Improving the nutritional evaluation in head neck cancer patients using bioelectrical impedance analysis: Not only the phase angle matters.

BACKGROUND: Malnutrition and sarcopenia are highly prevalent in patients with head neck cancer (HNC). An accurate early diagnosis is necessary for starting nutritional support, as both are clearly associated with clinical outcomes and mortality. We aimed to evaluate the applicability and accuracy of body composition analysis using electrical bioimpedance vectorial analysis (BIVA) for diagnosing malnutrition and sarcopenia in patients with HNC cancer undergoing systemic treatment with chemotherapy or radiotherapy. METHODS: Cross-sectional, observational study that included 509 HNC patients. A comprehensive nutritional evaluation that included BIVA was performed. RESULTS: The prevalence of malnutrition was higher in patients that received treatment with chemotherapy (59.2% vs. 40.8%, P < 0.001); increased mortality was observed in malnourished patients (33.3% vs. 20.1%; P < 0.001); ECOG status (1-4) was also worse in malnourished patients (59.2% vs. 22.8% P < 0.001). Body cell mass (BCM) and fat mass were the most significantly associated parameters with malnutrition [OR 0.88 (0.84-0.93) and 0.98 (0.95-1.01), respectively]; BCM and fat free mass index (FFMI) were associated with several aspects including (1) the patient-generated subjective global assessment [OR 0.93 (0.84-0.98) and 0.86 (0.76-0.97), respectively], (2) the presence of sarcopenia [OR 0.81 (0.76-0.87) and 0.78 (0.66-0.92), respectively]. A BCM index (BCMI) < 7.8 in combination with other parameters including FFMI and BCM accurately predicted patients with malnutrition [accuracy 95% CI: 0.803 (0.763-0.839); kappa index: 0.486; AUC: 0.618 (P < 0.01)]. A BCMI cutoff of 7.6 was enough for identifying males with malnutrition (P < 0.001), while it should be combined with other parameters in females. CONCLUSIONS: Body composition parameters determined by BIVA accurately identify patients with HNC and malnutrition. Phase angle, but other parameters including BCMI, FFMI and BCM provide significant information about nutritional status in patients with HNC.

'Patera syndrome' during the COVID-19 pandemic in the Canary Islands (Spain).

BACKGROUND: The number of migrants arriving on the shores of the Canary Islands continues to increase. The conditions under which the crossing is made, in small crowded, unsanitary boats (pateras or cayucos), have many and significant health problems. OBJECTIVE: To describe the demographic, clinical, microbiological characteristics and evolution of a series of patients who recently arrived by patera and required hospitalization. PATIENTS AND METHODS: This observational, cross-sectional, and retrospective study included all patients newly arrived in Gran Canaria (Spain) by patera or cayuco from 2020 to 2022. Acute patera syndrome (APS) was defined as one or more of the following: dehydration, hypothermia, shock or rhabdomyolysis. Skin and soft tissue or musculoskeletal patera syndrome (SSTMSPS) was defined as conditions characterized by lesions of the skin, subcutaneous tissue, bone, or joint, excluding superficial erosions. RESULTS: During the study period, 193 migrants were admitted, mostly males with a median age of 23 years from West Africa. A total of 36.99% presented with APS with a single diagnostic criterion (most commonly dehydration, 86.9%), 11.56% with SSTMPS and 51.44% with both syndromes. A total of 109 patients presented with SSTMSPS, the most common being lower extremity ulcers. The most frequently isolated microorganisms were gram-negative (i.e. Shewanella algae). The McMahon score effectively predicted the need for renal replacement therapy in cases of rhabdomyolysis. Twenty patients presented with pneumomediastinum, which was benign. SARS-CoV-2 infection was not a problem in any of them. Surgical intervention was required in 22% of cases, including 8 amputations, all of which were minor. No patient died during admission. CONCLUSION: Patera syndrome has specific characteristics that should be identified promptly to initiate the most effective treatment for optimal outcomes.

Is Fasting Superior to Continuous Caloric Restriction for Weight Loss and Metabolic Outcomes in Obese Adults? A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

BACKGROUND: fasting-based strategies (FBS) and continuous caloric restriction (CCR) are popular methods for weight loss and improving metabolic health. FBS alternates between eating and fasting periods, while CCR reduces daily calorie intake consistently. Both aim to create a calorie deficit, but it is still uncertain as to which is more effective for short- and long-term weight and metabolic outcomes. OBJECTIVES: this systematic review and meta-analysis aimed to compare the effectiveness of FBS and CCR on these parameters in obese adults. METHODS: after screening 342 articles, 10 randomized controlled trials (RCTs) with 623 participants were included. RESULTS: both interventions led to weight loss, with a reduction of 5.5 to 6.5 kg observed at the six-month mark. However, the results showed that FBS led to slightly greater short-term reductions in body weight (-0.94 kg, p = 0.004) and fat mass (-1.08 kg, p = 0.0001) compared to CCR, although these differences are not clinically significant. Both interventions had similar effects on lean mass, waist and hip circumference, blood pressure, lipid profiles, and glucose metabolism. However, FBS improved insulin sensitivity, with significant reductions in fasting insulin (-7.46 pmol/L, p = 0.02) and HOMA-IR (-0.14, p = 0.02). CONCLUSIONS: despite these short-term benefits, FBS did not show superior long-term outcomes compared to CCR. Both strategies are effective for weight management, but more research is needed to explore the long-term clinical relevance of FBS in obese populations.

Prodrug Nanomedicine for Synovium Targeted Therapy of Inflammatory Arthritis: Insights from Animal Model and Human Synovial Joint Fluid.

Many patients cannot tolerate low-dose weekly methotrexate (MTX) therapy for inflammatory arthritis treatment due to life-threatening toxicity. Although biologics offer a target-specific therapy, it raises the risk of serious infections and even cancer due to immune system suppression. We introduce an anti-inflammatory arthritis MTX ester prodrug using a long-circulating biocompatible polymeric macromolecule: folic acid (FA) functionalized hyperbranched polyglycerol (HPG). In vitro the drug MTX is incrementally released through pH and enzymatic degradation over 2 weeks. The role of matrix metalloproteinases (MMPs) in site-specific prodrug activation was verified using synovial fluid (SF) of 26 rheumatology patients and 4 healthy controls. Elevated levels of specific MMPs-markers of joint inflammation-positively correlated with enhanced prodrug release explained by acid-catalyzed hydrolysis of esters by proteases. Intravenously administered 111In-radiolabeled prodrug confirmed by SPECT/CT imaging that it accumulated preferentially in inflamed joints while reducing off-target side-effects in a mouse model of rheumatoid arthritis (RA). Added FA as a targeting vector prolonged prodrug action; prodrug with 4x less MTX applied every 2 weeks was as effective as weekly MTX therapy. The preclinical results suggest a prodrug-based strategy for the treatment of inflammatory joint diseases, with potential for other chronic inflammatory diseases and cancer.

Real-World Evaluation of the Effectiveness and Safety of Dupilumab in Bullous Pemphigoid: An Ambispective Multicenter Case Series.

BACKGROUND: Bullous pemphigoid affects elderly individuals with multiple comorbidities, making conventional treatments unsuitable. OBJECTIVE: Evaluate the effectiveness and safety of dupilumab in the treatment of bullous pemphigoid. METHODS: A multicenter ambispective cohort study was conducted in 34 hospitals. Patients with bullous pemphigoid treated with Dupilumab were included. Most of patients (97.1%) received an initial 600 mg dose followed by 300 mg every two weeks. OUTCOMES AND MEASURES: The primary outcome was the proportion of patients achieving complete remission within 4 weeks, defined as Investigator Global Assessment score of 0 or 1. Complete remission at weeks 16, 24, and 52, adverse events, reductions in peak pruritus numerical rating scale, and systemic glucocorticoid use were also assessed. RESULTS: The study included 103 patients with a median age of 77.3 years, 58.0% male. Complete remission was achieved by 53.4% within 4 weeks and 95.7% by week 52. Peak pruritus scale reduced by 70.0% by week 4 and was completely controlled by week 24. Thirteen patients presented adverse events, most of which were mild. Systemic glucocorticoid use reduced by 82.1% by week 52. Shorter disease duration and exclusive cutaneous involvement predicted better response at 16 weeks. No differences in response rates to dupilumab were observed between drug-associated bullous pemphigoid and idiopathic cases. No significant difference in response rates was observed between patients treated with dupilumab in monotherapy and those receiving dupilumab with concomitant treatments. CONCLUSIONS: Dupilumab is effective, rapid, and safe in managing bullous pemphigoid, reducing the need for corticosteroids and other treatments. Early initiation and exclusive skin involvement predict better outcomes.

Preclinical Evaluation of 226Ac as a Theranostic Agent: Imaging, Dosimetry, and Therapy.

226Ac (t½ = 29.37 h) has been proposed as a theranostic radioisotope leveraging both its diagnostic γ-emissions and therapeutic α-emissions. 226Ac emits 158 and 230 keV γ-photons ideal for quantitative SPECT imaging and acts as an in vivo generator of 4 high-energy α-particles. Because of these nuclear decay properties, 226Ac has potential to act as a standalone theranostic isotope. In this proof-of-concept study, we evaluated a preclinical 226Ac-radiopharmaceutical for its theranostic efficacy and present the first 226Ac-targeted α-therapy study. Methods: 226Ac was produced at TRIUMF and labeled with the chelator-peptide bioconjugate crown-TATE. [226Ac]Ac-crown-TATE was selected to target neuroendocrine tumors in male NRG mice bearing AR42J tumor xenografts for SPECT imaging, biodistribution, and therapy studies. A preclinical SPECT/CT scanner acquired quantitative images reconstructed from both the 158 and the 230 keV emissions. Mice in the biodistribution study were euthanized at 1, 3, 5, 24, and 48 h after injection, and internal radiation dosimetry was derived for the tumor and organs of interest to establish appropriate therapeutic activity levels. Mice in the therapy study were administered 125, 250, or 375 kBq treatments and were monitored for tumor size and body condition. Results: We present quantitative SPECT images of the in vivo biodistribution of [226Ac]Ac-crown-TATE, which showed agreement with ex vivo measurements. Biodistribution studies demonstrated high uptake (>30%IA/g at 5 h after injection) and retention in the tumor, with an estimated mean absorbed dose coefficient of 222 mGy/kBq. [226Ac]Ac-crown-TATE treatments significantly extended the median survival from 7 d in the control groups to 16, 24, and 27 d in the 125, 250, and 375 kBq treatment groups, respectively. Survival was prolonged by slowing tumor growth, and no weight loss or toxicities were observed. Conclusion: This study highlights the theranostic potential of 226Ac as a standalone therapeutic isotope in addition to its demonstrated diagnostic capabilities to assess dosimetry in matched 225Ac-radiopharmaceuticals. Future studies will investigate maximum dose and toxicity to further explore the therapeutic potential of 226Ac-radiopharmaceuticals.

Identification of new therapeutic targets related to endoplasmic reticulum stress and mitochondrial dysfunction to reduce the risk of rupture in degenerative ascending aortic aneurysm. / Identificación de nuevas dianas terapéuticas relacionadas con el estrés del retículo endoplasmático y con la disfunción mitocondrial para reducir el riesgo de rotura en el aneurisma de aorta ascendente degenerativo.

BACKGROUND: Ascending Thoracic Aortic Aneurysm (ATAA) is a progressive dilation of the aorta that can be complicated by its dissection leading to death in 80-90% of the patients. When associated with aging and atherosclerosis, the outcome is worse and reconstructive surgery is the only effective therapy. Our objective was to characterize differential expressed genes (DEG) involved in endoplasmic reticulum (ER) and mitochondria dysfunction in patients with degenerative ATAA. METHODS: A transcriptomic analysis was performed by RNA sequencing using RNA isolated from ATAA of patients classified as degenerative (n=13) and multi-organ healthy donors (n=6). DEGs related to ER stress and mitochondrial dysfunction were identified with the DESeq2 package. Enriched pathway (Reactome) and protein interaction (PPI) analysis was performed with the clusterProfiles package. PPI of the selected DEGs was analyzed based on the string database and visualized by Cytoscape software. RESULTS: Histology revealed a complete disorganization of the extracellular matrix (ECM) and cell loss in the aortic wall of ATAA patients where the upregulation of 15 DEGs and the downregulation of 13 DEGs that encode proteins related to ER stress (ATF4, EIF2AK3, HSPA5, ERN1, SEL1L), mitochondrial dysfunction (DNML1, IMMT, MT-CO3, MT-CYB, MT ND2, TIMM17B, MT-ERF1, TOMM5) and ECM was detected. The results of GO term and enriched pathway analysis indicated that these DEGs are mainly enriched in pathways related to aortic diseases. CONCLUSIONS: Our data show that proteins related to mitochondrial dysfunction and ER stress might be therapeutic targets for the treatment of ATAA.

Influence of microbiota on the growth and gene expression of Clostridioides difficile in an in vitro coculture model.

Clostridioides difficile is an anaerobic, spore-forming, Gram-positive pathogenic bacterium. This study aimed to analyze the effect of two samples of healthy fecal microbiota on C. difficile gene expression and growth using an in vitro coculture model. The inner compartment was cocultured with spores of the C. difficile polymerase chain reaction (PCR)-ribotype 078, while the outer compartment contained fecal samples from donors to mimic the microbiota (FD1 and FD2). A fecal-free plate served as a control (CT). RNA-Seq and quantitative PCR confirmation were performed on the inner compartment sample. Similarities in gene expression were observed in the presence of the microbiota. After 12 h, the expression of genes associated with germination, sporulation, toxin production, and growth was downregulated in the presence of the microbiota. At 24 h, in an iron-deficient environment, C. difficile activated several genes to counteract iron deficiency. The expression of genes associated with germination and sporulation was upregulated at 24 h compared with 12 h in the presence of microbiota from donor 1 (FD1). This study confirmed previous findings that C. difficile can use ethanolamine as a primary nutrient source. To further investigate this interaction, future studies will use a simplified coculture model with an artificial bacterial consortium instead of fecal samples.

Preparation and Characterization of Novel Poly(Lactic Acid) Composites Reinforced with "Latxa" Sheep Wool Fibers: The Effect of Peroxide Surface Treatments and Fiber Content.

"Latxa" sheep wool is rough, and it is not used in the textile industry because the fiber diameter is high compared with other wool fibers. Nowadays, this wool is considered as disposal and, with the aim to give it value, new uses must be explored. In the current work, the "Latxa" sheep wool fiber was evaluated as poly(lactic acid) (PLA) polymer reinforcement. With the objective to optimize fiber/matrix adhesion, fibers were surface modified with peroxide. Oxidation treatment with peroxide led to chemical modifications of the wool fibers that improved the fiber/PLA adhesion, but the strength values achieved for the composites were lower compared to the neat PLA ones. The mechanical properties obtained in the current work were compared with the literature data of the PLA composites reinforced with vegetable fibers. The wool fibers showed inferior mechanical properties compared to the vegetable fiber counterparts. However, the preliminary results indicated that the incorporation of wool fibers to PLA reduced the flammability of composites.

Lung function decline in people with serious mental illness: A call to action.

This prospective observational study aimed to evaluate the rate of change in forced expiratory volume in the first second (FEV1) and to explore the factors associated with changes in FEV1 in people with serious mental illness (SMI). Sixty subjects diagnosed with schizophrenia or bipolar disorder who were smokers and without history of respiratory illness agreed to participate. The mean (range) follow-up period was 3.54 (3.00-4.98) years. The mean (standard deviation) annual rate of change in FEV1 decreased by 39.1 (105.2) mL/year. Thirty-one (51.7 %) patients experienced a decrease in the FEV1 ≥40 mL/year (i.e. a rapid decline). The factors associated with the absolute change in FEV1 were the baseline International Physical Activity Questionnaire activity score in metabolic equivalents of tasks (ß 0.145, 95 % confidence interval [CI] 0.043 to 0.246; p = 0.005), baseline FEV1 (ß -0.025, 95 % CI -0.076 to 0.027; p = 0.352), and the interaction term of both variables (ß -3.172e-05, 95 % CI -6.025e-05 to -0.319e-05; p = 0.029). The factors associated with rapid FEV1 decline were income (odds ratio [OR] 0.999, 95 % CI 0.995 to 1.003; p = 0.572), the rate of change in abdominal circumference (OR 0.000, 95 % CI 0.000 to 0.890; p = 0.081), and the interaction term of both variables (OR 1.038, 95 % CI 1.010 to 1.082; p = 0.026). In conclusion, a substantial proportion of people with SMI experienced a rapid decrease in FEV1. If our results are confirmed in larger samples, the routine evaluation of lung function in people with SMI would be an opportunity to identify individuals at greater risk of morbidity and mortality.

Quantitative SPECT imaging of 155Tb and 161Tb for preclinical theranostic radiopharmaceutical development.

BACKGROUND: Element-equivalent matched theranostic pairs facilitate quantitative in vivo imaging to establish pharmacokinetics and dosimetry estimates in the development of preclinical radiopharmaceuticals. Terbium radionuclides have significant potential as matched theranostic pairs for multipurpose applications in nuclear medicine. In particular, 155Tb (t1/2 = 5.32 d) and 161Tb (t1/2 = 6.89 d) have been proposed as a theranostic pair for their respective applications in single photon emission computed tomography (SPECT) imaging and targeted beta therapy. Our study assessed the performance of preclinical quantitative SPECT imaging with 155Tb and 161Tb. A hot rod resolution phantom with rod diameters ranging between 0.85 and 1.70 mm was filled with either 155Tb (21.8 ± 1.7 MBq/mL) or 161Tb (23.6 ± 1.9 MBq/mL) and scanned with the VECTor preclinical SPECT/CT scanner. Image performance was evaluated with two collimators: a high energy ultra high resolution (HEUHR) collimator and an extra ultra high sensitivity (UHS) collimator. SPECT images were reconstructed from photopeaks at 43.0 keV, 86.6 keV, and 105.3 keV for 155Tb and 48.9 keV and 74.6 keV for 161Tb. Quantitative SPECT images of the resolution phantoms were analyzed to report inter-rod contrast, recovery coefficients, and contrast-to-noise metrics. RESULTS: Quantitative SPECT images of the resolution phantom established that the HEUHR collimator resolved all rods for 155Tb and 161Tb, and the UHS collimator resolved rods ≥ 1.10 mm for 161Tb and ≥ 1.30 mm for 155Tb. The HEUHR collimator maintained better quantitative accuracy than the UHS collimator with recovery coefficients up to 92%. Contrast-to-noise metrics were also superior with the HEUHR collimator. CONCLUSIONS: Both 155Tb and 161Tb demonstrated potential for applications in preclinical quantitative SPECT imaging. The high-resolution collimator achieves < 0.85 mm resolution and maintains quantitative accuracy in small volumes which is advantageous for assessing sub organ activity distributions in small animals. This imaging method can provide critical quantitative information for assessing and optimizing preclinical Tb-radiopharmaceuticals.

Adaptive optical third-harmonic generation microscopy for in vivo imaging of tissues.

Third-harmonic generation microscopy is a powerful label-free nonlinear imaging technique, providing essential information about structural characteristics of cells and tissues without requiring external labelling agents. In this work, we integrated a recently developed compact adaptive optics module into a third-harmonic generation microscope, to measure and correct for optical aberrations in complex tissues. Taking advantage of the high sensitivity of the third-harmonic generation process to material interfaces and thin membranes, along with the 1,300-nm excitation wavelength used here, our adaptive optical third-harmonic generation microscope enabled high-resolution in vivo imaging within highly scattering biological model systems. Examples include imaging of myelinated axons and vascular structures within the mouse spinal cord and deep cortical layers of the mouse brain, along with imaging of key anatomical features in the roots of the model plant Brachypodium distachyon. In all instances, aberration correction led to enhancements in image quality.

NFAT5 counters long-term IFN-1 responses in hematopoietic stem cells to preserve reconstitution potential.

ABSTRACT: Hematopoietic stem cells (HSCs) readily recover from acute stress, but persistent stress can reduce their viability and long-term potential. Here, we show that the nuclear factor of activated T cells 5 (NFAT5), a transcription modulator of inflammatory responses, protects the HSC pool under stress. NFAT5 restrains HSC differentiation to multipotent progenitors after bone marrow transplantation and bone marrow ablation with ionizing radiation or chemotherapy. Correspondingly, NFAT5-deficient HSCs fail to support long-term reconstitution of hematopoietic progenitors and mature blood cells after serial transplant. Evidence from competitive transplant assays shows that these defects are HSC intrinsic. NFAT5-deficient HSCs exhibit enhanced expression of type 1 interferon (IFN-1) response genes after transplant, and suppressing IFN-1 receptor prevents their exacerbated differentiation and cell death after reconstitution and improves long-term regeneration potential. Blockade of IFN-1 receptor also prevented the overdifferentiation of NFAT5-deficient HSCs after bone marrow ablation. These findings show that long-term IFN-1 responses to different hematopoietic stressors drive HSCs toward more differentiated progenitors, and that NFAT5 has an HSC-intrinsic role, limiting IFN-1 responses to preserve reconstitution potential. Our identification of cell-intrinsic mechanisms that strengthen the resistance of HSCs to stress could help to devise approaches to protect long-term stemness during the treatment of hematopoietic malignancies.

Inflammatory Bowel Disease and Cardiovascular Disease: An Integrative Review With a Focus on the Gut Microbiome.

Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, is a chronic inflammatory condition of the gastrointestinal tract. Recent research indicates a significant link between IBD and cardiovascular disease (CVD), the leading cause of global morbidity and mortality. This review examines the association between IBD and CVD, emphasizing the role of the gut microbiome in this relationship. IBD patients have a higher risk of cardiovascular events, such as coronary artery disease, heart failure, and cerebrovascular incidents, primarily due to chronic systemic inflammation, genetic factors, and gut microbiota imbalance (dysbiosis). Dysbiosis in IBD increases intestinal permeability, allowing bacterial products to enter the bloodstream, which promotes inflammation and endothelial dysfunction, contributing to CVD. Understanding the gut microbiome's role in IBD and CVD suggests new therapeutic interventions. Modulating the microbiome through diet, probiotics, and fecal microbiota transplantation (FMT) are promising research avenues. These interventions aim to restore a healthy gut microbiota balance, potentially reducing inflammation and improving cardiovascular outcomes. Additionally, the review emphasizes the importance of regular cardiovascular risk assessments and personalized preventive measures in managing IBD patients. Such measures include routine monitoring of cardiovascular health, tailored lifestyle modifications, and early intervention strategies to mitigate cardiovascular risk. By integrating current knowledge, this review aims to improve understanding and management of the interconnected pathophysiology of IBD and CVD. This approach will ultimately enhance patient outcomes and provide a foundation for future research and clinical practice guidelines in this area.

Underreporting of Cases in the COVID-19 Outbreak of Borriana (Spain) during Mass Gathering Events in March 2020: A Cross-Sectional Study.

Determining the number of cases of an epidemic is the first function of epidemiological surveillance. An important underreporting of cases was observed in many locations during the first wave of the COVID-19 pandemic. To estimate this underreporting in the COVID-19 outbreak of Borriana (Valencia Community, Spain) in March 2020, a cross-sectional study was performed in June 2020 querying the public health register. Logistic regression models were used. Of a total of 468 symptomatic COVID-19 cases diagnosed in the outbreak through anti-SARS-CoV-2 serology, 36 cases were reported (7.7%), resulting in an underreporting proportion of 92.3% (95% confidence interval [CI], 89.5-94.6%), with 13 unreported cases for every reported case. Only positive SARS-CoV-2 polymerase chain reaction cases were predominantly reported due to a limited testing capacity and following a national protocol. Significant factors associated with underreporting included no medical assistance for COVID-19 disease, with an adjusted odds ratio [aOR] of 10.83 (95% CI 2.49-47.11); no chronic illness, aOR = 2.81 (95% CI 1.28-6.17); middle and lower social classes, aOR = 3.12 (95% CI 1.42-6.85); younger age, aOR = 0.97 (95% CI 0.94-0.99); and a shorter duration of illness, aOR = 0.98 (95% CI 0.97-0.99). To improve the surveillance of future epidemics, new approaches are recommended.

Preclinical evaluation of [225Ac]Ac-crown-TATE - An alpha-emitting radiopharmaceutical for neuroendocrine tumors.

BACKGROUND: Targeted alpha therapy (TAT) of somatostatin receptor-2 (SSTR2) positive neuroendocrine tumors (NETs) involving Ac-225 ([225Ac]Ac-DOTA-TATE) has previously demonstrated improved therapeutic efficacy over conventional beta particle-emitting peptide receptor radionuclide therapy agents. DOTA-TATE requires harsh radiolabeling conditions for chelation of [225Ac]Ac3+, which can limit the achievable molar activities and thus therapeutic efficacy of such TAT treatments. Macropa-TATE was recently highlighted as a potential alternative to DOTA-TATE, owing to the mild radiolabeling conditions and high affinity toward [225Ac]Ac3+; however, elevated liver and kidney uptake were noted as a major limitation and a suitable imaging radionuclide is yet to be reported, which will be required for patient dosimetry studies and assessment of therapeutic benefit. Previously, [155Tb]Tb-crown-TATE has shown highly effective imaging of NETs in preclinical SPECT/CT studies, with high tumor uptake and low non-target accumulation; these favourable properties and the versatile coordination behavior of the crown chelator may therefore show promise for combination with Ac-225 for TAT. METHODS: Crown-TATE was labeled with Ac-225, and radiochemical yield was analyzed as the function of crown-TATE concentration. LogD7.4 was measured as the indication of hydrophilicity. Free [225Ac]Ac3+ release from [225Ac]Ac-crown-TATE in human serum was studied. Biodistribution studies of [225Ac]Ac-crown-TATE in mice bearing AR42J tumors was evaluated at 1, 4, 24, 48, and 120 h, and the absorbed dose to major organs calculated. Therapy-monitoring studies with AR42J tumor bearing mice were undertaken using 30 kBq and 55 kBq doses of [225Ac]Ac-crown-TATE and compared to controls treated with PBS or crown-TATE. RESULTS: [225Ac]Ac-crown-TATE was successfully prepared with high molar activity (640 kBq/nmol), and characterized as a moderately hydrophilic radioligand (LogD7.4 = -1.355 ± 0.135). No release of bound Ac-225 was observed over 9 days in human serum. Biodistribution studies of [225Ac]Ac-crown-TATE showed good initial tumor uptake (11.1 ± 1.7% IA/g at 4 h) which was sustained up to 120 h p.i. (6.92 ± 2.03% IA/g). Dosimetry calculations showed the highest absorbed dose was delivered to the tumors. Therapy monitoring studies demonstrated significant (log-rank test, P < 0.005) improved survival in both treatment groups compared to controls. CONCLUSIONS: This preclinical study demonstrated the therapeutic efficacy of [225Ac]Ac-crown-TATE for treatment of NETs, and highlights the potential of using crown chelator for stable chelation of Ac-225 under mild conditions.

Nephrotoxicity Associated with Cytoreductive Surgery Combined with Cisplatin-Based Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Malignant Disease: A Systematic Review and Meta-Analysis.

Background: Cisplatin is employed in hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery (CRS) for peritoneal surface malignancies (PSMs). The main concern regarding intraperitoneal cisplatin administration is nephrotoxicity. Numerous reports in this context are available. Our objective was to conduct a systematic review and meta-analysis to assess cisplatin-based HIPEC-related nephrotoxicity (CHRN). Methods: A systematic literature review on CHRN after CRS for the treatment of PSMs was performed. The literature search was carried out using Medline, Cochrane, and Embase. The last day of the search was 23 October 2023. PRISMA guidelines were used. A meta-analysis was then conducted. The main endpoint was the incidence of acute and chronic renal impairment after CHRN. Secondary endpoints included the potential impact of several clinical variables on the primary endpoint and a critical appraisal of the different renal impairment scales employed. Results: Our study included 26 articles with a total sample of 1473 patients. The incidence of acute kidney injury (AKI) was 18.6% (95% CI: 13.6-25%, range of true effects 3-59%). For chronic kidney disease, it was 7% (95% CI: 3-15.3%, range of true effects 1-53%). The variables that statistically influenced these results were the scale used to measure renal insufficiency, the use of nephroprotective agents, and the presence of pre-existing renal disease. Conclusions: The reported incidence of renal impairment following cisplatin-based HIPEC is highly variable. The incidence of renal failure obtained in this meta-analysis should be used as a reference for subsequent reports on this topic. Further prospective studies are warranted to establish optimal and standardized management.

Design and development of a new pictorial tool to facilitate communication around advance care planning.

BACKGROUND: Advance care planning (ACP) aims to ensure that people with chronic or advanced disease receive medical care that is consistent with their values and preferences. However, professionals may find it challenging to engage these patients in conversations about the end of life. We sought to develop a pictorial tool to facilitate communication around ACP. METHODS: This was a three-phase study. In phase 1, we used the nominal group and Delphi techniques to achieve expert consensus regarding the conceptual content of the tool. In phase 2, a professional cartoonist was commissioned to create a series of cartoons representing each of the content areas resulting from the Delphi process. The pictorial tool was then administered (phase 3) with a sample of individuals with advanced/chronic disease to explore whether the cartoons were easy to understand and conveyed the intended message. RESULTS: Following a three-round Delphi process, consensus was reached regarding a set of 12 key content areas that should be considered in the context of an ACP interview. The cartoons created to represent each of the 12 areas were then reviewed and ordered so as to reflect the typical stages of an end-of-life care interview. After administering the pictorial tool with 24 frail older adults with advanced/chronic disease, changes were made to 9 of the 12 cartoons. CONCLUSIONS: The new pictorial tool comprises a set of 12 cartoons that can guide professionals as they seek to engage frail older adults with advanced/chronic disease in conversations about the end of life and ACP.