Organizational and budget impact model (OBIM) of same™ a new autotransfusion medical device.

Objectives: This study aimed to assess the budget and organizational impact of progressively replacing the intraoperative cell salvage centrifugation-based systems currently installed in French hospitals with the same™ system, a new autotransfusion medical device.Methods: An Organizational and Budget Impact Model (OBIM) was developed based on two methodological guidelines issued by the French Health Authority (Haute Autorité de Santé, HAS). The OBIM was also developed based on a pragmatic literature review, hospital data and hospital pharmacists' expertise.Results: Considering an average hospital cohort of 600 cardio-thoracic surgery patients, with 57% experiencing mild hemorrhages, 23% moderate hemorrhages, and 20% massive hemorrhages, and a same™ market share of 33% in Year 1, the implementation of same™ resulted in significant savings. With an average allogeneic transfusion of 4.19 packed red blood cells (RBC) and 0.62 platelet concentrate per patient based on National Hemovigilance Report of the ANSM (French National Agency for the Safety of Medicines and Health Products) and when using same™ system a reduction of 45% of RBC transfusion associated with a reduction of 60% and 90% of platelet use for moderate and massive hemorrhages respectively, the first year annual saving amounted to €44,601 and the cumulated saving over 5 years to €535,206.Discussion: This model structure was developed based on overall hospitals' needs and acknowledged guidelines, with inputs based on French literatures and hospital data, so findings were specifics to a context. Among the inputs, the number of annual same™ procedure is not based on device capability but rather on hospital capability with the number of operating rooms used for cardio-thoracic surgery equipped with the device.Conclusions: The results of this OBIM demonstrated the economic and organizational benefits of same™ for hospitals. This benefit results mainly of a reduction in the use of allogeneic blood products (RBCs, platelets).

Measurable residual disease (MRD) dynamics in multiple myeloma and the influence of clonal diversity analyzed by artificial intelligence.

Minimal residual disease (MRD) assessment is a known surrogate marker for survival in multiple myeloma (MM). Here, we present a single institution's experience assessing MRD by NGS of Ig genes and the long-term impact of depth of response as well as clonal diversity on the clinical outcome of a large population of MM patients; 482 MM patients at the University of California, San Francisco (UCSF) diagnosed from 2008 to 2020 were analyzed retrospectively. MRD assessment was performed by NGS. PFS curves were plotted by the Kaplan-Meier method. In the newly diagnosed group, 119 of 304, achieved MRD negativity at the level of 10-6 at least once. These patients had a prolonged PFS versus patients who were persistently MRD positive at different levels (p > 0.0001). In the relapsed disease group, 64 of 178 achieved MRD negativity at 10-6, and PFS was prolonged versus patients who remained MRD positive (p = 0.03). Three categories of MRD dynamics were defined by artificial intelligence: (A) patients with ≥3 consistently MRD negative samples, (B) patients with continuously declining but detectable clones, and (C) patients with either increasing or a stable number of clones. Groups A and B had a more prolonged PFS than group C (p < 10-7). Patients who were MRD positive and had not yet relapsed had a higher clonal diversity than those patients who were MRD positive and had relapsed. MRD dynamics can accurately predict disease evolution and drive clinical decision-making. Clonal Diversity could complement MRD assessment in the prediction of outcomes in MM.

The impact of multicentric datasets for the automated tumor delineation in primary prostate cancer using convolutional neural networks on 18F-PSMA-1007 PET.

PURPOSE: Convolutional Neural Networks (CNNs) have emerged as transformative tools in the field of radiation oncology, significantly advancing the precision of contouring practices. However, the adaptability of these algorithms across diverse scanners, institutions, and imaging protocols remains a considerable obstacle. This study aims to investigate the effects of incorporating institution-specific datasets into the training regimen of CNNs to assess their generalization ability in real-world clinical environments. Focusing on a data-centric analysis, the influence of varying multi- and single center training approaches on algorithm performance is conducted. METHODS: nnU-Net is trained using a dataset comprising 161 18F-PSMA-1007 PET images collected from four distinct institutions (Freiburg: n = 96, Munich: n = 19, Cyprus: n = 32, Dresden: n = 14). The dataset is partitioned such that data from each center are systematically excluded from training and used solely for testing to assess the model's generalizability and adaptability to data from unfamiliar sources. Performance is compared through a 5-Fold Cross-Validation, providing a detailed comparison between models trained on datasets from single centers to those trained on aggregated multi-center datasets. Dice Similarity Score, Hausdorff distance and volumetric analysis are used as primary evaluation metrics. RESULTS: The mixed training approach yielded a median DSC of 0.76 (IQR: 0.64-0.84) in a five-fold cross-validation, showing no significant differences (p = 0.18) compared to models trained with data exclusion from each center, which performed with a median DSC of 0.74 (IQR: 0.56-0.86). Significant performance improvements regarding multi-center training were observed for the Dresden cohort (multi-center median DSC 0.71, IQR: 0.58-0.80 vs. single-center 0.68, IQR: 0.50-0.80, p < 0.001) and Cyprus cohort (multi-center 0.74, IQR: 0.62-0.83 vs. single-center 0.72, IQR: 0.54-0.82, p < 0.01). While Munich and Freiburg also showed performance improvements with multi-center training, results showed no statistical significance (Munich: multi-center DSC 0.74, IQR: 0.60-0.80 vs. single-center 0.72, IQR: 0.59-0.82, p > 0.05; Freiburg: multi-center 0.78, IQR: 0.53-0.87 vs. single-center 0.71, IQR: 0.53-0.83, p = 0.23). CONCLUSION: CNNs trained for auto contouring intraprostatic GTV in 18F-PSMA-1007 PET on a diverse dataset from multiple centers mostly generalize well to unseen data from other centers. Training on a multicentric dataset can improve performance compared to training exclusively with a single-center dataset regarding intraprostatic 18F-PSMA-1007 PET GTV segmentation. The segmentation performance of the same CNN can vary depending on the dataset employed for training and testing.

Transient cortical blindness following peripheral vascular trauma: A case report.

Cortical blindness is characterized by unilateral or bilateral vision loss despite an intact pupillary reflex, full extraocular movements, and normal fundoscopic examination. Common causes include stroke, cardiac emboli, head trauma or rarely, a hypoxic-ischemic event which results to decreased perfusion to the occipital lobes supplied by the posterior cerebral artery. Imaging with computed tomography is usually diagnostic documenting stroke or embolization as well as ensuring an intact cerebral circulation. Prognosis largely depends on the etiology as most reports document an irreversible condition or at least the patient is left with some residual visual symptoms. We present a case of a 25-year-old male who underwent brachial artery repair with reverse saphenous vein graft interposition after sustaining a right upper arm laceration associated with massive hemorrhage and shock due to delayed consult. He presented with profound bilateral loss of vision 12 h after surgery characterized as right homonymous hemianopsia. Computed tomography of the brain demonstrated ischemic infarcts in the occipital lobes. Close observation was instituted, and his symptom resolved spontaneously within a week. This case highlights the importance of considering atypical causes of perioperative vision loss as early recognition and timely diagnosis are essential to improve patient outcomes. To our knowledge, this is the first report of transient cortical blindness after peripheral vascular trauma.

Real-World Use of Semaglutide for Weight Management: Patient Characteristics and Dose Titration-A Danish Cohort Study.

OBJECTIVE: To determine patient characteristics and dose titration patterns of real-world semaglutide (Wegovy) users. RESEARCH DESIGN AND METHODS: We used a population-based cohort study including Danish adults who filled semaglutide prescriptions from 12 December 2022 to 31 December 2023. Outcomes were patient characteristics, prescriber type, and dose titration patterns. RESULTS: We identified 110,748 individuals (median age 49 years; 70% female) filling 773,708 prescriptions for semaglutide. General practitioners initiated treatment in 86%. Common comorbidities included hypertension (30%), dyslipidemia (17%), and arthrosis (17%). Only 13% reached the maximum dose of 2.4 mg by their fifth prescription, while 5.7% stopped after the first prescription. Few users (10%) followed recommended dose increases every 4 weeks. Overall, 25% filled at least one prescription of 2.4 mg, while 33-48% continued with the 1.0-mg dosage from the fourth prescription onward. CONCLUSIONS: Real-world semaglutide users generally resembled trial participants, but few follow the dose titration schemes tested in premarket clinical trials.

Symmetry, separation, and stability: Physical properties for effective dosimetric space with a stabilized hyaluronic acid spacer.

BACKGROUND: The proximity of the rectum to the prostate in radiation therapy (RT) for prostate cancer presents a significant dosimetric challenge, leading to high rectal doses and resulting in detrimental side effects. Perirectal tissue spacing reduces rectal dose and gastrointestinal toxicities by mechanically separating these organs. A variety of materials have been explored for use as rectal spacers, most recently, a stabilized hyaluronic acid (HA) gel, which can be formed into deliberate a shape, and retains the definition of that shape, while remaining flexible, unlike polyethylene glycol (PEG) hydrogels. PURPOSE: This study evaluates the dosimetric impact of the spacer, including shape symmetry, the degree of separation at different locations, and the temporal stability of the space. Our goal is to provide physics-informed guidance on the optimal use of this sculptable spacer. METHODS: A secondary analysis was performed on data from a 13-center prospective randomized trial (NCT04189913), involving 136 patients with centrally-reviewed treatment plans conducted on CT/MR simulation scans before and after receiving HA spacer implants. Patients were treated with 60 Gy in 20 fractions to the prostate. For this study, python software was utilized for automated processing of DICOM RTstruct and RTdose files, facilitating detailed analysis of the spacer's impact on anatomical displacement and dosimetric outcomes. Complete dose-volume histograms (DVHs) were reconstructed, and combined into composite population DVHs before and after implant, verified against trial-reported dose points. Patients were divided into similar groups of separation and symmetry, and differences in their composite DVHs were tested for significance. Stability of the spacer was studied by comparing serial MRI images and by computing the distance between contours at four axial planes, at simulation and 3-month follow-up, post RT. RESULTS: The introduction of the HA spacer significantly enhanced rectal sparing, as evidenced by a reduction in the mean rectal integral dose by over 6 Gy. High rates of implant symmetry (>95%) were observed, indicating nearly optimal lateral spacer placement. In superior-inferior coverage, this study like many others, saw the spacing largest at the superior extent but becoming more variable inferiorly at the level of the prostate apex. This allowed study of the apex as a specific area for dosimetric concern. Stability assessments confirmed that the spacer maintained its position and dimensions between the simulation and the 3-month post-RT, implying stable geometry during treatment, with only minimal separation changes observed. Statistical analysis using the Kruskal-Wallis test revealed significant correlations of larger separations at the inferior and apical planes with improved dosimetric outcomes, including rV30Gy. CONCLUSION: The use of a stabilized HA spacer in prostate RT effectively enhances prostate-rectum separation, leading to significant rectal sparing without undesirable dose compromises. This study underscores the role of strategic placement and shape, specifically including > 1 cm separation from the base down to the prostate apex. When combined with the treatment planning techniques used in the trial to create a steep dosimetric gradient across the spacer, these findings elucidate the dosimetric outcomes that can be expected in the clinical implementation of HA spacer. This is particularly relevant in the evolution of hypofractionated treatment regimens for prostate cancer therapy.

Inflammation in aortic surgery: postoperative evolution of biomarkers according pathologies and segments of the aorta.

OBJECTIVES: Aortic pathologies often present with elevated inflammatory biomarkers due to the nature of the disease. Open aortic surgery causes significant trauma to the body due to often mandatory ischemic periods, long cardiopulmonary bypass times and polytransfusion. We aim to determine postoperative trends on inflammation biomarkers for different aortic pathologies and type of surgery in different segments of the aorta. METHODS: Retrospective review of prospectively collected data of 193 consecutive patients who underwent aortic surgery in our centre between 2017 and 2021, grouped according to the type of aortic intervention: (1) Type A aortic dissection (AD) repair with ascending aorta/hemiarch replacement, (2) Aortic root replacement (ARR), (3) Aortic arch + Frozen elephant trunk (FET), (4) Descending thoracic aorta (DTA)/Thoraco-Abdominal aortic repair (TAA). Primary outcomes were daily values of white blood cells (WBC) and C-Reactive Protein (CRP) during the first 15 postoperative days. RESULTS: All groups had a similar inflammatory peak in the first 2-4 days (WBC 12-15 × 109 c/L). AD and FET groups show similar trends with WBC and CRP peaks on days 2 and 10. The ARR group didn't experience the 2nd peak as most patients were already discharged. DTA/TAA patients experienced a more prolonged inflammatory response, reaching a plateau by day 5-10. AD group shows the highest WBC levels and the DTA/TAAA group the highest CRP levels. CRP levels remain elevated (100-200 mg/L) in all groups after 15 postoperative days. CONCLUSIONS: Inflammatory biomarkers show different postoperative trends depending on the clinical presentation and complexity of the aortic procedure performed. Further understanding of the inflammatory response to different aortic pathologies and surgical procedures will permit reduction on the liberal use of antibiotics that this cohort of patients are usually exposed to. An earlier version of the data included in this manuscript was presented as Oral Abstract in the UK Society of Cardiothoracic Surgery Annual meeting in 2021.

Exploring the role of combined external beam radiotherapy and targeted radioligand therapy with [177Lu]Lu-PSMA-617 for prostate cancer - from bench to bedside.

Management of prostate cancer (PC) might be improved by combining external beam radiotherapy (EBRT) and prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) with lutetium-177 (177Lu)-labeled PSMA inhibitors. We hypothesized a higher efficacy of the combination due to augmentation of the radiation dose to the tumor and interactions of EBRT with PSMA expression potentially increasing radiopharmaceutical uptake. Therefore, this study analyzed the influence of radiation on PSMA expression levels in vitro. The results were translated to evaluate the efficacy of the combination of photon EBRT and [177Lu]Lu-PSMA-617 in a murine PC xenograft model. Finally, a clinical case report on a combined elective field EBRT with RLT dose escalation illustrates a proof-of-concept. Methods: PSMA gene and protein expression were assessed in human PSMA-overexpressing LNCaP cells after irradiation using reverse transcription quantitative polymerase chain reaction (RT-qPCR), flow cytometry and On-Cell Western assays. In the in vivo therapy study, LNCaP tumor-bearing BALB/c nu/nu mice were irradiated once with 2 Gy X-ray EBRT and injected with 40 MBq [177Lu]Lu-PSMA-617 after 4 h or received single or no treatment (n = 10 each). Tumor-absorbed doses by [177Lu]Lu-PSMA-617 were calculated according to the Medical Internal Radiation Dosimetry (MIRD) formalism after deriving time-activity curves using a gamma probe. An exemplified patient case is demonstrated where fractionated EBRT (54 Gy to prostate; 45 Gy to pelvic lymphatics) and three cycles of [177Lu]Lu-PSMA-617 (3.4-6.0 GBq per cycle) were sequentially combined under concurrent androgen deprivation for treating locally advanced PC. Results: At 4 h following irradiation with 2-8 Gy, LNCaP cells displayed a PSMA protein upregulation by around 18% relative to non-irradiated cells, and a stronger upregulation on mRNA level (up to 2.6-fold). This effect was reversed by 24 h when PSMA protein levels were downregulated by up to 22%. Mice treated with the combination therapy showed significantly improved outcomes regarding tumor control and median survival (p < 0.0001) as compared to single or no treatment. Relative to monotherapy with PSMA-RLT or EBRT, the tumor doubling time was prolonged 1.7- or 2.7-fold and the median survival was extended by 24% or 60% with the combination, respectively. Additionally, tumors treated with EBRT exhibited a 14% higher uptake of the radiopharmaceutical as evident from the calculated tumor-absorbed dose, albeit with high variability in the data. Concerning the patient case, the tri-modality treatment was well tolerated and the patient responded with a long-lasting complete biochemical remission for five years following end of PSMA-RLT. The patient then developed a biochemical relapse with oligo-recurrent disease on follow-up imaging. Conclusion: The present preclinical and clinical data demonstrate that the combination of EBRT with dose escalation by PSMA-RLT improves tumor control and potentially prolongs survival. This may pave the way for further clinical investigations of this approach to explore the curative potential of the combination therapy.

Multidisciplinary analysis of cancer-related fatigue at the time of diagnosis: preliminary results of the BIOCARE FActory cohort.

PURPOSE: Cancer-related fatigue (CRF) is a common side effect of cancer and cancer treatment that significantly impairs the quality of life and can persist for years after treatment completion. Although fatigue is often associated with cancer treatment, it is also a result of the disease itself, even before intervention. CRF at the time of diagnosis may affect treatment timing or completion and is a consistent predictor of post-treatment fatigue at any time. The mechanisms underlying CRF are multidimensional and not well understood, particularly at the time of diagnosis. METHODS: Sixty-five breast cancer patients at the time of diagnosis were included. The participants completed self-assessment questionnaires about CRF, sleep disturbances, and emotional symptoms and wore an accelerometer to assess levels of spontaneous physical activity and sleep quality. During the experimental session, the participants underwent cognitive, neuromuscular, and exercise metabolism evaluations. RESULTS: Using augmented backward elimination regression, this study found that emotional symptoms and perceived sleep disturbances were the strongest predictors of CRF (adjusted r2 = 0.51). Neuromuscular fatigability and sleep disturbance were also associated with physical dimensions, whereas cognitive performance was associated with cognitive dimensions. CONCLUSION: At the time of diagnosis, emotional and cognitive dimensions are over-represented compared to the general population, and specific subdimensions have specific predictors that support the idea of distinct mechanisms. Evaluating CRF subdimensions and their potential mechanisms at the time of diagnosis would be particularly relevant for identifying high-risk patients and offering them appropriate interventions. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov (NCT04391543) in May, 2020.

Bone marrow disease in rhabdomyosarcoma visualized by 2-[18F]fluorodeoxyglucose positron emission tomography/computed tomography.

Bone marrow metastases-noted in 6% of patients with rhabdomyosarcoma-have been linked to very poor outcomes. Bilateral bone marrow sampling from iliac crests has been the gold standard for bone marrow examination in rhabdomyosarcoma, but sampling errors due to patchy bone marrow involvement may limit its sensitivity. Here, we report the case of a 6-year-old boy with embryonal rhabdomyosarcoma of the skull base and multiple 2-[18F]fluoro-2-deoxy-D-glucose (2-[18F]FDG)-avid bone marrow metastases visualized by positron emission tomography and computed tomography (2-[18F]FDG PET/CT). His bone marrow aspirates were tumor-free. This case illustrates the diagnostic value of 2-[18F]FDG PET/CT in the detection of bone marrow metastases in rhabdomyosarcoma patients, which may re-shape the definition of bone marrow disease and, ultimately, alter disease staging and risk stratification.

Primary Mucinous Carcinoma of the Thyroid: A Case Report, Literature Review, and Immunohistochemistry Summary.

Introduction: Primary mucinous carcinoma of the thyroid is an exceedingly rare malignancy that is histologically similar to mucinous carcinoma of other sites. Accurate diagnosis is a challenging yet crucial component of clinical management for both patients and our understanding of this rare disease. Case Presentation: We report the case of a 69-year-old male patient with primary mucinous carcinoma of the thyroid. Microscopic examination of a biopsy specimen showed fibrous tissue, which was extensively and irregularly infiltrated by a cytologically malignant epithelial neoplasm showing glandular differentiation with mucin production. Immunohistochemistry demonstrated that tumor cells were positive for TTF1, thyroglobulin, CK7, and PAX8. Co-expression of TTF1 and PAX8 is most commonly seen in thyroid tumors. These findings support our diagnosis of mucinous carcinoma of thyroid origin, which is rare and highly aggressive. Conclusion: In this report, we present the only documented case of primary mucinous carcinoma of the thyroid reported in the United States in the last decade. The diagnosis of primary mucinous carcinoma of the thyroid can be challenging. Therefore, we discuss and detail the clinicopathologic tumor profile and provide more current, detailed histological criteria to assist in the diagnosis of this rare disease.

Protein Aggregation on Metal Oxides Governs Catalytic Activity and Cellular Uptake.

Engineering of catalytically active inorganic nanomaterials holds promising prospects for biomedicine. Catalytically active metal oxides show applications in enhancing wound healing but have also been employed to induce cell death in photodynamic or radiation therapy. Upon introduction into a biological system, nanomaterials are exposed to complex fluids, causing interaction and adsorption of ions and proteins. While protein corona formation on nanomaterials is acknowledged, its modulation of nanomaterial catalytic efficacy is less understood. In this study, proteomic analyses and nano-analytic methodologies quantify and characterize adsorbed proteins, correlating this protein layer with metal oxide catalytic activity in vitro and in vivo. The protein corona comprises up to 280 different proteins, constituting up to 38% by weight. Enhanced complement factors and other opsonins on nanocatalyst surfaces lead to their uptake into macrophages when applied topically, localizing >99% of the nanomaterials in tissue-resident macrophages. Initially, the formation of the protein corona significantly reduces the nanocatalysts' activity, but this activity can be partially recovered in endosomal conditions due to the proteolytic degradation of the corona. Overall, the research reveals the complex relationship between physisorbed proteins and the catalytic characteristics of specific metal oxide nanoparticles, providing design parameters for optimizing nanocatalysts in complex biological environments.

Should Pediatric Surgical Oncologists Receive Training in Vascular Surgery ? A Practice Survey Report From the International Society of Paediatric Surgical Oncology (IPSO).

BACKGROUND: Is vascular training in paediatric surgical oncology considered desirable ? METHODS: A voluntary survey of work practice was undertaken with the surgeon membership of The International Society Of Paediatric Surgical Oncology (IPSO) using a structured designed questionnaire. RESULTS: A total of 149 IPSO surgeon members completed the survey. 57% (N = 84) of surgeons surveyed had no specific training in vascular surgery. 43% surgeons (N = 63) stated they had acquired some skills in residency training and/or with transplantation surgery. 65% (N = 96) of respondent surgeons stated that vascular surgical training must be incorporated into pediatric surgical oncology training and 27% (N = 40) agreed that it was considered desirable. 89% (N = 133) of surgeon respondents had encountered major vascular injury during work practice while operating on pediatric solid tumors. Vascular injury repairs were undertaken and attempted by pediatric surgeons though expert assistance of vascular surgeons proved crucially essential in many instances. Emergent operations included patch repairs, vessel ligation techniques and insertion of vascular graft prostheses. Interventional radiology services to arrest life-threatening hemorrhage were also reportedly utilized by respondents. CONCLUSION: Vascular injuries have significant potential for devastating patient outcomes including never event 'mortality'. The IPSO surgeon survey highlights that there are visible 'gaps' in skills training. Training to be a pediatric oncology surgeon must incorporate acquisition of skill sets proficiency in vascular surgery.

Consensus statement-graft treatment in cardiovascular bypass graft surgery.

Coronary artery bypass grafting (CABG) is and continues to be the preferred revascularization strategy in patients with multivessel disease. Graft selection has been shown to influence the outcomes following CABG. During the last almost 60 years saphenous vein grafts (SVG) together with the internal mammary artery have become the standard of care for patients undergoing CABG surgery. While there is little doubt about the benefits, the patency rates are constantly under debate. Despite its acknowledged limitations in terms of long-term patency due to intimal hyperplasia, the saphenous vein is still the most often used graft. Although reendothelialization occurs early postoperatively, the process of intimal hyperplasia remains irreversible. This is due in part to the persistence of high shear forces, the chronic localized inflammatory response, and the partial dysfunctionality of the regenerated endothelium. "No-Touch" harvesting techniques, specific storage solutions, pressure controlled graft flushing and external stenting are important and established methods aiming to overcome the process of intimal hyperplasia at different time levels. Still despite the known evidence these methods are not standard everywhere. The use of arterial grafts is another strategy to address the inferior SVG patency rates and to perform CABG with total arterial revascularization. Composite grafting, pharmacological agents as well as latest minimal invasive techniques aim in the same direction. To give guide and set standards all graft related topics for CABG are presented in this expert opinion document on graft treatment.

PTHrP intracrine actions divergently influence breast cancer growth through p27 and LIFR.

The role of parathyroid hormone (PTH)-related protein (PTHrP) in breast cancer remains controversial, with reports of PTHrP inhibiting or promoting primary tumor growth in preclinical studies. Here, we provide insight into these conflicting findings by assessing the role of specific biological domains of PTHrP in tumor progression through stable expression of PTHrP (-36-139aa) or truncated forms with deletion of the nuclear localization sequence (NLS) alone or in combination with the C-terminus. Although the full-length PTHrP molecule (-36-139aa) did not alter tumorigenesis, PTHrP lacking the NLS alone accelerated primary tumor growth by downregulating p27, while PTHrP lacking the NLS and C-terminus repressed tumor growth through p27 induction driven by the tumor suppressor leukemia inhibitory factor receptor (LIFR). Induction of p27 by PTHrP lacking the NLS and C-terminus persisted in bone disseminated cells, but did not prevent metastatic outgrowth, in contrast to the primary tumor site. These data suggest that the PTHrP NLS functions as a tumor suppressor, while the PTHrP C-terminus may act as an oncogenic switch to promote tumor progression through differential regulation of p27 signaling.

Impact of immunosuppressive therapy on SARS-CoV-2 mRNA vaccine effectiveness in patients with immune-mediated inflammatory diseases: a Danish nationwide cohort study.

OBJECTIVE: Patients receiving immunosuppressives have been excluded from trials for SARS-CoV-2 vaccine efficacy. Investigation of immunosuppressants' impact on effectiveness of vaccines, particularly in patients with immune-mediated inflammatory diseases (IMID), is therefore required. DESIGN: We performed a nationwide cohort study to assess the risk of COVID-19 infection in vaccinated patients with IMID exposed to immunosuppressives compared with IMID unexposed to immunosuppressives. Exposure to immunosuppressives in the 120 days before receiving the second SARS-CoV-2 mRNA vaccination was assessed. Patients were followed from date of second vaccination and weighted Cox models were used to estimate the risk of infection associated with immunosuppressives. Secondary outcomes included hospitalisation and death associated with a positive SARS-CoV-2 test. Risk of infection by immunosuppressant drug class was also analysed. SETTING: This study used population-representative data from Danish national health registries in the period from 1 January to 30 November 2021. RESULTS: Overall, 152 440 patients were followed over 19 341 person years. Immunosuppressants were associated with a significantly increased risk of infection across IMID (HR: 1.4, 95% CI 1.2 to 1.5), in inflammatory bowel disease (IBD) (HR: 1.6, 95% CI 1.4 to 1.9) and arthropathy (HR: 1.3, 95% CI 1.1 to 1.4) but not psoriasis (HR: 1.1, 95% CI 0.9 to 1.4). Immunosuppressants were also associated with an increased risk of hospitalisation across IMID (HR: 1.4, 95% CI 1.1 to 2.0), particularly in IBD (HR: 2.1, 95% CI 1.0 to 4.1). No significantly increased risk of death in immunosuppressant exposed patients was identified. Analyses by immunosuppressant drug class showed increased COVID-19 infection and hospitalisation with anti-tumour necrosis factor (TNF), systemic corticosteroid, and rituximab and other immunosuppressants in vaccinated patients with IMID. CONCLUSION: Immunosuppressive therapies reduced effectiveness of mRNA SARS-CoV-2 vaccination against infection and hospitalisation in patients with IMID. Anti-TNF, systemic corticosteroids, and rituximab and other immunosuppressants were particularly associated with these risks.

Peptide Receptor Radionuclide Therapy Is Effective for Clinical Control of Symptomatic Metastatic Insulinoma: A Long-Term Retrospective Analysis.

Metastatic insulinoma is a rare malignant neuroendocrine tumor characterized by inappropriate insulin secretion, resulting in life-threatening hypoglycemia, which is often difficult to treat. There is currently very limited information about the efficacy of peptide receptor radionuclide therapy (PRRT) for clinical control of hypoglycemia. The aim of this long-term retrospective study was to evaluate the therapeutic efficacy of PRRT for improving hypoglycemia, to evaluate the change of medication after PRRT, and to calculate progression-free survival (PFS) and overall survival (OS). Methods: Inclusion criteria were histologically proven somatostatin receptor-positive metastatic malignant insulinoma and at least 2 cycles of [90Y]Y-DOTATOC or [177Lu]Lu-DOTATOC therapy from early 2000 to early 2022. A semiquantitative scoring system was used to quantify the severity and frequency of hypoglycemic episodes under background antihypoglycemic therapy (somatostatin analog, diazoxide, everolimus, corticosteroids): score 0, no hypoglycemic episodes; score 1, hypoglycemic events requiring additional conservative treatment with optimization of nutrition; score 2, severe hypoglycemia necessitating hospitalization and combined medication or history of hypoglycemic coma. Hypoglycemic score before and after PRRT was analyzed. Time of benefit was defined as a time range of fewer hypoglycemic episodes in the observation period than at baseline. Information on antihypoglycemic medication before and after therapy, PFS, and OS was recorded. Results: Twenty-six of 32 patients with a total of 106 [90Y]Y-DOTATOC/[177Lu]Lu-DOTATOC cycles were included. The average observation period was 21.5 mo (range, 2.3-107.4 mo). Before therapy, 81% (n = 21) of the patients had a hypoglycemia score of 2 and 19% (n = 5) had a score of 1. After PRRT, 81% of patients (n = 21) had a decreased score, and the remaining 5 patients showed a stable situation. There was temporary worsening of hypoglycemia just after injection of [90Y]Y-DOTATOC/[177Lu]Lu-DOTATOC in 19% of patients. The average time of benefit in the observation period was 17.2 mo (range, 0-70.2 mo). Antihypoglycemic medication reduction was achieved in 58% (n = 15) of patients. The median OS and PFS after the start of PRRT were 19.7 mo (95% CI, 6.5-32.9 mo) and 11.7 mo (95% CI, 4.9-18.5 mo), respectively. Conclusion: To our knowledge, our study included the largest cohort of patients with malignant insulinoma to be evaluated. Long-lasting symptom control and reduction of antihypoglycemic medications were shown in most patients after late-line PRRT.