Radiopalmar ganglion cysts: prevalence, morphology, and clinical significance in wrist MRI.

OBJECTIVES: To assess radiopalmar ganglion cysts' (RPG) prevalence, morphology, and clinical significance in consecutive patients. MATERIALS AND METHODS: In this retrospective single-center study, two radiologists assessed the presence of RPG and morphologic features on wrist MRI. Radiopalmar complaints and scapholunate ligament (SLL) tears were evaluated. RESULTS: A total of 1053 wrists in 909 patients (mean age 43.4 ± 15.5 years, 602 females) were evaluated. All 308 RPG (Group 1; 308 patients, 29.2%) originated from the palmar capsule; 49 were unilocular, 95 oligolocular, and 164 multilocular; 745 wrists had no RPG (Group 2; 601 patients). One hundred and twenty-six RPG showed internal debris. The mean diameter was 8.5 ± 5.6 mm (cranio-caudal) (1.0-32.9 mm), 8.0 ± 4.1 mm (medio-lateral) (1.0-31.9 mm), and 3.7 ± 2.3 mm (dorso-palmar) (0.4-16.0 mm). 168 RPG showed direct contact with the radial vascular bundle, 24 with the flexor carpi radialis tendon, and 123 with the flexor pollicis longus tendon. In Group 1, significantly more patients showed partial (82/308) [group 2: 45/745, p < 0.001] or complete SLL tears (22/308) [group 2: 20/745, p < 0.001]. Of the patients with RPG, 15.3% presented with radiopalmar complaints. Only the dorso-palmar RPG diameter was positively correlated with radiopalmar complaints (for readers 1 and 2: rs = 0.66/0.61, p < 0.001, respectively), and the best dorso-palmar diameter cut-off value for the probability of having radiopalmar complaints was defined at 3 mm (area under the curve (AUC) 0.74). Other morphologic features were not eligible to discriminate symptomatic patients (AUC range 0.53-0.61). CONCLUSION: This study found RPG in 29% of patients, most of them asymptomatic. However, a dorso-palmar cyst diameter > 3 mm may be clinically significant. CLINICAL RELEVANCE STATEMENT: Radiopalmar ganglion cysts, observed in 29% of wrist MR examinations, are mostly asymptomatic, but those with a larger dorso-palmar diameter may be associated with radiopalmar complaints. KEY POINTS: Radiopalmar ganglion cysts are found in 29% of patients undergoing wrist MRI. Most patients with evidence of radiopalmar ganglion cysts do not show radiopalmar symptoms (85%). A dorso-palmar cyst diameter > 3 mm may be associated with radiopalmar complaints.

EEG spectral power in developmental coordination disorder and attention-deficit/hyperactivity disorder: a pilot study.

Developmental coordination disorder (DCD) and attention-deficit/hyperactivity disorder (ADHD) overlap in symptoms and often co-occur. Differentiation of DCD and ADHD is crucial for a better understanding of the conditions and targeted support. Measuring electrical brain activity with EEG may help to discern and better understand the conditions given that it can objectively capture changes and potential differences in brain activity related to externally measurable symptoms beneficial for targeted interventions. Therefore, a pilot study was conducted to exploratorily examine neurophysiological differences between adults with DCD and/or ADHD at rest. A total of N = 46 adults with DCD (n = 12), ADHD (n = 9), both DCD + ADHD (n = 8), or typical development (n = 17) completed 2 min of rest with eyes-closed and eyes-open while their EEG was recorded. Spectral power was calculated for frequency bands: delta (0.5-3 Hz), theta (3.5-7 Hz), alpha (7.5-12.5 Hz), beta (13-25 Hz), mu (8-13 Hz), gamma (low: 30-40 Hz; high: 40-50 Hz). Within-participants, spectral power in a majority of waveforms significantly increased from eyes-open to eyes-closed conditions. Groups differed significantly in occipital beta power during the eyes-open condition, driven by the DCD versus typically developing group comparison. However, other group comparisons reached only marginal significance, including whole brain alpha and mu power with eyes-open, and frontal beta and occipital high gamma power during eyes-closed. While no strong markers could be determined to differentiate DCD versus ADHD, we theorize that several patterns in beta activity were indicative of potential motor maintenance differences in DCD at rest. Therefore, larger studies comparing EEG spectral power may be useful to identify neurological mechanisms of DCD and continued differentiation of DCD and ADHD.

Unravelling genetic architecture of circulatory amino acid levels, and their effect on risk of complex disorders.

Variations in serum amino acid levels are linked to a multitude of complex disorders. We report the largest genome-wide association study (GWAS) on nine serum amino acids in the UK Biobank participants (117 944, European descent). We identified 34 genomic loci for circulatory levels of alanine, 48 loci for glutamine, 44 loci for glycine, 16 loci for histidine, 11 loci for isoleucine, 19 loci for leucine, 9 loci for phenylalanine, 32 loci for tyrosine and 20 loci for valine. Our gene-based analysis mapped 46-293 genes associated with serum amino acids, including MIP, GLS2, SLC gene family, GCKR, LMO1, CPS1 and COBLL1.The gene-property analysis across 30 tissues highlighted enriched expression of the identified genes in liver tissues for all studied amino acids, except for isoleucine and valine, in muscle tissues for serum alanine and glycine, in adrenal gland tissues for serum isoleucine and leucine, and in pancreatic tissues for serum phenylalanine. Mendelian randomization (MR) phenome-wide association study analysis and subsequent two-sample MR analysis provided evidence that every standard deviation increase in valine is associated with 35% higher risk of type 2 diabetes and elevated levels of serum alanine and branched-chain amino acids with higher levels of total cholesterol, triglyceride and low-density lipoprotein, and lower levels of high-density lipoprotein. In contrast to reports by observational studies, MR analysis did not support a causal association between studied amino acids and coronary artery disease, Alzheimer's disease, breast cancer or prostate cancer. In conclusion, we explored the genetic architecture of serum amino acids and provided evidence supporting a causal role of amino acids in cardiometabolic health.

Patient-Relevant Costs for Organ Preservation versus Radical Resection in Locally Advanced Rectal Cancer.

Total neoadjuvant therapy (TNT) is an evolving treatment schedule for locally advanced rectal cancer (LARC), allowing for organ preservation in a relevant number of patients in the case of complete response. Patients who undergo this so-called "watch and wait" approach are likely to benefit regarding their quality of life (QoL), especially if definitive ostomy could be avoided. In this work, we performed the first cost-effectiveness analysis from the patient perspective to compare costs for TNT with radical resection after neoadjuvant chemoradiation (CRT) in the German health care system. Individual costs for patients insured with a statutory health insurance were calculated with a Markov microsimulation. A subgroup analysis from the prospective "FinTox" trial was used to calibrate the model's parameters. We found that TNT was less expensive (-1540 EUR) and simultaneously resulted in a better QoL (+0.64 QALYs) during treatment and 5-year follow-up. The average cost for patients under TNT was 4711 EUR per year, which was equivalent to 3.2% of the net household income. CRT followed by resection resulted in higher overall costs for ostomy care, medication and greater loss of earnings. Overall, TNT appeared to be more efficacious and cost-effective from a patient's point of view in the German health care system.

Sudden gains in routine clinical care: application of a permutation test for trauma-focused cognitive behavioural therapy.

Background: Sudden gains, defined as large and stable improvements of psychopathological symptoms, are a ubiquitous phenomenon in psychotherapy. They have been shown to occur across several clinical contexts and to be associated with better short-term and long-term treatment outcome. However, the approach of sudden gains has been criticized for its tautological character: sudden gains are included in the computation of treatment outcomes, ultimately resulting in a circular conclusion. Furthermore, some authors criticize sudden gains as merely being random fluctuations.Objective: Use of efficient methods to evaluate whether the amount of sudden gains in a given sample lies above chance level.Method: We used permutation tests in a sample of 85 patients with posttraumatic stress disorder (PTSD) treated with trauma-focused cognitive behaviour therapy in routine clinical care. Scores of self-reported PTSD symptom severity were permuted 10.000 times within sessions and between participants to receive a random distribution.Results: Altogether, 18 participants showed a total of 24 sudden gains within the first 20 sessions. The permutation test yielded that the frequency of sudden gains was not beyond chance level. No significant predictors of sudden gains were identified and sudden gains in general were not predictive of treatment outcome. However, subjects with early sudden gains had a significantly lower symptom severity after treatment.Conclusions: Our data suggest that a significant proportion of sudden gains are due to chance. Further research is needed on the differential effects of early and late sudden gains.

Treatment-related sudden gains exhibit clinical significance when their manifestation is above chance level.We used permutation tests to examine their occurrence in trauma-focused cognitive behaviour therapy as applied in a naturalistic treatment setting.The occurrence of sudden gains in general was not significantly higher than chance, yet early sudden gains were associated with improved treatment outcome.

Static spacers play a crucial role in the treatment of complex periprosthetic joint infections of the knee.

PURPOSE: To determine the superior spacer design, a growing number of studies are comparing treatment results between patients having been treated with articulating and static knee spacers in the setting of two-stage revision for periprosthetic joint infection (PJI). In contrast, the primary objective of this study was to compare preoperative characteristics between patients from both spacer groups and examine whether significant differences were present prior to spacer implantation. METHODS: This retrospective, single-centre, cohort study examined the preoperative situation of 80 consecutive knee PJIs between 2017 and 2020. All patients underwent two-stage revision, with 35 (44%) receiving an articulating and 45 (56%) a static spacer. RESULTS: No significant differences were observed in terms of patient gender (p = 0.083), age (p = 0.666), comorbidity (p = 0.1) and preoperative clinical function (p = 0.246). Static spacers were significantly more often used in the presence of a periarticular fistula (p = 0.033), infection of a revision implant (p < 0.001), higher degree of bone loss (p < 0.001) and infection caused by a difficult-to-treat pathogen (p = 0.038). Complication and revision rates were similar for both spacer types during the interim period, while patients with articulating spacers demonstrated a superior clinical function (p < 0.001) during the interim period and after reimplantation. CONCLUSION: Static spacers are being utilised in significantly more complex and unfavourable preoperative scenarios. Therefore, a preoperative selection bias may be at least partially accountable for any disparities observed in postoperative outcomes. To achieve the best possible results, surgeons should know and respect the distinct indications of static and articulating spacers and consequently understand and use them as complementary surgical options. LEVEL OF EVIDENCE: Level III.

Photon-Counting Detector CT: Clinical Utility of Virtual Monoenergetic Imaging Combined With Tin Prefiltration to Reduce Metal Artifacts in the Postoperative Ankle.

OBJECTIVES: The aim of this study was to compare the effectiveness and clinical utility of virtual monoenergetic image (VMI) reconstructions in computed tomography (CT) scans with and without tin prefiltration on a photon-counting detector (PCD) CT system to reduce metal implant artifacts in the postoperative ankle. MATERIALS AND METHODS: This retrospective study included patients with internal fixation of the ankle scanned with and without tin prefiltration (Sn) on a PCD CT scanner between March and October 2023. Virtual monoenergetic images between 60 and 190 keV were reconstructed with a 10-keV increment in a bone kernel for both acquisitions (VMI Sn and VMI Std , respectively). Noise measurements assessed artifact reduction in the most prominent near-metal image distortions and were compared between acquisitions modes as well as between polychromatic images and VMIs. Three readers assessed the visibility of osseous healing along with interpretability and artifact extent for 5 reconstruction levels. RESULTS: A total of 48 patients (21 females, 27 males; mean age, 55.1 ± 19.4 years) were included in this study. Tin-prefiltered acquisitions (n = 30) had a lower artifact level for polychromatic images and VMIs compared with non-tin-prefiltered acquisitions (n = 18; P ≤ 0.043). A significant reduction of metal artifacts was observed for VMI Sn ≥120 keV compared with polychromatic images (hyperdense artifacts: 40.2 HU [interquartile range (IQR) 39.8] vs 14.0 HU [IQR 11.1]; P ≤ 0.01 and hypodense artifacts: 91.2 HU [IQR 82.4] vs 29.7 HU [IQR 39.6]; P ≤ 0.001). For VMI Std , this applied to reconstructions ≥100 keV (hyperdense artifacts: 57.7 HU [IQR 33.4] vs 19.4 HU [IQR 27.6]; P ≤ 0.001 and hypodense artifacts: 106.9 HU [IQR 76.1] vs 57.4 HU [IQR 55.7]; P ≤ 0.021). For visibility of osseous healing, VMI Sn at 120 keV yielded higher ratings compared with polychromatic images ( P ≤ 0.001), whereas image interpretability was rated better ( P = 0.023), and artifact extent was rated lower ( P ≤ 0.001) compared with polychromatic images. CONCLUSIONS: Tin-prefiltered VMI at 120 keV showed a significant reduction in metal artifacts compared with polychromatic images, whereas visibility of osseous healing and image interpretability was improved. Therefore, tin-prefiltration PCD CT with VMI reconstructions may be a helpful complement to postsurgical CT imaging of the ankle in patients with metal implants.

7-Dehydrocholesterol is an endogenous suppressor of ferroptosis.

Ferroptosis is a form of cell death that has received considerable attention not only as a means to eradicate defined tumour entities but also because it provides unforeseen insights into the metabolic adaptation that tumours exploit to counteract phospholipid oxidation1,2. Here, we identify proferroptotic activity of 7-dehydrocholesterol reductase (DHCR7) and an unexpected prosurvival function of its substrate, 7-dehydrocholesterol (7-DHC). Although previous studies suggested that high concentrations of 7-DHC are cytotoxic to developing neurons by favouring lipid peroxidation3, we now show that 7-DHC accumulation confers a robust prosurvival function in cancer cells. Because of its far superior reactivity towards peroxyl radicals, 7-DHC effectively shields (phospho)lipids from autoxidation and subsequent fragmentation. We provide validation in neuroblastoma and Burkitt's lymphoma xenografts where we demonstrate that the accumulation of 7-DHC is capable of inducing a shift towards a ferroptosis-resistant state in these tumours ultimately resulting in a more aggressive phenotype. Conclusively, our findings provide compelling evidence of a yet-unrecognized antiferroptotic activity of 7-DHC as a cell-intrinsic mechanism that could be exploited by cancer cells to escape ferroptosis.

[Bone-RADS: Diagnostic algorithm for management of incidental solitary bone lesions]. / Bone-RADS: Diagnostischer Algorithmus zum Management von inzidentellen solitären Knochenläsionen.

The bone reporting and data system (Bone-RADS) is a guideline of the Society of Skeletal Radiology for the standardized assessment of incidentally found solitary bone lesions. It consists of basic definitions and continuative algorithms for the radiological diagnosis of bone lesions in computed tomography (CT) and magnetic resonance imaging (MRI). This Continuing Medical Education (CME) article gives a compact summary of the Bone-RADS classification for users. After reading this article Bone-RADS can be used by anyone. The authors have compiled the critical comments and obstacles at the end of the article.

Alcohol does not influence trust in others or oxytocin, but increases positive affect and risk-taking: a randomized, controlled, within-subject trial.

BACKGROUND: Alcohol consumption to facilitate social interaction is an important drinking motive. Here, we tested whether alcohol influences trust in others via modulation of oxytocin and/or androgens. We also aimed at confirming previously shown alcohol effects on positive affect and risk-taking, because of their role in facilitating social interaction. METHODS: This randomized, controlled, within-subject, parallel group, alcohol-challenge experiment investigated the effects of alcohol (versus water, both mixed with orange juice) on perceived trustworthiness via salivary oxytocin (primary and secondary endpoint) as well as testosterone, dihydrotestosterone, positive affect, and risk-taking (additional endpoints). We compared 56 male participants in the alcohol condition (1.07 ± 0.18 per mille blood alcohol concentration) with 20 in the control condition. RESULTS: The group (alcohol versus control condition) × time (before [versus during] versus after drinking) interactions were not significantly associated with perceived trustworthiness (η2 < 0.001) or oxytocin (η2 = 0.003). Bayes factors provided also substantial evidence for the absence of these effects (BF01 = 3.65; BF01 = 7.53). The group × time interactions were related to dihydrotestosterone (η2 = 0.018 with an increase in the control condition) as well as positive affect and risk-taking (η2 = 0.027 and 0.007 with increases in the alcohol condition), but not significantly to testosterone. DISCUSSION: The results do not verify alcohol effects on perceived trustworthiness or oxytocin in male individuals. However, they indicate that alcohol (versus control) might inhibit an increase in dihydrotestosterone and confirm that alcohol amplifies positive affect and risk-taking. This provides novel mechanistic insight into social facilitation as an alcohol-drinking motive.

Reply to Alt et al. Comment on "Lunz et al. Impact and Modification of the New PJI-TNM Classification for Periprosthetic Joint Infections. J. Clin. Med. 2023, 12, 1262".

We greatly appreciate the comments made by Alt et al. [...].

Generation of four gene-edited human induced pluripotent stem cell lines with mutations in the ATM gene to model Ataxia-Telangiectasia.

Ataxia-Telangiectasia (A-T) is an autosomal recessive multi-system disorder caused by mutations in the ataxia-telangiectasia mutated (ATM) gene, resulting, among other symptoms, in neurological dysfunction. ATM is known to be a master controller of signal transduction for DNA damage response, with additional functions that are poorly understood. CRISPR/Cas9 technology was used to introduce biallelic mutations at selected sites of the ATM gene in human induced pluripotent stem cells (hiPSCs). This panel of hiPSCs with nonsense and missense mutations in ATM can help understand the molecular basis of A-T.

Enhanced antibiotic release from bone cement spacers utilizing dual antibiotic loading with elevated vancomycin concentrations in two-stage revision for periprosthetic joint infection.

PURPOSE: Antibiotic loaded bone cement spacers provide high local antibiotic concentrations, preserve bone stock, and reduce soft tissue contractions. The objective of this in-vitro study was to compare antibiotic release from spacers, aiming to discover the most optimal preparation and identify modifiable factors that can further enhance antibiotic release. METHODS: Six distinct spacer preparation were created using three different bone cements and manual incorporation of antibiotics. During a six-week period, the release of antibiotics from each spacer was measured individually at ten predetermined time points using a chemiluminescent immunoassay. RESULTS: Manually adding 4 g of vancomycin to every 40 g of "Palacos R + G" yielded the most favorable release profile. Throughout all preparations, antibiotic release consistently and significantly decreased over the six-week period. When incorporating a higher concentration of vancomycin, a significantly higher cumulative release of vancomycin was observed, with varying effects on the release of gentamicin. The choice of bone cement had a significant impact on antibiotic release. CONCLUSION: To enhance antibiotic release from spacers, surgeons should manually incorporate high antibiotic concentrations into the most appropriate bone cement and keep the interim period as short as possible. Specifically, we suggest manual incorporation of 4 g of vancomycin to every 40 g of gentamicin premixed "Palacos R + G" to create bone cement spacers.

Getting specific: participation preference in urooncological decision-making.

BACKGROUND: Shared decision-making is the gold standard for good clinical practice, and thus, psychometric instruments have been established to assess patients' generic preference for participation (e.g., the Autonomy Preference Index, API). However, patients' preferences may vary depending on the specific disease and with respect to the specific decision context. With a modified preference index (API-Uro), we assessed patients' specific participation preference in preference-sensitive decisions pertaining to urological cancer treatments and compared this with their generic participation preference. METHODS: In Study 1, we recruited (N = 469) urological outpatients (43.1% urooncological) at a large university hospital. Participation preference was assessed with generic measures (API and API case vignettes) and with the disease-specific API-Uro (urooncological case vignettes describing medical decisions of variable difficulty). A polychoric exploratory factor analysis was used to establish factorial validity and reduce items. In Study 2, we collected data from N = 204 bladder cancer patients in a multicenter study to validate the factorial structure with confirmatory factor analysis. Differences between the participation preference for different decision contexts were analyzed. RESULTS: Study 1: Scores on the specific urooncological case vignettes (API-Uro) correlated with the generic measure (r = .44) but also provided incremental information. Among the disease-specific vignettes of the API-Uro, there were two factors with good internal consistency (α ≥ .8): treatment versus diagnostic decisions. Patients desired more participation for treatment decisions (77.8%) than for diagnostic decisions (22%), χ2(1) = 245.1, p ≤ .001. Study 2: Replicated the correlation of the API-Uro with the API (r = .39) and its factorial structure (SRMR = .08; CFI = .974). Bladder cancer patients also desired more participation for treatment decisions (57.4%) than for diagnostic decisions (13.3%), χ²(1) =84, p ≤ .001. CONCLUSIONS: The desire to participate varies between treatment versus diagnostic decisions among urological patients. This underscores the importance of assessing participation preference for specific contexts. Overall, the new API-Uro has good psychometric properties and is well suited to assess patients' preferences. In routine care, measures of participation preference for specific decision contexts may provide incremental, allowing clinicians to better address their patients' individual needs.

Long-Term Total Neoadjuvant Therapy Leads to Impressive Response Rates in Rectal Cancer: Results of a German Single-Center Cohort.

Intensified preoperative chemotherapy after (chemo)radiotherapy, (Total Neoadjuvant Therapy-TNT), increases pathological complete response (pCR) rates and local control. In cases of clinically complete response (cCR) and close follow-up, non-operative management (NOM) is feasible. We report early outcomes and toxicities of a long-term TNT regime in a single-center cohort. Fifteen consecutive patients with distal or middle-third locally advanced rectal cancer (UICC stage II-III) were investigated, who received neoadjuvant chemoradiotherapy (total adsorbed dose: 50.4 Gy in 28 fractions and two concomitant courses 5-fluorouracil (250 mg/m2/d)/oxaliplatin (50 mg/m2), followed by consolidating chemotherapy (nine courses of FOLFOX4). NOM was offered if staging revealed cCR 2 months after TNT, with resection performed otherwise. The primary endpoint was complete response (pCR + cCR). Treatment-related side effects were quantified for up two years after TNT. Ten patients achieved cCR, of whom five opted for NOM. Ten patients (five cCR and five non-cCR) underwent surgery, with pCR confirmed in the five patients with cCR. The main toxicities comprised leukocytopenia (13/15), fatigue (12/15) and polyneuropathy (11/15). The most relevant CTC °III + IV events were leukocytopenia (4/15), neutropenia (2/15) and diarrhea (1/15). The long-term TNT regime resulted in promising response rates that are higher than the response rates of short TNT regimes. Overall tolerability and toxicity were comparable with the results of prospective trials.

Automatic facial coding predicts self-report of emotion, advertisement and brand effects elicited by video commercials.

Introduction: Consumers' emotional responses are the prime target for marketing commercials. Facial expressions provide information about a person's emotional state and technological advances have enabled machines to automatically decode them. Method: With automatic facial coding we investigated the relationships between facial movements (i.e., action unit activity) and self-report of commercials advertisement emotion, advertisement and brand effects. Therefore, we recorded and analyzed the facial responses of 219 participants while they watched a broad array of video commercials. Results: Facial expressions significantly predicted self-report of emotion as well as advertisement and brand effects. Interestingly, facial expressions had incremental value beyond self-report of emotion in the prediction of advertisement and brand effects. Hence, automatic facial coding appears to be useful as a non-verbal quantification of advertisement effects beyond self-report. Discussion: This is the first study to measure a broad spectrum of automatically scored facial responses to video commercials. Automatic facial coding is a promising non-invasive and non-verbal method to measure emotional responses in marketing.

Do changes in dysfunctional posttraumatic cognitions differentially predict PTSD symptom clusters?

OBJECTIVE: In recent years, it has been suggested that the modification of dysfunctional posttraumatic cognitions plays a central role as a mechanism of change in cognitive behavioral therapy (CBT) for posttraumatic stress disorder (PTSD). Indeed, several studies have shown that changes in dysfunctional posttraumatic cognitions precede and predict symptom change. However, these studies have investigated the influence on overall symptom severity-despite the well-known multidimensionality of PTSD. The present study therefore aimed to explore differential associations between change in dysfunctional conditions and change in PTSD symptom clusters. METHOD: As part of a naturalistic effectiveness study evaluating trauma-focused cognitive behavioral therapy for PTSD in routine clinical care, 61 patients with PTSD filled out measures of dysfunctional posttraumatic cognitions and PTSD symptom severity every five sessions during the course of treatment. Lagged associations between dysfunctional cognitions and symptom severity at the following timepoint were examined using linear mixed models. RESULTS: Over the course of therapy, both dysfunctional cognitions and PTSD symptoms decreased. Posttraumatic cognitions predicted subsequent total PTSD symptom severity, although this effect was at least partly explained by the time factor. Moreover, dysfunctional cognitions predicted three out of four symptom clusters as expected. However, these effects were no longer statistically significant when the general effect for time was controlled for. CONCLUSION: The present study provides preliminary evidence that dysfunctional posttraumatic cognitions predict PTSD symptom clusters differentially. However, different findings when employing a traditional versus a more rigorous statistical approach make interpretation of findings difficult. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Planning adaptive treatment by longitudinal response assessment implementing MR imaging, liquid biopsy and analysis of microenvironment during neoadjuvant treatment of rectal cancer (PRIMO).

INTRODUCTION: Conducting neoadjuvant chemoradiotherapy (CRT) and additional preoperative consolidating chemotherapy (CTx), that is, total neoadjuvant therapy (TNT), improves local control and complete response (CR) rates in locally advanced rectal cancer (LARC), putting the focus on organ preservation concepts. Therefore, assessing response before surgery is crucial. Some LARC patients would either not benefit from intensification by TNT or may reach CR, making resection not mandatory. Treatment of LARC should therefore be based on patient individual risk and response to avoid overtreatment.The "PRIMO" pilot study aims to determine early response assessment to form a basis for development and validation of a noninvasive response prediction model by a subsequent prospective multicenter trial, which is highly needed for individual, response-driven therapy adaptions. METHODS: PRIMO is a prospective observational cohort study including adult patients with LARC receiving neoadjuvant CRT. At least 4 multiparametric magnetic resonance imaging (MRI) scans (diffusion-weighted imaging [DWI] and hypoxia-sensitive sequences) as well as repeated blood samples in order to analyze circulating tumor cells (CTC) and cell-free tumor DNA (ctDNA) are scheduled. Pelvic radiotherapy (RT, 50.4 Gy) will be performed in combination with a 5-fluorouracil/oxaliplatin regimen in all patients (planned: N = 50), succeeded by consolidation CTx (FOLFOX4) if feasible. Additional (immuno)histochemical markers, such as tumor-infiltrating lymphocytes (TIL) and programmed death ligand 1 (PD-L1) status will be analyzed before and after CRT. Routine resection is scheduled subsequently, nonoperative management is offered alternatively in case of clinical CR (cCR).The primary endpoint is pathological response; secondary endpoints comprise longitudinal changes in MRI as well as in CTCs and TIL. These are evaluated for early response prediction during neoadjuvant therapy, in order to develop a noninvasive response prediction model for subsequent analyses. DISCUSSION: Early response assessment is the key in differentiating "good" and "bad" responders during neoadjuvant CRT, allowing adaption of subsequent therapies (additional consolidating CTx, organ preservation). This study will contribute in this regard, by advancing MR imaging and substantiating new surrogate markers. Adaptive treatment strategies might build on these results in further studies.