Learning the facts in medical school is not enough: which factors predict successful application of procedural knowledge in a laboratory setting?

BACKGROUND: Medical knowledge encompasses both conceptual (facts or “what” information) and procedural knowledge (“how” and “why” information). Conceptual knowledge is known to be an essential prerequisite for clinical problem solving. Primarily, medical students learn from textbooks and often struggle with the process of applying their conceptual knowledge to clinical problems. Recent studies address the question of how to foster the acquisition of procedural knowledge and its application in medical education. However, little is known about the factors which predict performance in procedural knowledge tasks. Which additional factors of the learner predict performance in procedural knowledge? METHODS: Domain specific conceptual knowledge (facts) in clinical nephrology was provided to 80 medical students (3(rd) to 5(th) year) using electronic flashcards in a laboratory setting. Learner characteristics were obtained by questionnaires. Procedural knowledge in clinical nephrology was assessed by key feature problems (KFP) and problem solving tasks (PST) reflecting strategic and conditional knowledge, respectively. RESULTS: Results in procedural knowledge tests (KFP and PST) correlated significantly with each other. In univariate analysis, performance in procedural knowledge (sum of KFP+PST) was significantly correlated with the results in (1) the conceptual knowledge test (CKT), (2) the intended future career as hospital based doctor, (3) the duration of clinical clerkships, and (4) the results in the written German National Medical Examination Part I on preclinical subjects (NME-I). After multiple regression analysis only clinical clerkship experience and NME-I performance remained independent influencing factors. CONCLUSIONS: Performance in procedural knowledge tests seems independent from the degree of domain specific conceptual knowledge above a certain level. Procedural knowledge may be fostered by clinical experience. More attention should be paid to the interplay of individual clinical clerkship experiences and structured teaching of procedural knowledge and its assessment in medical education curricula

The maximum standardized uptake value in patients with recurrent or persistent prostate cancer after radical prostatectomy and PSMA-PET-guided salvage radiotherapy-a multicenter retrospective analysis

Purpose This study aims to evaluate the association of the maximum standardized uptake value (SUVmax) in positron-emission tomography targeting prostate-specific membrane antigen (PSMA-PET) prior to salvage radiotherapy (sRT) on biochemical recurrence free survival (BRFS) in a large multicenter cohort.Methods Patients who underwent (68) Ga-PSMA11-PET prior to sRT were enrolled in four high-volume centers in this retrospective multicenter study. Only patients with PET-positive local recurrence (LR) and/or nodal recurrence (NR) within the pelvis were included. Patients were treated with intensity-modulated-sRT to the prostatic fossa and elective lymphatics in case of nodal disease. Dose escalation was delivered to PET-positive LR and NR. Androgen deprivation therapy was administered at the discretion of the treating physician. LR and NR were manually delineated and SUVmax was extracted for LR and NR. Cox-regression was performed to analyze the impact of clinical parameters and the SUVmax-derived values on BRFS.Results Two hundred thirty-five patients with a median follow-up (FU) of 24 months were included in the final cohort. Two-year and 4-year BRFS for all patients were 68% and 56%. The presence of LR was associated with favorable BRFS (p = 0.016). Presence of NR was associated with unfavorable BRFS (p = 0.007). While there was a trend for SUVmax values >= median (p = 0.071), SUVmax values >= 75% quartile in LR were significantly associated with unfavorable BRFS (p = 0.022, HR: 2.1, 95%CI 1.1-4.6). SUVmax value in NR was not significantly associated with BRFS. SUVmax in LR stayed significant in multivariate analysis (p = 0.030). Sensitivity analysis with patients for who had a FU of > 12 months (n = 197) confirmed these results.Conclusion The non-invasive biomarker SUVmax can prognosticate outcome in patients undergoing sRT and recurrence confined to the prostatic fossa in PSMA-PET. Its addition might contribute to improve risk stratification of patients with recurrent PCa and to guide personalized treatment decisions in terms of treatment intensification or de-intensification. This article is part of the Topical Collection on Oncology-Genitourinary

Suppression of intratumoral CCL22 by type I interferon inhibits migration of regulatory T cells and blocks cancer progression

The chemokine CCL22 is abundantly expressed in many types of cancer and is instrumental for intratumoral recruitment of regulatory T cells (Treg), an important subset of immunosuppressive and tumor-promoting lymphocytes. In this study, we offer evidence for a generalized strategy to blunt Treg activity that can limit immune escape and promote tumor rejection. Activation of innate immunity with Toll-like receptor (TLR) or RIG-I-like receptor (RLR) ligands prevented accumulation of Treg in tumors by blocking their immigration. Mechanistic investigations indicated Treg blockade was a consequence of reduced intratumoral CCL22 levels caused by type I interferon. Notably, stable expression of CCL22 abrogated the antitumor effects of treatment with RLR or TLR ligands. Taken together, our findings argue that type I interferon blocks the Treg-attracting chemokine CCL22 and thus helps limit the recruitment of Treg to tumors, a finding with implications for cancer immunotherapy

In breast cancer, a high ratio of tumour-infiltrating intraepithelial CD8+ to FoxP3+ cells is characteristic for the medullary subtype

Aims:  Medullary breast cancer (MBC) is a biologically distinct subtype of breast cancer characterized by prominent lymphocytic infiltrates and a favourable clinical outcome. Tumour-infiltrating CD8+ effector T cells may contribute to the good prognosis of this type of cancer; however, certain subtypes of lymphocyte, such as FoxP3+ regulatory T cells (Tregs), can also suppress antitumour immunity.Methods and results:  We determined tumour infiltration by FoxP3+, CCL22+ and CD8+ cells in paraffin-embedded sections of MBC, and, as a reference, in samples of grade 3 ductal, lobular and mucinous breast cancer. All analysed MBCs were strongly infiltrated by FoxP3+ cells, whereas only weak infiltrates were detected in ductal or lobular breast cancer. This finding was unexpected, given the good prognosis of MBC. Strikingly, the number of CD8+ T cells exceeded the number of FoxP3+ cells in MBC (ratio of CD8+ to FoxP3+ cells of 2.6), whereas equal amounts of both cell types were found in ductal breast cancer (ratio of CD8+ to FoxP3+ cells of 1.1). In both types of breast cancer, we also detected cells expressing the Treg-attracting chemokine CCL22.Conclusions:  In breast cancer, a predominance of tumour-infiltrating CD8+ over FoxP3+ cells was observed in MBC. Thus, the ratio of CD8+ to FoxP3+ cells rather than the absolute number of intratumoral FoxP3+ cells may be predictive for the clinical outcome of cancer

Suppression of Intratumoral CCL22 by Type I Interferon Inhibits Migration of Regulatory T Cells and Blocks Cancer Progression

The chemokine CCL22 is abundantly expressed in many types of cancer and is instrumental for intratumoral recruitment of regulatory T cells (Treg), an important subset of immunosuppressive and tumor-promoting lymphocytes. In this study, we offer evidence for a generalized strategy to blunt Treg activity that can limit immune escape and promote tumor rejection. Activation of innate immunity with Toll-like receptor (TLR) or RIG-I-like receptor (RLR) ligands prevented accumulation of Treg in tumors by blocking their immigration. Mechanistic investigations indicated that Treg blockade was a consequence of reduced intratumoral CCL22 levels caused by type I IFN. Notably, stable expression of CCL22 abrogated the antitumor effects of treatment with RLR or TLR ligands. Taken together, our findings argue that type I IFN blocks the Treg-attracting chemokine CCL22 and thus helps limit the recruitment of Treg to tumors, a finding with implications for cancer immunotherapy

Almost 10 years of PET/MR attenuation correction: the effect on lesion quantification with PSMA: clinical evaluation on 200 prostate cancer patients

Purpose!#!After a decade of PET/MR, the case of attenuation correction (AC) remains open. The initial four-compartment (air, water, fat, soft tissue) Dixon-based AC scheme has since been expanded with several features, the latest being MR field-of-view extension and a bone atlas. As this potentially changes quantification, we evaluated the impact of these features in PET AC in prostate cancer patients.!##!Methods!#!Two hundred prostate cancer patients were examined with either !##!Results!#!High correlation and no visually perceivable differences between all evaluated methods (r > 0.996) were found. The mean relative difference in lesion uptake of !##!Conclusions!#!Based on these results and the encountered bone atlas registration inaccuracy, we deduce that including bones and extending the MR field-of-view did not introduce clinically significant differences in PSMA diagnostic accuracy and tracer uptake quantification in prostate cancer pelvic lesions, facilitating the analysis of serial studies respectively. However, in the absence of ground truth data, we advise against atlas-based methods when comparing serial scans for bone lesions

Diagnostic performance of quantitative and qualitative parameters for the diagnosis of aortic graft infection using [18F]-FDG PET/CT

Purpose The aim of this study was the evaluation of quantitative and qualitative parameters for the diagnosis of aortic graft infection (AGI) using [F-18]-FDG PET/CT. Methods PET/CT was performed in 50 patients with clinically suspected AGI. 12 oncological patients with aortic repair but without suspicion of AGI were included in the analysis to serve as control cohort. The [F-18]-FDG uptake pattern around the graft was assessed using (a) a five-point visual grading scale (VGS), (b) SUV(max)and (c) different graft-to-background ratios (GBRs). The diagnostic performance of VGS, SUV(max)and GBRs was assessed and compared by ROC analysis. Results 28 infected and 34 uninfected grafts were identified by standard of reference. SUV(max)and VGS were the most powerful predictors for the diagnosis of AGI according to the area under the curve (AUC 0.988 and 0.983, respectively) without a significant difference compared to GBRs. SUV(max)and VGS showed congruent and accurate findings in 54 patients (i.e. either both positive or negative), yielding sensitivity and specificity (100%) in this subgroup of patients. Conclusion Quantitative analysis by SUV(max)and qualitative analysis by VGS are highly effective in the diagnosis of AGI and should be tested as an outcome measure in prospective trials

Preclinical comparison of [177Lu]Lu-rhPSMA-10.1 and [177Lu]Lu-rhPSMA-10.2 for endoradiotherapy of prostate cancer: biodistribution and dosimetry studies

Abstract Background Radiohybrid PSMA-targeted ligands (rhPSMA) have been introduced as a novel platform for theranostic applications. Among a variety of rhPSMA-ligands developed for radioligand therapy, two stereoisomers [177Lu]Lu-rhPSMA-10.1 and -10.2 have been synthesized and initially characterized in preclinical experiments with the aim to provide an optimized binding profile to human serum albumin, a reduction of charge, and thus accelerated kidney excretion, and unaffected or even improved tumor uptake. As both isomers showed similar in vitro characteristics and tumor uptake at 24 h post injection in tumor bearing mice and in order to identify the isomer with the most favorable pharmacokinetics for radioligand therapy, we carried out in-depth biodistribution and dosimetry studies in tumor-bearing and healthy mice. Results rhPSMA-10.1 and -10.2 were radiolabeled with lutetium-177 according to the established procedures of other DOTA-based PSMA ligands and displayed a high and comparable stability in all buffers and human serum (> 97%, 24 h). Biodistribution studies revealed fast clearance from the blood pool (0.3–0.6%ID/g at 1 h) and other background tissues within 48 h. Distinctive differences were found in the kidneys, where [177Lu]Lu-rhPSMA-10.1 displayed lower initial uptake and faster excretion kinetics compared to [177Lu]Lu-rhPSMA-10.2 expressed by a 1.5-fold and ninefold lower uptake value at 1 h and 24 h in healthy animals, respectively. Tumor uptake was comparable and in the range of 8.6–11.6%ID/g for both isomers over 24 h and was maintained up to 168 h at a level of 2.2 ± 0.8 and 4.1 ± 1.4%ID/g for [177Lu]Lu-rhPSMA-10.1 and [177Lu]Lu-rhPSMA-10.2, respectively. Conclusion Our preclinical data on biodistribution and dosimetry indicate a more favorable profile of [177Lu]Lu-rhPSMA-10.1 compared to [177Lu]Lu-rhPSMA-10.2 for PSMA-targeted radioligand therapy. [177Lu]Lu-rhPSMA-10.1 shows fast kidney clearance kinetics resulting in excellent tumor-to-organ ratios over a therapy relevant time course. Meanwhile, [177Lu]Lu-rhPSMA-10.1 is currently being investigated in clinical phase I/II studies in patients with mCRPC (NCT05413850), in patients with high-risk localized PC (NCT06066437, Nautilus Trial) and after external beam radiotherapy (NCT06105918)

Is there more than meets the eye in PSMA imaging in prostate cancer with PET/MRI? Looking closer at uptake time, correlation with PSA and Gleason score

Abstract Background In patients with increasing PSA and suspicion for prostate cancer, but previous negative biopsies, PET/MRI is used to test for tumours and target potential following biopsy. We aimed to determine different PSMA PET timing effects on signal kinetics and test its correlation with the patients’ PSA and Gleason scores (GS). Methods A total of 100 patients were examined for 900 s using PET/MRI approximately 1–2 h p.i. depending on the tracer used (68Ga-PSMA-11, 18F-PSMA-1007 or 18F-rhPSMA7). The scans were reconstructed in static and dynamic mode (6 equal frames capturing “late” PSMA dynamics). TACs were computed for detected lesions as well as linear regression plots against time for static (SUV) and dynamic (SUV, SUL, and percent injected dose per gram) parameters. All computed trends were tested for correlation with PSA and GS. Results Static and dynamic scans allowed unchanged lesion detection despite the difference in statistics. For all tracers, the lesions in the pelvic lymph nodes and bones had a mostly negative activity concentration trend (78% and 68%, resp.), while a mostly positive, stronger trend was found for the lesions in the prostate and prostatic fossa following RPE (84% and 83%, resp.). In case of 68Ga-PSMA-11, a strong negative (R min = − 0.62, R max = − 0.73) correlation was found between the dynamic parameters and the PSA. 18F-PSMA-1007 dynamic data showed no correlation with PSA, while for 18F-rhPSMA7 dynamic data, it was consistently low positive (R min = 0.29, R max = 0.33). All tracers showed only moderate correlation against GS (R min = 0.41, R max = 0.48). The static parameters showed weak correlation with PSA (R min = 0.24, R max = 0.36) and no correlation with GS. Conclusion “Late” dynamic PSMA data provided additional insight into the PSMA kinetics. While a stable moderate correlation was found between the PSMA kinetics in pelvic lesions and GS, a significantly variable correlation with the PSA values was shown depending on the radiotracer used, the highest being consistently for 68Ga-PSMA-11. We reason that with such late dynamics, the PSMA kinetics are relatively stable and imaging could even take place at earlier time points as is now in the clinical routine