Development of an automated production process of [64Cu][Cu (ATSM)] for positron emission tomography imaging and theranostic applications

Cyclotron-produced copper-64 radioisotope tracers offer the possibility to perform both diagnostic investigation by positron emission tomography (PET) and radiotherapy by a theranostic approach with bifunctional chelators. The versatile chemical properties of copper add to the importance of this isotope in medicinal investigation. [⁶⁴Cu][Cu (ATSM)] has shown to be a viable candidate for imaging of tumor hypoxia; a critical tumor microenvironment characteristic that typically signifies tumor progression and resistance to chemo-radiotherapy. Various production and radiosynthesis methods of [⁶⁴Cu][Cu (ATSM)] exist in labs, but usually involved non-standardized equipment with varying production qualities and may not be easily implemented in wider hospital settings. [⁶⁴Cu][Cu (ATSM)] was synthesized on a modified GE TRACERlab FXN automated synthesis module. End-of-synthesis (EOS) molar activity of [⁶⁴Cu][Cu (ATSM)] was 2.2–5.5 Ci/μmol (HPLC), 2.2–2.6 Ci/μmol (ATSM-titration), and 3.0–4.4 Ci/μmol (ICP-MS). Radiochemical purity was determined to be >99% based on radio-HPLC. The final product maintained radiochemical purity after 20 h. We demonstrated a simple and feasible process development and quality control protocols for automated cyclotron production and synthesis of [⁶⁴Cu][Cu (ATSM)] based on commercially distributed standardized synthesis modules suitable for PET imaging and theranostic studies.     

The Cost-Effectiveness of Intermediate-Acting,Long-Acting,Ultralong-Acting,and Biosimilar Insulins for Type 1 Diabetes Mellitus: A Systematic Review

ObjectivesThe incidence of type 1 diabetes mellitus is increasing every year requiring substantial expenditure on treatment and complications. A systematic review was conducted on the cost-effectiveness of insulin formulations, including ultralong-, long-, or intermediate-acting insulin, and their biosimilar insulin equivalents.MethodsMEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, HTA, and NHS EED were searched from inception to June 11, 2021. Cost-effectiveness and cost-utility analyses were included if insulin formulations in adults (≥ 16 years) with type 1 diabetes mellitus were evaluated. Two reviewers independently screened titles, abstracts, and full-text articles, extracted study data, and appraised their quality using the Drummond 10-item checklist. Costs were converted to 2020 US dollars adjusting for inflation and purchasing power parity across currencies.ResultsA total of 27 studies were included. Incremental cost-effectiveness ratios ranged widely across the studies. All pairwise comparisons (11 of 11, 100%) found that ultralong-acting insulin was cost-effective compared with other long-acting insulins, including a long-acting biosimilar. Most pairwise comparisons (24 of 27, 89%) concluded that long-acting insulin was cost-effective compared with intermediate-acting insulin. Few studies compared long-acting insulins with one another.ConclusionsLong-acting insulin may be cost-effective compared with intermediate-acting insulin. Future studies should directly compare biosimilar options and long-acting insulin options and evaluate the long-term consequences of ultralong-acting insulins.     

How do peer support interventions for the self-management of chronic pain,support basic psychological needs? A systematic review and framework synthesis using self-determination theory

ObjectiveTo identify how peer support interventions, for self-management of chronic pain, support basic psychological needs from a self-determination theory (SDT) perspective, using a systematic review.MethodsTen databases were searched for studies reporting qualitative research about peer interactions in pain management interventions. ‘Best fit’ framework synthesis methodology was applied to identify strategies that support the satisfaction of competence, autonomy and motivation. These were matched to definitions of strategies provided by standardised taxonomies.Results18 studies were selected for inclusion. The synthesis resulted in a conceptual model, identifying 12 peer strategies that support psychological needs for self-management of chronic pain; 10 overlapped with existing taxonomies.ConclusionThis was the first known attempt to synthesise evidence about peer support strategies for people living with pain, using SDT as an a priori framework. The model demonstrates commonality between the motivation-promoting processes of peer support and those of other behaviour change interventions and identifies additional unique strategies provided by peers. This systematic classification of peer support strategies provides a means for future study of the efficacy and comprehensiveness of peer interventions.Practice implicationsThe model could assist healthcare professionals and support groups to optimise the potential of peer processes.     

Weekly and seasonal variation in the circadian melatonin rhythm in humans: A response

We read with interest the commentary by Skeldon and Dijk about our article “Weekly, seasonal and chronotype-dependent variation of dim light melatonin onset.” The discussion points raised by Skeldon and Dijk are currently among the most hotly debated in human circadian science. What external factors determine human phase of entrainment? How great is the contribution of natural versus artificial light and sun time versus social time? Our intra-individual data add to the still limited evidence from field studies in this matter. In their commentary, Skeldon and Dijk formulate two either-or hypotheses, postulating that humans entrain either solely to the natural light-dark cycle (sun time referenced by midday) (H₁) or solely to the light selected by local clock time and social constraints (H₂). Neither hypothesis accounts for the effect of season on human light exposure. We interpreted our findings along more complex lines, speculating that the 1-h earlier melatonin rise in summer found in our sample is likely the combined result of daylight saving time (DST)-induced behavioral advances and a stronger natural zeitgeber in summer (light exposure determined by social and seasonal factors, H_original). Here, we show how the criticism by Skeldon and Dijk is based on two sentences quoted out of context (misrepresenting our hypothesis as H₁) and that their hypothesis H₂ leaves out important seasonal components in light exposure.     

Role of serum and synovial procalcitonin in differentiating septic from non-septic arthritis- a prospective study

IntroductionSeptic arthritis is a serious orthopaedic emergency that must be diagnosed and managed early to prevent devastating complications. The current gold standard for diagnosing septic arthritis is synovial fluid culture, but results are delayed by 48–72 h, and the sensitivity of the test is very low. Differentiating Septic from non-septic arthritis is vital to prevent unnecessary use of antibiotics and prevent complications. Serum Procalcitonin (PCT) is a useful marker in differentiating septic from non-septic arthritis but there are very few studies that have studied the role of synovial PCT for the same.AimTo determine the role of serum and synovial PCT in differentiating acute Septic from non-septic arthritis.Materials and methodsProspective clinical study in which 60 patients presenting with acute inflammatory arthritis (<2 weeks duration) were enrolled from May 2018 to May 2020. Serum and synovial fluid samples were drawn at presentation and routine blood investigations, synovial fluid culture sensitivity, and Procalcitonin levels were measured. Patients were divided into 3 groups, with group-1 having confirmed pyogenic, group-2 having presumed pyogenic, and group-3 having non –pyogenic patients, respectively. All data was tabulated and statistically analysed using appropriate tests.ResultsMean serum PCT values in groups 1, 2 and 3 were 1.06 ± 1.11, 0.85 ± 0.74, and 0.11 ± 0.24, respectively. Patients in the Pyogenic group (group1 and group 2) had significantly higher mean serum PCT as compared to group3 (p < 0.0001). Group 1 had higher serum PCT as compared to group 2, but the difference was not significant (p = 0.58). Mean synovial PCT in group 1, 2 and 3 were 2.42 ± 1.98, 1.89 ± 1.18, and 0.22 ± 0.40, respectively. Patients in the Pyogenic group (Group1 and Group2) had significantly higher mean synovial PCT as compared to Group 3 (p < 0.0001). Group 1 had higher mean synovial PCT as compared to group 2, but the difference was not significant (p = 0.54). The area under the ROC curve of the serum levels of PCT was 0.0.895, and the area under the ROC curve of the synovial fluid levels of PCT was 0.914, which was higher than the serum PCT level.ConclusionSerum and synovial Procalcitonin may be used as a diagnostic marker in differentiating septic from inflammatory arthritis and can help in reducing unnecessary use of antibiotics and early diagnosis and management of septic arthritis, thereby preventing complications.     

Comparison of quantitative susceptibility mapping methods on evaluating radiation-induced cerebral microbleeds and basal ganglia at 3T and 7T

Quantitative susceptibility mapping (QSM) has the potential for being a biomarker for various diseases because of its ability to measure tissue susceptibility related to iron deposition, myelin, and hemorrhage from the phase signal of a T₂*-weighted MRI. Despite its promise as a quantitative marker, QSM is faced with many challenges, including its dependence on preprocessing of the raw phase data, the relatively weak tissue signal, and the inherently ill posed relationship between the magnetic dipole and measured phase. The goal of this study was to evaluate the effects of background field removal and dipole inversion algorithms on noise characteristics, image uniformity, and structural contrast for cerebral microbleed (CMB) quantification at both 3T and 7T. We selected four widely used background phase removal and five dipole field inversion algorithms for QSM and applied them to volunteers and patients with CMBs, who were scanned at two different field strengths, with ground truth QSM reference calculated using multiple orientation scans. 7T MRI provided QSM images with lower noise than did 3T MRI. QSIP and VSHARP + iLSQR achieved the highest white matter homogeneity and vein contrast, with QSIP also providing the highest CMB contrast. Compared with ground truth COSMOS QSM images, overall good correlations between susceptibility values of dipole inversion algorithms and the COSMOS reference were observed in basal ganglia regions, with VSHARP + iLSQR achieving the susceptibility values most similar to COSMOS across all regions. This study can provide guidance for selecting the most appropriate QSM processing pipeline based on the application of interest and scanner field strength.     

First‐in‐human phase I study of E7090, a novel selective fibroblast growth factor receptor inhibitor,in patients with advanced solid tumors

Fibroblast growth factor receptors (FGFR) are a family of transmembrane receptor tyrosine kinases involved in regulating cellular processes. FGFR mutations are implicated in oncogenesis, representing therapeutic potential in the form of FGFR inhibitors. This phase I, first‐in‐human study in Japan evaluated safety and tolerability of E7090, a potent selective FGFR1‐3 inhibitor, in patients with advanced solid tumors. Dose escalation (daily oral dose of 1‐180 mg) was carried out to assess dose‐limiting toxicity (DLT), maximum tolerated dose, and pharmacokinetics. Pharmacodynamic markers (serum phosphate, fibroblast growth factor 23, and 1,25‐(OH)₂‐vitamin D) were also evaluated. A total of 24 patients refractory to standard therapy or for whom no appropriate treatment was available were enrolled. No DLT were observed up to the 140‐mg dose; one patient in the 180‐mg cohort experienced a DLT (increased aspartate aminotransferase/alanine aminotransferase, grade 3). The maximum tolerated dose was not reached. Dose‐dependent increases in the maximum concentration and area under the curve from time 0 to the last measurable concentration were observed up to 180 mg. Dose‐dependent increases were observed in all pharmacodynamic markers and plateaued at 100‐140 mg, indicating sufficient FGFR pathway inhibition at doses ≥100 mg. In conclusion, E7090 showed a manageable safety profile with no DLT at doses ≤140 mg. Maximum tolerated dose was not determined. The recommended dose for the follow‐up expansion part, restricted to patients with tumors harboring FGFR alterations, was determined as 140 mg, once daily.     

胰腺囊性肿瘤诊疗及进展

胰腺囊性肿瘤(PCNs)是少见肿瘤，发病原因尚不明确，不良生活习惯（吸烟、饮酒、重咖啡、高脂高蛋白饮食等）、慢性胰腺炎、环境污染因素及遗传因素等是潜在致病因素。PCNs分为浆液性囊性肿瘤（SCN）、黏液性囊性肿瘤（MCN）、胰腺导管内乳头状黏液肿瘤(IPMN)和实性假乳头状瘤（SPN）四种类型。发病症状常不典型，早期诊断难。PCNs具有典型影像特点，单个影像检查技术对PCNs的准确性和局限性不同，CT检查在胰腺病变中仍是最基本、最主要的检查方式。MRI对于小的囊性病灶比CT更有优势。超声内镜（EUS）充分结合了内镜和超声检查的优势，与CT、MRI检查相辅相成，同时还可进行细针穿刺取病理及囊液分析。尽管PCNs大部分为良性，但只要达到切除标准，均应推荐患者进行手术治疗，严格遵循PCNs诊治流程，制订个体化PCNs治疗策略，使患者利益最大化。