Early versus late response to PD-1-based immunotherapy in metastatic melanoma.

BACKGROUND: Immune checkpoint inhibition (ICI) currently is the most effective treatment to induce durable responses in metastatic melanoma. The aims of this study are the characterization of patients with early, late and non-response to ICI and analysis of survival outcomes in a real-world patient cohort. METHODS: Patients who received PD-1-based immunotherapy for non-resectable stage-IV melanoma in any therapy line were selected from the prospective multicenter real-world DeCOG study ADOREG-TRIM (NCT05750511). Patients showing complete (CR) or partial (PR) response already during the first 3 months of treatment (Early Responders, EarlyR) were compared to patients showing CR/PR at a later time (Late Responders, LateR), a stable disease (SD) and to patients showing progressive disease (Non-Responders, NonR). RESULTS: Of 522 patients, 8.2 % were EarlyR (n = 43), 19.0 % were LateR (n = 99), 37.0 % had a SD (n = 193) and 35.8 % were NonR (n = 187). EarlyR, LateR and SD patients had comparable baseline characteristics. Multivariate logbinomial regression analyses adjusted for age and sex revealed positive tumor PD-L1 (RR=1.99, 95 %-CI=1.14-3.46, p = 0.015), and normal serum CRP (RR=1.59, 95 %-CI=0.93-2.70, p = 0.036) as independently associated with the achievement of an early response compared to NonR. The median progression-free and overall survival was 46.0 months (95 % CI 19.1; NR) and 47.8 months (95 %-CI 36.9; NR) for EarlyR, NR (95 %-CI NR; NR) for LateR, 8.1 months (7.0; 10.4) and 35.4 months (29.2; NR) for SD, and 2.0 months (95 %-CI 1.9; 2.1) and 6.1 months (95 %-CI 4.6; 8.8) for NonR patients. CONCLUSION: Less than 10 % of metastatic melanoma patients achieved an early response during the first 3 months of PD-1-based immunotherapy. Early responders were not superior to late responders in terms of response durability and survival.

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.

Shortened progression free and overall survival to immune-checkpoint inhibitors in BRAF-, RAS- and NF1- ("Triple") wild type melanomas.

BACKGROUND: Melanomas lacking mutations in BRAF, NRAS and NF1 are frequently referred to as "triple wild-type" (tWT) melanomas. They constitute 5-10 % of all melanomas and remain poorly characterized regarding clinical characteristics and response to therapy. This study investigates the largest multicenter collection of tWT-melanomas to date. METHODS: Targeted next-generation sequencing of the TERT promoter and 29 melanoma-associated genes were performed on 3109 melanoma tissue samples of the prospective multicenter study ADOREG/TRIM of the DeCOG revealing 292 patients suffering from tWT-melanomas. Clinical characteristics and mutational patterns were analyzed. As subgroup analysis, we analyzed 141 tWT-melanoma patients receiving either anti-CTLA4 plus anti-PD1 or anti PD1 monotherapy as first line therapy in AJCC stage IV. RESULTS: 184 patients with cutaneous melanomas, 56 patients with mucosal melanomas, 34 patients with acral melanomas and 18 patients with melanomas of unknown origin (MUP) were included. A TERT promoter mutation could be identified in 33.2 % of all melanomas and 70.5 % of all tWT-melanomas harbored less than three mutations per sample. For the 141 patients with stage IV disease, mPFS independent of melanoma type was 6.2 months (95 % CI: 4-9) and mOS was 24.8 months (95 % CI: 14.2-53.4) after first line anti-CTLA4 plus anti-PD1 therapy. After first-line anti-PD1 monotherapy, mPFS was 4 months (95 %CI: 2.9-8.5) and mOS was 29.18 months (95 % CI: 17.5-46.2). CONCLUSIONS: While known prognostic factors such as TERT promoter mutations and TMB were equally distributed among patients who received either anti-CTLA4 plus anti-PD1 combination therapy or anti-PD1 monotherapy as first line therapy, we did not find a prolonged mPFS or mOS in either of those. For both therapy concepts, mPFS and mOS were considerably shorter than reported for melanomas with known oncogene mutations.

Chondrosarcoma evaluation using hematein-based x-ray staining and high-resolution 3D micro-CT: a feasibility study.

BACKGROUND: Chondrosarcomas are rare malignant bone tumors diagnosed by analyzing radiological images and histology of tissue biopsies and evaluating features such as matrix calcification, cortical destruction, trabecular penetration, and tumor cell entrapment. METHODS: We retrospectively analyzed 16 cartilaginous tumor tissue samples from three patients (51-, 54-, and 70-year-old) diagnosed with a dedifferentiated chondrosarcoma at the femur, a moderately differentiated chondrosarcoma in the pelvis, and a predominantly moderately differentiated chondrosarcoma at the scapula, respectively. We combined a hematein-based x-ray staining with high-resolution three-dimensional (3D) microscopic x-ray computed tomography (micro-CT) for nondestructive 3D tumor assessment and tumor margin evaluation. RESULTS: We detected trabecular entrapment on 3D micro-CT images and followed bone destruction throughout the volume. In addition to staining cell nuclei, hematein-based staining also improved the visualization of the tumor matrix, allowing for the distinction between the tumor and the bone marrow cavity. The hematein-based staining did not interfere with further conventional histology. There was a 5.97 ± 7.17% difference between the relative tumor area measured using micro-CT and histopathology (p = 0.806) (Pearson correlation coefficient r = 0.92, p = 0.009). Signal intensity in the tumor matrix (4.85 ± 2.94) was significantly higher in the stained samples compared to the unstained counterparts (1.92 ± 0.11, p = 0.002). CONCLUSIONS: Using nondestructive 3D micro-CT, the simultaneous visualization of radiological and histopathological features is feasible. RELEVANCE STATEMENT: 3D micro-CT data supports modern radiological and histopathological investigations of human bone tumor specimens. It has the potential for being an integrative part of clinical preoperative diagnostics. KEY POINTS: • Matrix calcifications are a relevant diagnostic feature of bone tumors. • Micro-CT detects all clinically diagnostic relevant features of x-ray-stained chondrosarcoma. • Micro-CT has the potential to be an integrative part of clinical diagnostics.

Tumor-Like Distal Femoral Cortical Irregularities of the Knee in Adolescent Competitive Alpine Skiers: Longitudinal Assessment Over 48 Months.

BACKGROUND: Tumor-like distal femoral cortical irregularities (DFCIs) are a frequent incidental finding on knee magnetic resonance imaging (MRI) and are common in young competitive athletes. PURPOSE: To assess and compare the morphology and prevalence of DFCIs in competitive alpine skiers over 48 months during adolescence. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Adolescent competitive alpine skiers were prospectively recruited in 2018 and received bilateral 3-T MRI of the knee at baseline and after 48 months. All MRIs were evaluated for the presence and location of DFCIs, which were marked at 1 of 3 anatomic positions: (1) the femoral attachment of the medial head of the gastrocnemius muscle, (2) the lateral head of the gastrocnemius muscle, or (3) the attachment of the adductor magnus aponeurosis. The size of the DFCI was measured by 2 radiologists independently. The measurements were compared using the Wilcoxon signed-rank test, the interclass correlation coefficient (ICC), and Cohen Kappa. RESULTS: A total of 63 athletes (mean age at follow-up, 19.6 ± 1.2 years; n = 25 female) were included in the study. At baseline, DFCIs were detected in 84 out of 126 knees (67%). At the 48-month follow-up, DFCIs were found in 88 out of 126 knees (70%), with multiple DFCIs in 3 knees and no significant difference between male and female patients (n = 24 male, n = 19 female; P = .71). No significant increase was detected for the number (P = .21) and size of the DFCIs between the baseline and the 48-month follow-up (mean size: baseline, 3.7 ± 0.8 mm; 48-month follow-up: 3.6 ± 0.9 mm; P = .66). The interrater agreement for the mean size measurements of DFCIs was good to excellent (ICC 0.88). CONCLUSION: DFCIs remain a frequent finding on knee MRI in competitive alpine skiers after skeletal maturation and do not disappear during adolescence. The DFCI size was constant in athletes aged between 15 and 19 years. Moreover, DFCIs should not be mistaken for a pathologic finding.

Deep Learning to Differentiate Benign and Malignant Vertebral Fractures at Multidetector CT.

Background Differentiating between benign and malignant vertebral fractures poses diagnostic challenges. Purpose To investigate the reliability of CT-based deep learning models to differentiate between benign and malignant vertebral fractures. Materials and Methods CT scans acquired in patients with benign or malignant vertebral fractures from June 2005 to December 2022 at two university hospitals were retrospectively identified based on a composite reference standard that included histopathologic and radiologic information. An internal test set was randomly selected, and an external test set was obtained from an additional hospital. Models used a three-dimensional U-Net encoder-classifier architecture and applied data augmentation during training. Performance was evaluated using the area under the receiver operating characteristic curve (AUC) and compared with that of two residents and one fellowship-trained radiologist using the DeLong test. Results The training set included 381 patients (mean age, 69.9 years ± 11.4 [SD]; 193 male) with 1307 vertebrae (378 benign fractures, 447 malignant fractures, 482 malignant lesions). Internal and external test sets included 86 (mean age, 66.9 years ± 12; 45 male) and 65 (mean age, 68.8 years ± 12.5; 39 female) patients, respectively. The better-performing model of two training approaches achieved AUCs of 0.85 (95% CI: 0.77, 0.92) in the internal and 0.75 (95% CI: 0.64, 0.85) in the external test sets. Including an uncertainty category further improved performance to AUCs of 0.91 (95% CI: 0.83, 0.97) in the internal test set and 0.76 (95% CI: 0.64, 0.88) in the external test set. The AUC values of residents were lower than that of the best-performing model in the internal test set (AUC, 0.69 [95% CI: 0.59, 0.78] and 0.71 [95% CI: 0.61, 0.80]) and external test set (AUC, 0.70 [95% CI: 0.58, 0.80] and 0.71 [95% CI: 0.60, 0.82]), with significant differences only for the internal test set (P < .001). The AUCs of the fellowship-trained radiologist were similar to those of the best-performing model (internal test set, 0.86 [95% CI: 0.78, 0.93; P = .39]; external test set, 0.71 [95% CI: 0.60, 0.82; P = .46]). Conclusion Developed models showed a high discriminatory power to differentiate between benign and malignant vertebral fractures, surpassing or matching the performance of radiology residents and matching that of a fellowship-trained radiologist. © RSNA, 2024 See also the editorial by Booz and D'Angelo in this issue.

Natural History of Quantitative Fatty Infiltration and 3D Muscle Volume After Nonoperative Treatment of Symptomatic Rotator Cuff Tears: A Prospective MRI Study of 79 Patients.

BACKGROUND: The severity of fatty infiltration (FI) predicts the treatment outcome of rotator cuff tears. The purpose of this investigation was to quantitatively analyze supraspinatus (SSP) muscle FI and volume at the initial presentation and after a 3-month minimum of conservative management. We hypothesized that progression of FI could be predicted with initial tear size, FI, and muscle volume. METHODS: Seventy-nine shoulders with rotator cuff tears were prospectively enrolled, and 2 magnetic resonance imaging (MRI) scans with 6-point Dixon sequences were acquired. The fat fraction within the SSP muscle was measured on 3 sagittal slices, and the arithmetic mean was calculated (FI SSP ). Advanced FI SSP was defined as ≥8%, pathological FI SSP was defined as ≥13.5%, and relevant progression was defined as a ≥4.5% increase in FI SSP . Furthermore, muscle volume, tear location, size, and Goutallier grade were evaluated. RESULTS: Fifty-seven shoulders (72.2%) had normal FI SSP , 13 (16.5%) had advanced FI SSP , and 9 (11.4%) had pathological FI SSP at the initial MRI scan. Eleven shoulders (13.9%) showed a ≥4.5% increase in FI SSP at 19.5 ± 14.7 months, and 17 shoulders (21.5%) showed a ≥5-mm 3 loss of volume at 17.8 ± 15.3 months. Five tears (7.1%) with initially normal or advanced FI SSP turned pathological. These tears, compared with tears that were not pathological, had significantly higher initial mediolateral tear size (24.8 compared with 14.3 mm; p = 0.05), less volume (23.5 compared with 34.2 mm 3 ; p = 0.024), more FI SSP (9.6% compared with 5.6%; p = 0.026), and increased progression of FI SSP (8.6% compared with 0.5%; p < 0.001). An initial mediolateral tear size of ≥20 mm yielded a relevant FI SSP progression rate of 81.8% (odds ratio [OR], 19.0; p < 0.001). Progression rates of 72.7% were found for both initial FI SSP of ≥9.9% (OR, 17.5; p < 0.001) and an initial anteroposterior tear size of ≥17 mm (OR, 8.0; p = 0.003). Combining these parameters in a logistic regression analysis led to an area under the receiver operating characteristic curve (AUC) of 0.913. The correlation between FI SSP progression and the time between MRI scans was weak positive (ρ = 0.31). CONCLUSIONS: Three risk factors for relevant FI progression, quantifiable on the initial MRI, were identified: ≥20-mm mediolateral tear size, ≥9.9% FI SSP , and ≥17-mm anteroposterior tear size. These thresholds were associated with a higher risk of tear progression: 19 times higher for ≥20-mm mediolateral tear size, 17.5 times higher for ≥9.9% FI SSP , and 8 times higher for ≥17-mm anteroposterior tear size. The presence of all 3 yielded a 91% chance of ≥4.5% progression of FI SSP within a mean of 19.5 months. LEVEL OF EVIDENCE: Diagnostic Level II . See Instructions for Authors for a complete description of levels of evidence.

Continuous Interscalene Brachial Plexus Blocks: An Anatomical Challenge between Scylla and Charybdis?

Brachial plexus blocks at the interscalene level are frequently chosen by physicians and recommended by textbooks for providing regional anesthesia and analgesia to patients scheduled for shoulder surgery. Published data concerning interscalene single-injection or continuous brachial plexus blocks report good analgesic effects. The principle of interscalene catheters is to extend analgesia beyond the duration of the local anesthetic's effect through continuous infusion, as opposed to a single injection. However, in addition to the recognized beneficial effects of interscalene blocks, whether administered as a single injection or through a catheter, there have been reports of consequences ranging from minor side effects to severe, life-threatening complications. Both can be simply explained by direct mispuncture, as well as undesired local anesthetic spread or misplaced catheters. In particular, catheters pose a high risk when advanced or placed uncontrollably, a fact confirmed by reports of fatal outcomes. Secondary catheter dislocations explain side effects or loss of effectiveness that may occur hours or days after the initial correct function has been observed. From an anatomical and physiological perspective, this appears logical: the catheter tip must be placed near the plexus in an anatomically tight and confined space. Thus, the catheter's position may be altered with the movement of the neck or shoulder, e.g., during physiotherapy. The safe use of interscalene catheters is therefore a balance between high analgesia quality and the control of side effects and complications, much like the passage between Scylla and Charybdis. We are convinced that the anatomical basis crucial for the brachial plexus block procedure at the interscalene level is not sufficiently depicted in the common regional anesthesia literature or textbooks. We would like to provide a comprehensive anatomical survey of the lateral neck, with special attention paid to the safe placement of interscalene catheters.

Photon-Counting Detector CT Versus Energy-Integrating Detector CT of the Lumbar Spine: Comparison of Radiation Dose and Image Quality.

BACKGROUND. Photon-counting detector (PCD) CT could be useful to help address the typically high radiation doses of conventional energy-integrating detector (EID) CT of the lumbar spine. OBJECTIVE. The purpose of our study was to compare PCD CT and EID CT of the lumbar spine, both performed using tin filtration, in terms of radiation dose and image quality. METHODS. This study included a prospective sample of 39 patients (22 men, 17 women; mean age, 27.2 years) who underwent investigational PCD CT of the lumbar spine as part of a separate study and a retrospective sample of 39 patients (22 men, 17 women; mean age, 34.9 years) who underwent clinically indicated EID CT of the lumbar spine. In both groups, all examinations were performed using unenhanced technique with tin prefiltration between June 2022 and January 2023. Patients were matched between groups using age, sex, and BMI. A custom gaussian curve-fitting algorithm was used to automatically calculate image noise, SNR, and CNR for each examination, on the basis of all voxels within the image set. Three radiologists independently reviewed examinations to perform a subjective visual assessment of visualization of trabecular architecture, cortical bone, neuroforaminal content, paraspinal muscles, and intervertebral disk, as well as overall image quality, using a 4-point Likert scale (1 = poor, 4 = excellent). PCD CT and EID CT examinations were compared. RESULTS. Mean CTDIvol was 4.4 ± 1.0 (SD) mGy for PCD CT versus 11.1 ± 1.9 mGy for EID CT (p < .001). Mean size-specific dose estimate (SSDE) was 6.2 ± 1.0 (SD) mGy for PCD CT versus 14.2 ± 1.8 mGy for EID CT (p < .001). PCD CT and EID CT examinations were not significantly different in terms of image noise or SNR (both p > .05). PCD CT, in comparison with EID CT, showed significantly higher CNR (mean ± SD, 33.6 ± 3.3 vs 29.3 ± 4.1; p < .001). For all three readers, the median score for overall image quality was 4 (range, 3-4) for both PCD CT and EID CT. PCD CT and EID CT examinations showed no significant difference in terms of any qualitative measure for any reader (all p > .05). CONCLUSION. PCD CT, in comparison with EID CT, yielded significantly lower radiation dose with preserved image quality. CLINICAL IMPACT. The findings support expanded use of PCD CT for lumbar spine evaluation.

Photon-Counting Detector CT With Denoising for Imaging of the Osseous Pelvis at Low Radiation Doses: A Phantom Study.

BACKGROUND. Photon-counting detector (PCD) CT may allow lower radiation doses than used for conventional energy-integrating detector (EID) CT, with preserved image quality. OBJECTIVE. The purpose of this study was to compare PCD CT and EID CT, reconstructed with and without a denoising tool, in terms of image quality of the osseous pelvis in a phantom, with attention to low radiation doses. METHODS. A pelvic phantom comprising human bones in acrylic material mimicking soft tissue underwent PCD CT and EID CT at various tube potentials and radiation doses ranging from 0.05 to 5.00 mGy. Additional denoised reconstructions were generated using a commercial tool. Noise was measured in the acrylic material. Two readers performed independent qualitative assessments that entailed determining the denoised EID CT reconstruction with the lowest acceptable dose and then comparing this reference reconstruction with PCD CT reconstructions without and with denoising, using subjective Likert scales. RESULTS. Noise was lower for PCD CT than for EID CT. For instance, at 0.05 mGy and 100 kV with tin filter, noise was 38.4 HU for PCD CT versus 48.8 HU for EID CT. Denoising further reduced noise; for example, for PCD CT at 100 kV with tin filter at 0.25 mGy, noise was 19.9 HU without denoising versus 9.7 HU with denoising. For both readers, lowest acceptable dose for EID CT was 0.10 mGy (total score, 11 of 15 for both readers). Both readers somewhat agreed that PCD CT without denoising at 0.10 mGy (reflecting reference reconstruction dose) was relatively better than the reference reconstruction in terms of osseous structures, artifacts, and image quality. Both readers also somewhat agreed that denoised PCD CT reconstructions at 0.10 mGy and 0.05 mGy (reflecting matched and lower doses, respectively, with respect to reference reconstruction dose) were relatively better than the reference reconstruction for the image quality measures. CONCLUSION. PCD CT showed better-quality images than EID CT when performed at the lowest acceptable radiation dose for EID CT. PCD CT with denoising yielded better-quality images at a dose lower than lowest acceptable dose for EID CT. CLINICAL IMPACT. PCD CT with denoising could facilitate lower radiation doses for pelvic imaging.

Charlson-Deyo Comorbidity Index as a Novel Predictor for Recurrence in Non-Muscle-Invasive Bladder Cancer.

PURPOSE: To test the association between the Charlson-Deyo Comorbidity Index (CCI) and the recurrence of non-muscle-invasive bladder cancer (NMIBC). METHODS: NMIBC (Ta, T1, TIS) patients who underwent transurethral resection of bladder tumor (TURB) between 2010 and 2018 were identified within a retrospective data repository of a large university hospital. Kaplan-Meier estimates and uni- and multivariable Cox regression models tested for differences in risk of recurrence according to low vs. high comorbidity burden (CCI ≤ 4 vs. >4) and continuously coded CCI. RESULTS: A total of 1072 NMIBC patients were identified. The median follow-up time of the study population was 55 months (IQR 29.6-79.0). Of all 1072 NMIBC patients, 423 (39%) harbored a low comorbidity burden vs. 649 (61%) with a high comorbidity burden. Overall, the rate of recurrence was 10% at the 12-month follow-up vs. 22% at the 72-month follow-up. In low vs. high comorbidity burden groups, rates of recurrence were 6 vs. 12% at 12 months and 18 vs. 25% at 72 months of follow-up (p = 0.02). After multivariable adjustment, a high comorbidity burden (CCI > 4) independently predicted a higher risk of recurrence (HR 1.42, 95% confidence interval (CI) 1.06-1.92, p = 0.018). After multivariable adjustment, the hazard of recurrence increased by 5% per each one-unit increase on the CCI scale (HR 1.05, 95% CI 1.00-1.10, p = 0.04). CONCLUSIONS: Comorbidities in NMIBC patients are common. Our data suggest that patients with higher CCI have an increased risk of BC recurrence. As a consequence, patients with a high comorbidity burden should be particularly encouraged to adhere to NMIBC guidelines and conform to follow-up protocols.

Adjuvant treatment and outcome of stage III melanoma patients: Results of a multicenter real-world German Dermatologic Cooperative Oncology Group (DeCOG) study.

PURPOSE: Clinical trials demonstrated significantly improved recurrence-free survival (RFS) of melanoma patients receiving adjuvant treatment. As data from controlled trials are based on selected populations, we investigated adjuvantly treated stage III melanoma patients under real-world conditions. PATIENTS AND METHODS: In a prior multicenter cohort study, stage III-IV melanoma patients were analysed for their choice of adjuvant therapy. In this follow-up study, we examined RFS, overall and melanoma-specific survival (MSS) and response to the subsequent treatment of 589 stage III patients (232 BRAF-mutated) receiving adjuvant PD-1 inhibitors (PD1; n = 479) or targeted therapy (TT; n = 110). RESULTS: The median follow-up of the total cohort was 25.7 months. The main reason for premature discontinuation of adjuvant therapy was disease progression in PD1- (28.8%, n = 138/479) and adverse events in TT-treated patients (28.2%, n = 31/110). Among BRAF-mutated patients, RFS at 24 months was 49% (95% CI 40.6-59.0%) for PD1- and 67% (95% CI 58-77%) for TT-treated patients. The risk of recurrence was higher for BRAF-mutated PD1 than TT (hazard ratio 1.99; 95% CI 1.34-2.96; hazard ratio adjusted for age, sex and tumour stage, 2.21; 95% CI 1.48-3.30). Twenty-four months MSS was 87% (95% CI 81.0-94.1) for PD1 and 92% (95% CI 86.6-97.0) for TT. Response to subsequent systemic treatment for unresectable disease was 22% for all PD1- and 16% for TT-treated patients. CONCLUSIONS: PD1-treated patients had more and earlier recurrences than TT patients. In BRAF-mutated patients, adjuvant TT might prevent early recurrences more effectively than PD1 treatment. Management of recurrence despite adjuvant treatment is challenging, with low response to current therapeutic options.

Evaluation of 3D MRI for early detection of bone edema associated with apical periodontitis.

OBJECTIVES: To detect and evaluate early signs of apical periodontitis using MRI based on a 3D short-tau-inversion-recovery (STIR) sequence compared to conventional panoramic radiography (OPT) and periapical radiographs in patients with apical periodontitis. MATERIALS AND METHODS: Patients with clinical evidence of periodontal disease were enrolled prospectively and received OPT as well as MRI of the viscerocranium including a 3D-STIR sequence. The MRI sequences were assessed for the occurrence and extent of bone changes associated with apical periodontitis including bone edema, periradicular cysts, and dental granulomas. OPTs and intraoral periapical radiographs, if available, were assessed for corresponding periapical radiolucencies using the periapical index (PAI). RESULTS: In total, 232 teeth of 37 patients (mean age 62±13.9 years, 18 women) were assessed. In 69 cases reactive bone edema was detected on MRI with corresponding radiolucency according to OPT. In 105 cases edema was detected without corresponding radiolucency on OPT. The overall extent of edema measured on MRI was significantly larger compared to the radiolucency on OPT (mean: STIR 2.4±1.4 mm, dental radiograph 1.3±1.2 mm, OPT 0.8±1.1 mm, P=0.01). The overall PAI score was significantly higher on MRI compared to OPT (mean PAI: STIR 1.9±0.7, dental radiograph 1.3±0.5, OPT 1.2±0.7, P=0.02). CONCLUSION: Early detection and assessment of bone changes of apical periodontitis using MRI was feasible while the extent of bone edema measured on MRI exceeded the radiolucencies measured on OPT. CLINICAL RELEVANCE: In clinical routine, dental MRI might be useful for early detection and assessment of apical periodontitis before irreversible bone loss is detected on conventional panoramic and intraoral periapical radiographs.

Preoperative fibrinogen/CRP score predicts survival in upper urothelial tract carcinoma patients undergoing radical curative surgery.

PURPOSE: Upper tract urothelial carcinoma (UTUC) represents an often aggressive malignancy associated with poor prognosis. Therefore, finding reliable prognostic biomarkers in patients undergoing curative surgery for improved risk stratification is crucial. We evaluated the prognostic value of the Fibrinogen/C-reactive protein (FC)-score in a cohort of surgically treated UTUC patients. METHODS: 170 patients with radiologically and histologically verified UTUC who underwent radical curative surgery between 1990 and 2020, were included. The FC-score was calculated for each patient, with patients receiving 1 point each if Fibrinogen and/or CRP levels were elevated above the 25th or 75th percentile, respectively. Patients were divided into three subgroups according to their FC-score of 0, 1 or 2 point(s). Kaplan-Meier analysis, uni- and multivariable Cox proportional hazard models were implemented. We determined cancer-specific survival (CSS) as primary endpoint, whereas overall survival (OS) and recurrence-free survival (RFS) were considered secondary endpoints. RESULTS: High FC-score (2 points) was significantly associated with adverse histological features such as vascular invasion (OR = 4.08, 95%CI 1.18-14.15, p = .0027) and tumour necrosis (OR = 6.67, 95%CI 1.35-32.96, p = 0.020). Both, uni- and multivariable Cox proportional hazard models showed the FC-score as a significant predictor for CSS (univariable analysis: FC-score = 1: HR = 1.90, 95%CI 0.92-3.93, p = 0.085 | FC-score = 2: HR = 2.86, 95%CI 1.22-6.72, p = 0.016). Furthermore, in univariable analysis, patients with higher FC-score had significantly shorter OS (FC-score = 1: HR = 1.32, 95%CI 0.70-2.49, p = 0.387 | FC-score = 2: HR = 2.19, 95%CI 1.02-4.67, p = 0.043). However, this did not prevail in multivariable analysis. CONCLUSION: The FC-score represents a novel potential biomarker in patients with UTUC undergoing radical curative surgery.

Development and Evaluation of MR-Based Radiogenomic Models to Differentiate Atypical Lipomatous Tumors from Lipomas.

BACKGROUND: The aim of this study was to develop and validate radiogenomic models to predict the MDM2 gene amplification status and differentiate between ALTs and lipomas on preoperative MR images. METHODS: MR images were obtained in 257 patients diagnosed with ALTs (n = 65) or lipomas (n = 192) using histology and the MDM2 gene analysis as a reference standard. The protocols included T2-, T1-, and fat-suppressed contrast-enhanced T1-weighted sequences. Additionally, 50 patients were obtained from a different hospital for external testing. Radiomic features were selected using mRMR. Using repeated nested cross-validation, the machine-learning models were trained on radiomic features and demographic information. For comparison, the external test set was evaluated by three radiology residents and one attending radiologist. RESULTS: A LASSO classifier trained on radiomic features from all sequences performed best, with an AUC of 0.88, 70% sensitivity, 81% specificity, and 76% accuracy. In comparison, the radiology residents achieved 60-70% accuracy, 55-80% sensitivity, and 63-77% specificity, while the attending radiologist achieved 90% accuracy, 96% sensitivity, and 87% specificity. CONCLUSION: A radiogenomic model combining features from multiple MR sequences showed the best performance in predicting the MDM2 gene amplification status. The model showed a higher accuracy compared to the radiology residents, though lower compared to the attending radiologist.

Efficacy and toxicity of adjuvant radiotherapy in recurrent melanoma after adjuvant immunotherapy.

BACKGROUND: In patients with stage III melanoma, despite surgical resection and adjuvant systemic therapy, locoregional recurrences still occur. The randomized, phase III Trans-Tasman Radiation Oncology Group (TROG) 02.01 trial demonstrated that adjuvant radiotherapy (RT) after complete lymphadenectomy (CLND) halves the incidence of melanoma recurrence within local nodal basins without improving overall survival or quality of life. However, the study was conducted prior to the current era of adjuvant systemic therapies and when CLND was the standard approach for microscopic nodal disease. As such, there is currently no data on the role of adjuvant RT in patients with melanoma who recur during or after adjuvant immunotherapy, including those that may or may not have undergone prior CLND. In this study, we aimed to answer this question. METHODS: Patients with resected stage III melanoma who received adjuvant anti-programmed cell death protein-1 (PD-1) (±ipilimumab) immunotherapy with a subsequent locoregional (lymph node and/or in-transit metastases) recurrence were retrospectively identified. Multivariable logistic and Cox regression analyses were conducted. Primary outcome was rate of subsequent locoregional recurrence; secondary outcomes were locoregional recurrence-free survival (lr-RFS2) and overall RFS (RFS2) to second recurrence. RESULTS: In total, 71 patients were identified: 42 (59%) men, 30 (42%) BRAF V600E mutant, 43 (61%) stage IIIC at diagnosis. Median time to first recurrence was 7 months (1-44), 24 (34%) received adjuvant RT and 47 (66%) did not. Thirty-three patients (46%) developed a second recurrence at a median of 5 months (1-22). The rate of locoregional relapse at second recurrence was lower in those who received adjuvant RT (8%, 2/24) compared with those who did not (36%, 17/47, p=0.01). Adjuvant RT at first recurrence was associated with an improved lr-RFS2 (HR 0.16, p=0.015), with a trend towards an improved RFS2 (HR 0.54, p=0.072) and no effect on risk of distant recurrence or overall survival. CONCLUSION: This is the first study to investigate the role of adjuvant RT in patients with melanoma with locoregional disease recurrence during or after adjuvant anti-PD-1-based immunotherapy. Adjuvant RT was associated with improved lr-RFS2, but not risk of distant recurrence, demonstrating a likely benefit in locoregional disease control in the modern era. Further prospective studies are required to validate these results.

Characterisation and outcome of RAC1 mutated melanoma.

BACKGROUND: Activating hot spot R29S mutations in RAC1, a small GTPase influencing several cellular processes including cell proliferation and cytoskeleton rearrangement, have been reported in up to 9% of sun-exposed melanomas. Clinical characteristics and treatment implications of RAC1 mutations in melanoma remain unclear. METHODS: We investigated the largest set (n = 64) of RAC1 mutated melanoma patients reported to date, including a retrospective single institution cohort (n = 34) from the University Hospital Essen and a prospective multicentre cohort (n = 30) from the translational study Tissue Registry in Melanoma (TRIM; CA209-578), for patient and tumour characteristics as well as therapy outcomes. RESULTS: From 3037 sequenced melanoma samples screened RAC1 mutations occurred in ∼2% of samples (64/3037). The most common RAC1 mutation was P29S (95%, 61/64). The majority of tumours had co-occuring MAP kinase mutations (88%, 56/64); mostly activating NRAS (47%, 30/64) mutations, followed by activating BRAF (28%, 18/64) and NF1 (25%, 16/64) mutations. RAC1 mutated melanomas were almost exclusively of cutaneous origin (84%, 54/64) or of unknown primary (MUP, 14%, 9/64). C > T alterations were the most frequent mutation type identified demonstrating a UV-signature for RAC1 mutated melanoma. Most patients with unresectable disease (39) received immune checkpoint inhibitors (ICI) (77%, 30/39). Objective response rate of first-line treatment in patients with stage III/IV disease was 21%; median overall survival was 47.8 months. CONCLUSIONS: RAC1 mutated melanomas are rare, mostly of cutaneous origin and frequently harbour concomitant MAP kinase mutations, particularly in NRAS. Patients with advanced disease benefit from systemic treatment with ICI.

The relationship between the lateral cutaneous antebrachial nerve and the superficial branch of the radial nerve and its impact on regional anesthetic and pain blocks of the thumb; What is more important: Nerves or dermatomes?

BACKGROUND: Innervation of the thumb and radial part of the dorsum of the hand is achieved primarily by the radial nerve, which is usually blocked for hand surgery. Inefficient blocks occur because the lateral antebrachial cutaneous nerve also extends into this area. The question then arises, whether skin innervation and peripheral blocking techniques should be directed at from the innervation by these nerves or more by the dermatome and its spinal segments. METHODS: In 68 human upper limbs embalmed with Thiel's method, the topography of the lateral antebrachial cutaneous nerve (LACN), the superficial branch of the radial nerve (sbRN) and communicating branch (CB) were investigated by meticulous dissection from the cubital fossa to the most distal macroscopically dissectible branch, and the areas reached by these nerves were compared to the described dermatome. RESULTS: In 52.9% of all specimens, the LACN was found proximal to the rascetta, in 35.3% it extended to the base of the thumb, and in 8 cases (11.8%) it extended distally to the base of the thumb. In 50%, the LACN was anterolateral to the brachioradialis muscle, and in 38.2%, strictly lateral. Only in 8 cases (11.8%) the LACN presented itself running more dorsally and laterally. A CB was observed in 28 specimens (41.2%). Both investigated nerves were found to innervate the dermatomes of C6 and C7. CONCLUSIONS: The LACN should be considered for individual targeted blocks for surgical procedures and pain therapy within the wrist and thumb region as all nerves that might contribute to innervation of a targeted dermatome should be blocked.

Derotational distal femoral osteotomy for patients with recurrent patellar instability and increased femoral antetorsion improves knee function and adequately treats both torsional and valgus malalignment.

PURPOSE: The aim of the study was to evaluate the functional and radiological outcome following derotational distal femoral osteotomy (D-DFO) in patients with high-grade patellofemoral instability (PFI) and an associated increased femoral antetorsion (FA). It was hypothesized that D-DFO would lead to a good functional and radiological outcome, and that both torsional and coronal malalignment could be normalized. METHODS: Patients that underwent D-DFO between 06/2011 and 12/2018 for high-grade PFI with an increased FA (> 20°) were included. Patient-reported outcome measures (Visual Analog Scale [VAS] for pain, Kujala score, Lysholm score, International Knee Documentation Committee subjective knee form [IKDC], and Tegner Activity Scale [TAS]) were evaluated pre- and minimum 24 months postoperatively. Magnetic resonance imaging of the lower extremity and weight-bearing whole-leg anteroposterior radiographs were conducted pre- and postoperatively. The change in FA, coronal limb alignment, and PROMs were tested for statistical significance. RESULTS: In total, 27 patients (30 knees) were included. The D-DFO aimed to only correct FA (Group 1) or to additionally perform a varization (Group 2) in 14 cases each. In the remaining two cases, double-level osteotomies were performed to correct additional tibial deformities. In 25 cases (83.3%), concomitant procedures also addressing patellofemoral instability were performed. At follow-up (38.0 months [25-75% interquartile range 31.8-52.5 months]), a significant reduction in pain (VAS for pain: 2.0 [1.0-5.0] vs. 0 [0-1.0], p < 0.05), significant improvement in knee function (Kujala Score: 55.6 ± SD 13.6 vs. 80.3 ± 16.7, p < 0.05; Lysholm Score: 58.6 ± 17.4 vs. 79.5 ± 16.6, p < 0.05; IKDC: 54.6 ± 18.7 vs. 74.1 ± 15.0, p < 0.05), and an increase in sporting activity (TAS: 3.0 [3.0-4.0] vs. 4.0 [3.0-5.0], p = n.s.) were reported. Femoral antetorsion was significantly reduced (28.2 ± 6.4° vs. 13.6 ± 5.2°, p < 0.05). A significant varization was observed in Group 2 (2.4 ± 1.2° valgus vs. 0.3 ± 2.4° valgus; p < 0.05). In one case, patellar redislocation occurred 70 months postoperatively. CONCLUSION: In patients with PFI and an associated increased FA, D-DFO achieved a significant reduction in pain, an improvement of subjective knee function, as well as an adequate correction of torsional and coronal alignment. LEVEL OF EVIDENCE: Retrospective case series, Level IV.