targeted MRT treat cancer through internal ionizing radiation causing DNA damage and demonstrate promising efficacy in clinical trials. In the field of immunotherapy, checkpoint inhibition as well as sipuleucel-T and PROSTVAC demonstrated only limited efficacy in mCRPC when used as monotherapy. This review discusses recent therapeutic strategies for mCRPC highlighting the need for rational combination of treatment options.

Imaging Inflammation with Positron Emission Tomography.

The impact of inflammation on the outcome of many medical conditions such as cardiovascular diseases, neurological disorders, infections, cancer, and autoimmune diseases has been widely acknowledged. However, in contrast to neurological, oncologic, and cardiovascular disorders, imaging plays a minor role in research and management of inflammation. Imaging can provide insights into individual and temporospatial biology and grade of inflammation which can be of diagnostic, therapeutic, and prognostic value. There is therefore an urgent need to evaluate and understand current approaches and potential applications for imaging of inflammation. This review discusses radiotracers for positron emission tomography (PET) that have been used to image inflammation in cardiovascular diseases and other inflammatory conditions with a special emphasis on radiotracers that have already been successfully applied in clinical settings.

Imaging inflammation after myocardial infarction: implications for prognosis and therapeutic guidance.

Inflammation after myocardial infarction (MI) has been in the focus of cardiovascular research for several years as it influences the remodeling process of the ischemic heart and thereby critically determines the clinical outcome of the patient. Today, it is well appreciated that inflammation is a crucial necessity for the initiation of the natural wound healing process; however, excessive inflammation can have detrimental effects and might result in adverse ventricular remodeling which is associated with an increased risk of heart failure. Newly emerged imaging techniques facilitate the non-invasive assessment of immune cell infiltration into the ischemic myocardium and can provide greater insight into the underlying complex and dynamic repair mechanisms. Molecular imaging of inflammation in the context of MI may help with stratification of patients at high risk of adverse ventricular remodeling post-MI which may be of diagnostic, therapeutic, and prognostic value. Novel radiopharmaceuticals may additionally provide a way to combine patient monitoring and therapy. In spite of great advances in recent years in the field of imaging sciences, clinicians still need to overcome some obstacles to a wider implementation of inflammation imaging post-MI. This review focuses on inflammation as a molecular imaging target and its potential implication in prognosis and therapeutic guidance.

Cryopreservation of primary human monocytes does not negatively affect their functionality or their ability to be labelled with radionuclides: basis for molecular imaging and cell therapy.

BACKGROUND: Circulating white blood cells crucially contribute to maintenance and repair of solid organs. Therefore, certain cell populations such as monocytes are attractive targets for use in molecular imaging and cell imaging, e.g. after labelling with radionuclides, as well as for cell therapies. However, the preparation of monocytes may require freezing and thawing to preserve cells for timely and standardised applications. Additional modifications of these cells such as radioisotope labelling are necessary prior to their application in vivo. We therefore tested the hypothesis whether cryopreservation of freshly isolated circulating human monocytes affects their functional phenotype or their suitability for radionuclide labelling. RESULTS: CD14+CD16- monocytes were isolated from human peripheral blood. They were either directly used for cellular assays and labelling or frozen down using cryoprotectants. In the latter case, cells were thawed prior to further use and analysed for survival, chemotactic responses to various growth factors and adhesion on endothelial cells. In addition, both fresh and cryopreserved monocytes were labelled with radiotracers followed by assessment of survival and chemotactic responses. In all functional assays performed, cryopreserved monocytes did not significantly differ from freshly isolated monocytes with regard to their functionality. Cryopreservation did not affect cell survival. There was no effect on the chemotactic response of monocytes towards different growth factors. Likewise, adhesion properties remained unchanged following cryopreservation. Moreover, the labelling efficiency was similar for freshly isolated and cryopreserved monocytes. Labelling did not negatively affect monocyte survival and function. CONCLUSIONS: Our data indicate that cryopreservation of freshly isolated human primary monocytes is feasible and does not negatively affect their functionality when used for labelling and functional assessment.

The potassium channels TASK2 and TREK1 regulate functional differentiation of murine skeletal muscle cells.

Two-pore domain potassium (K2P) channels influence basic cellular parameters such as resting membrane potential, cellular excitability, or intracellular Ca2+-concentration [Ca2+]i While the physiological importance of K2P channels in different organ systems (e.g., heart, central nervous system, or immune system) has become increasingly clear over the last decade, their expression profile and functional role in skeletal muscle cells (SkMC) remain largely unknown. The mouse SkMC cell line C2C12, wild-type mouse muscle tissue, and primary mouse muscle cells (PMMs) were analyzed using quantitative PCR, Western blotting, and immunohistochemical stainings as well as functional analysis including patch-clamp measurements and Ca2+ imaging. Mouse SkMC express TWIK-related acid-sensitive K+ channel (TASK) 2, TWIK-related K+ channel (TREK) 1, TREK2, and TWIK-related arachidonic acid stimulated K+ channel (TRAAK). Except TASK2 all mentioned channels were upregulated in vitro during differentiation from myoblasts to myotubes. TASK2 and TREK1 were also functionally expressed and upregulated in PMMs isolated from mouse muscle tissue. Inhibition of TASK2 and TREK1 during differentiation revealed a morphological impairment of myoblast fusion accompanied by a downregulation of maturation markers. TASK2 and TREK1 blockade led to a decreased K+ outward current and a decrease of ACh-dependent Ca2+ influx in C2C12 cells as potential underlying mechanisms. K2P-channel expression was also detected in human muscle tissue by immunohistochemistry pointing towards possible relevance for human muscle cell maturation and function. In conclusion, our findings for the first time demonstrate the functional expression of TASK2 and TREK1 in muscle cells with implications for differentiation processes warranting further investigations in physiologic and pathophysiologic scenarios.