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Examines Robert Browning's novel `The Ring and the Book,' and the ring metaphor. Browning equates the currency of a transparent text with the self-generating logic of usury. Names, like usury, literalize a figurative sign, and it is this displacement that is at the basis of Browning's ring metaphor, the parent-child configurations, and the dynamics of `reading' within the poem.

Purpose: Radiolabelled fibroblast activation protein inhibitors (FAPIs) are becoming increasingly important for imaging various tumour diseases. However, it is essential to be aware of potential pitfalls. Here, we investigate FAP expression in the thyroid gland in autoimmune thyroiditis (AIT)., Methods: AIT patients with pathological thyroid uptake on [ 68 Ga]Ga-FAPI PET were compared with glucose metabolism on 2-[ 18 F]FDG PET in terms of SUV max /SUV peak /SUV mean /tissue-to-background ratio (TBR), and with a healthy control group., Results: Between September 2019 and July 2021, 6 patients presented with a visually increased thyroid uptake and TBR on [ 68 Ga]Ga-FAPI PET. In the retrospective clinical work-up, all patients had known or newly diagnosed AIT. Compared to a matched healthy control group, FAP expression and glucose metabolism were significantly increased ([ 68 Ga]Ga-FAPI (SUV peak ): 7.0 vs. 1.7; p = 0.004/(TBR bloodpool ): 6.8 vs. 1.7; p = 0.002; 2-[ 18 F]FDG (SUV peak ): 3.9 vs. 1.4; p = 0.004/(TBR bloodpool ): 4.0 vs. 1.2; p = 0.041). However, there was no significant difference in median uptake between [ 68 Ga]Ga-FAPI and 2-[18F]FDG PET (SUV peak : 7.3 vs. 5.6; p = 0.104)., Conclusion: Patients with AIT show higher thyroid uptake on [ 68 Ga]Ga-FAPI and 2-[ 18 F]FDG PET. Incidental thyroid uptake is another pitfall in the interpretation of [ 68 Ga]Ga-FAPI PET and should prompt a clinical work-up., (© 2024. The Author(s).)

Radiosynoviorthesis is approved in several European countries and the United States to treat refractory synovitis in many inflammatory joint diseases, such as rheumatoid arthritis, spondyloarthropathies, and other arthritic joint diseases. No radiopharmaceuticals for radiosynoviorthesis are currently approved in Canada. The aim of this Health Canada-approved trial was to demonstrate the safety and efficacy of radiosynoviorthesis. Methods: Between July 2012 and November 2017, we conducted a multicenter, prospective, interventional Canadian trial. Patients ( n = 360) with synovitis refractory to standard treatments after failing 2 intraarticular glucocorticoid injections were included. They were followed up at 3, 6, and 12 mo. Outcome measures included adverse events (AEs) and clinical signs of synovitis (pain, swelling, and joint effusion) measured with the Health Assessment Questionnaire Disability Index, the Disease Activity Score, and the Visual Analog Scale. Results: In total, 392 joints were treated, including those reinjected after 6 mo ( n = 34). Of these, 83.4% (327/392) were injected with [ 90 Y]Y-citrate for the knees and 9.9% (39/392) with [ 186 Re]Re-sulfide for medium-sized joints. Of the joints treated, 82.7% (324/392) were knees. Fifty-five AEs, most of them of mild grade, occurred and resolved without sequelae and were not life-threatening. The incidence of radiosynoviorthesis-related AEs was 9.4% (34/360). The proportion of patients showing an improvement in synovitis symptoms after radiosynoviorthesis was significant at 3 mo and was maintained up to 12 mo ( P < 0.001). Conclusion: This study confirmed the safety of radiosynoviorthesis in the treatment of patients with synovitis refractory to standard treatments. There is evidence of sustained clinical efficacy at 12 mo, suggesting that radiosynoviorthesis is an effective treatment for improving synovitis symptoms., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Prospective results have demonstrated favorable safety and efficacy of [ 177 Lu]Lu-PSMA radiopharmaceutical therapy for up to 6 cycles in men with metastatic castration-resistant prostate cancer. However, no systematic data are available outlining the feasibility of extended therapy beyond 6 cycles. We aim to evaluate the safety and efficacy of extended [ 177 Lu]Lu-PSMA radiopharmaceutical therapy in patients who have received more than 6 cycles. Methods: In total, 111 patients were included in this multicenter retrospective analysis. Based on individual decisions, patients underwent uninterrupted continuation of therapy (continuous treatment) or reexposure after a therapy break (rechallenge treatment) between 2014 and 2023. Overall survival, 50% prostate-specific antigen (PSA) decline (measured 8-12 wk after treatment initiation or rechallenge), PSMA PET response, and grades per Common Terminology Criteria for Adverse Events were assessed. χ 2 tests, multivariable Cox regression analysis, and log-rank tests were applied for statistical analyses. Results: Patients received extended treatment with [ 177 Lu]Lu-PSMA, either as a continuous treatment (43/111, 38.7%) or as a rechallenge (68/111, 61.3%) treatment, with median cumulative doses of 57.4 or 60.8 GBq, respectively. Overall survival from the initiation of [ 177 Lu]Lu-PSMA was 31.3, 23.2, and 40.2 mo for the entire cohort, the continuous treatment group, and the rechallenge treatment group, respectively. The initial 50% PSA decline was significantly higher in the retreated group than in the continuous group (57/63 [90.4%] vs. 26/42 [61.9%]; P = 0.006). A 50% PSA decline was observed in 23 of 62 patients (37.1%) after the first rechallenge. The rate of grades 3-4 toxicity was comparable between continuous and rechallenge treatments (anemia, 7/43 [16.3%] vs. 13/68 [19.1%)], P = 0.6; leukocytopenia, 1/43 [2.3%] vs. 2/67 [3.0%], P = 0.3; thrombocytopenia, 3/43 [7.0%] vs. 3/68 [4.4%], P = 0.3; renal, 2/43 [4.7%] vs. 5/68 [7.4%], P = 0.2). Conclusion: Extended therapy with [ 177 Lu]Lu-PSMA is safe and has not been associated with increased grades 3-4 toxicity. Patient candidates for extended treatment experienced a favorable median survival of 31.3 mo from the first administration. Response under [ 177 Lu]Lu-PSMA rechallenge demonstrated preserved efficacy of [ 177 Lu]Lu-PSMA after a treatment break., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Fibroblast activation protein-α (FAP) is often highly expressed by sarcoma cells and by sarcoma-associated fibroblasts in the tumor microenvironment. This makes it a promising target for imaging and therapy. The level of FAP expression and the diagnostic value of 68 Ga-FAP inhibitor (FAPI) PET for sarcoma subtypes are unknown. We assessed the diagnostic performance and accuracy of 68 Ga-FAPI PET in various bone and soft-tissue sarcomas. Potential eligibility for FAP-targeted radiopharmaceutical therapy (FAP-RPT) was evaluated. Methods: This prospective observational trial enrolled 200 patients with bone and soft-tissue sarcoma who underwent 68 Ga-FAPI PET/CT and 18 F-FDG PET/CT (186/200, or 93%) for staging or restaging. The number of lesions detected and the uptake (SUV max ) of the primary tumor, lymph nodes, and visceral and bone metastases were analyzed. The Wilcoxon test was used for semiquantitative assessment. The association of 68 Ga-FAPI uptake intensity, histopathologic grade, and FAP expression in sarcoma biopsy samples was analyzed using Spearman r correlation. The impact of 68 Ga-FAPI PET on clinical management was investigated using questionnaires before and after PET/CT. Eligibility for FAP-RPT was defined by an SUV max greater than 10 for all tumor regions. Results: 68 Ga-FAPI uptake was heterogeneous among sarcoma subtypes. The 3 sarcoma entities with the highest uptake (mean SUV max ± SD) were solitary fibrous tumor (24.7 ± 11.9), undifferentiated pleomorphic sarcoma (18.8 ± 13.1), and leiomyosarcoma (15.2 ± 10.2). Uptake of 68 Ga-FAPI versus 18 F-FDG was significantly higher in low-grade sarcomas (10.4 ± 8.5 vs. 7.0 ± 4.5, P = 0.01) and in potentially malignant intermediate or unpredictable sarcomas without a World Health Organization grade (not applicable [NA]; 22.3 ± 12.5 vs. 8.5 ± 10.0, P = 0.0004), including solitary fibrous tumor. The accuracy, as well as the detection rates, of 68 Ga-FAPI was higher than that of 18 F-FDG in low-grade sarcomas (accuracy, 92.2 vs. 80.0) and NA sarcomas (accuracy, 96.9 vs. 81.9). 68 Ga-FAPI uptake and the histopathologic FAP expression score ( n = 89) were moderately correlated (Spearman r = 0.43, P < 0.0002). Of 138 patients, 62 (45%) with metastatic sarcoma were eligible for FAP-RPT. Conclusion: In patients with low-grade and NA sarcomas, 68 Ga-FAPI PET demonstrates uptake, detection rates, and accuracy superior to those of 18 F-FDG PET. 68 Ga-FAPI PET criteria identified eligibility for FAP-RPT in about half of sarcoma patients., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Musculoskeletal disorders of nononcological origin are one of the most frequent reasons for consultation. Patients suffering from musculoskeletal disorders also consult more than once for the same reason. This results in multiple clinical follow-ups after several radiological and serum examinations, the main ones including X-rays targeting the painful anatomical region and inflammatory serum parameters. As part of their work up, patients suffering from musculoskeletal disorders often require multisequence, multi-parameter MRI. PET/MRI is a promising imaging modality for their diagnosis, with the added advantage of being able to be performed in a single visit. PET/MRI is particularly useful for diagnosing osteomyelitis, spondylodiscitis, arthritis, many pediatric pathologies, and a wide range of other musculoskeletal pathologies. PET/MRI is already used to diagnose malignant bone tumors such as osteosarcoma. However, current knowledge of the indications for PET/MRI in nononcological musculoskeletal disorders is based on studies involving only a few patients. This review focuses on the usefulness of PET/MRI for diagnosing nononcological musculoskeletal disorders., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tugce Telli reports a relationship with ABX GmbH that includes: speaking and lecture fees. Robert Seifert reports a relationship with Böhringer Ingelheim Fonds and Else Köner-Fresenius-Stiftung that includes: funding grants. Wolfgang P. Fendler reports a relationship with Janssen Pharmaceuticals Inc, Calyx Chemicals and Pharmaceuticals Ltd, Novartis Pharmaceuticals Corporation, Telix Pharmaceuticals Limited, GE Healthcare, Eczacibasi Pharmaceuticals Marketing, ABX GmbH, and Amgen Inc that includes: consulting or advisory, funding grants, and speaking and lecture fees. Federico Caobelli reports a relationship with Siemens Healthineers, Bracco AG and Pfizer AG that includes: funding grants and speaking and lecture fees. Additionally, Wolfgang P. Fendler reports fees from SOFIE Bioscience (Research funding) and Bayer (consultant, speaker, research finding). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The other authors declare no conflict of interest regarding this manuscript., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Vaccinia virus (VACV) is a double-stranded DNA virus that devotes a large portion of its 200 kbp genome to suppressing and manipulating the immune response of its host. Here, we investigated how targeted removal of immunomodulatory genes from the VACV genome impacted immune cells in the tumor microenvironment with the intention of improving the therapeutic efficacy of VACV in breast cancer. We performed a head-to-head comparison of six mutant oncolytic VACVs, each harboring deletions in genes that modulate different cellular pathways, such as nucleotide metabolism, apoptosis, inflammation, and chemokine and interferon signaling. We found that even minor changes to the VACV genome can impact the immune cell compartment in the tumor microenvironment. Viral genome modifications had the capacity to alter lymphocytic and myeloid cell compositions in tumors and spleens, PD-1 expression, and the percentages of virus-targeted and tumor-targeted CD8 + T cells. We observed that while some gene deletions improved responses in the nonimmunogenic 4T1 tumor model, very little therapeutic improvement was seen in the immunogenic HER2/ neu TuBo model with the various genome modifications. We observed that the most promising candidate genes for deletion were those that interfere with interferon signaling. Collectively, this research helped focus attention on the pathways that modulate the immune response in the context of VACV oncolytic virotherapy. They also suggest that the greatest benefits to be obtained with these treatments may not always be seen in "hot tumors.", (©2020 American Association for Cancer Research.)

Up to 30% of patients with stage II (pN0) colon cancer develop recurrences, suggesting that the presence of lymph node (LN) metastases escaped detection at histopathologic staging. A simple way to overcome this limitation and to improve staging accuracy is to use reverse transcription-polymerase chain reaction (RT-PCR) to examine a larger fraction or an entire specimen. The Guanylyl cyclase C (GCC) gene is uniquely expressed in apical cells of the gastrointestinal tract. Its expression in colon cancer cells and metastases is conserved. Therefore, detection of GCC mRNA in LNs has been shown to be indicative of the presence of colon cancer metastases. As the current processing of LNs involves formalin fixation and paraffin embedding, we developed a method for extracting RNA from formalin-fixed paraffin-embedded LN specimens and detecting GCC mRNA by quantitative RT-PCR. The assay has a dynamic range of 5 logs, an average amplification efficiency of 98.4% (95% confidence interval, 96.6-100.3), a reaction linearity of 0.998 (95% confidence interval, 0.997-0.999), and also intraplate and interplate CVs of <1% and <5%, respectively. The test specificity was 98% with LNs collected from patients affected by conditions other than colon cancer (n=380). Sensitivity was 97% for patients with stage III colon cancer (n=34), whereas 35% of patients with stages I and II disease (n=51) had at least 1 GCC mRNA-positive LN. The high specificity of GCC mRNA suggests that routine utilization of the quantitative RT-PCR test has the potential to improve the detection of colon cancer metastases in LNs.

Objectives: Men with elevated serum prostate-specific antigen (PSA) levels and negative prostate biopsy findings present a dilemma because of the lack of an accurate diagnostic test. We evaluated the potential utility of the investigational prostate cancer gene 3 (PCA3) urine assay to predict the repeat biopsy outcome., Methods: Urine was collected after digital rectal examination (three strokes per lobe) from 233 men with serum PSA levels persistently 2.5 ng/mL or greater and at least one previous negative biopsy. The specimens were collected from April 2004 to January 2006. The PCA3 scores were determined using a highly sensitive quantitative assay with transcription-mediated amplification. The ability of the PCA3 score to predict the biopsy outcome was assessed and compared with the serum PSA levels., Results: The RNA yield was adequate for analysis in the urine samples from 226 of 233 men (ie, the informative specimen rate was 97%). Repeat biopsy revealed prostate cancer in 60 (27%) of the of 226 remaining subjects. Receiver operating characteristic curve analysis yielded an area under the curve of 0.68 for the PCA3 score. In contrast, the area under the curve for serum PSA was 0.52. Using a PCA3 score cutoff of 35, the assay sensitivity was 58% and specificity 72%, with an odds ratio of 3.6. At PCA3 scores of less than 5, only 12% of men had prostate cancer on repeat biopsy; at PCA3 scores greater than 100, the risk of positive biopsy was 50%., Conclusions: In men undergoing repeat prostate biopsy to rule out cancer, the urinary PCA3 score was superior to serum PSA determination for predicting the biopsy outcome. The high specificity and informative rate suggest that the PCA3 assay could have an important role in prostate cancer diagnosis.

Background: Diversity of clinical reasoning paths of thought among experts is well known. Nevertheless, in written clinical reasoning assessment, the common practice is to ask experts to reach a consensus on each item and to assess students on a unique "good answer.", Purposes: To explore the effects of taking the variability of experts answers into account in a method of clinical reasoning assessment based on authentic tasks: the Script Concordance Test., Methods: Two different methods were used to build answer keys. The first incorporated variability among a group of experts (criterion experts) through an aggregate scoring method. The second was made with the consensus obtained from the group of criterion experts for each answer. Scores obtained with the two methods by students and another group of experts (tested experts) were compared. The domain of assessment was gynecology-obstetric clinical knowledge. The sample consisted of 150 clerkship students and seven other experts (tested experts)., Results: In a context of authentic tasks, experts' answers on items varied substantially. Amazingly, 59% of answers given individually by criterion group experts differed from the answer they provided when they were asked in a group to provide the "good answer" required from students. The aggregate scoring method showed several advantages and was more sensitive to detecting expertise., Conclusions: The findings suggest that, in assessment of complex performance in ill-defined situations, the usual practice of asking experts to reach a consensus on each item reduces and hinders the detection of expertise. If these results are confirmed by other researches, this practice should be reconsidered.

Although there are numerous minor histocompatibility antigens (MiHA), T cell responses leading to graft-versus-host (GVH) and graft-versus-tumor effects involve only a small number of immunodominant MiHA. The goal of the present study was to analyze at the cellular and molecular levels the mechanisms responsible for MiHA immunodominance. Cytotoxic T lymphocytes (CTL) generated in eight combinations of H2b strains of mice were tested against syngeneic targets sensitized with HPLC-fractionated peptides eluted from immunizing cells. The number of dominant MiHA was found to range from as little as two up to ten depending on the strain combination used. The nature of dominant MiHA was influenced by both the antigen profile of the antigen-presenting cells (APC) and the repertoire of responding CTL. When C57BL/6 dominant MiHA (B6dom) and H-Y were presented on separate APC, they showed similar immunogenicity. In contrast, when they were presented on the same APC, B6dom MiHA totally dominated H-Y. B6dom MiHA did not suppress anti-H-Y responses by acting as T cell receptor antagonists for anti-H-Y CTL, nor were anti-B6dom CTL precursors more abundant than anti-H-Y CTL precursors. Dominance resulted from competition for the APC surface between anti-B6dom and anti-H-Y CTL; the crucial difference between the dominant and the dominated MiHA appears to depend on the differential avidity of their respective CTL for APC. The only B6dom epitope thus far identified is the nonapeptide AAPDNRETF presented by H2-D(b). We found that compared with other known D(b)-binding peptides, AAPDNRETF is expressed at very high levels on the cell surface, binds to the D(b) molecule with very high affinity, and dissociates very slowly from its presenting class I molecule. These data indicate that one cannot predict which MiHA will be dominant or dominated based simply on their respective immunogenicity when presented on separate APC. Indeed, the avidity of T cell/APC interactions appears to determine which antigen(s) will trigger T cell responses when numerous epitopes are presented by the same APC.

Nurses from a CLSC in Hull, Quebec are defining a positive role for community health nurses in a multidisciplinary environment. They base their professional day-to-day practice on Orem's conceptual nursing framework. Many of these home care nurses studied in a post-RN baccalaureate nursing program at the University of Quebec in Hull, where they learned different aspects of conceptual frameworks and the nursing process. Two nurse clinicians and a nurse administrator submitted a project based on Orem's model to the administrators of their community health centre. Once it was approved, a nursing professor from the university agreed to act as a consultant and principal researcher to implement the process. The authors describe this three-year collaborative project between home care nurses and the researcher. This includes its objectives, the participants' roles, the tools developed, the process, and the repercussions on nursing care, nurses, and the multidisciplinary team.