University Hospital Heidelberg

RET fusions appear in 1%-2% of non-small cell lung cancers (NSCLCs). The results from the ARROW study (ClinicalTrials.gov identifier: NCT03037385) supported US Food and Drug Administration approval of pralsetinib, an oral selective RET inhibitor, for metastatic RET-altered NSCLC and RET fusion-positive thyroid cancers. ARROW was a phase I/II open-label study of pralsetinib 400 mg once daily in RET fusion-positive NSCLCs. Coprimary end points were overall response rate (ORR) and safety. Key secondary end points included duration of response, progression-free survival, and overall survival (OS). At data lock (May 20, 2024), 281 patients initiated pralsetinib (median treatment duration, 15.0 months). ORR (measurable disease patients; n = 259) was 78% (95% CI, 69 to 86) for treatment-naïve patients and 63% (95% CI, 54 to 71) for prior platinum-based chemotherapy patients. Median OS was 44.3 months (95% CI, 30.9 to 53.1), 50.1 months (95% CI, 28.3 to not reached) in treatment-naïve patients, and 39.7 months (95% CI, 27.8 to 53.2) in prior platinum patients. Common grade ≥3 treatment-related adverse events were anemia (21%), hypertension (15%), and decreased neutrophils (13%). Three treatment-related deaths occurred (pneumonia, n = 2; interstitial lung disease and rhabdomyolysis, n = 1 each). Safety was consistent with previous ARROW reports; no hypersensitivity was reported in patients receiving prior immunotherapies. Pralsetinib produced robust, durable responses with manageable safety in treatment-naïve and previously treated patients with RET fusion-positive NSCLCs, confirming previous findings with longer follow-up.

Pineoblastoma is a clinically aggressive childhood brain tumor composed of distinct molecular subgroups with divergent driver genes, demographics, and clinical outcomes. To identify developmental origins and mechanisms governing disease pathogenesis, we derive single-cell transcriptomes from pineal parenchymal tumors, aligning malignant cells with developmental counterparts to retrace cellular origins. Integrative computational analyses map pineoblastoma origins to transient, cycling pinealocyte progenitors during development. Lineage-specific perturbation of suspected drivers in the early pineal gland yields preclinical models representative of consensus molecular subgroups. Multi-omic characterization of patient tumors and these models uncover a tumor-associated photoreceptor signature (TAPS) common to pineoblastoma, retinoblastoma, and Group 3 medulloblastoma. Transcriptional activity of this signature within respective cellular origins establishes a developmental basis for molecular similarities between entities. Photoreceptor signature constituents are selective dependencies across these anatomically distinct central nervous system malignancies, motivating future studies evaluating developmentally encoded programs of malignancy as potential therapeutic liabilities.

Penicillin allergy is the most frequently reported allergy in hospitalized patients, although rarely confirmed. Given the negative outcomes associated with incorrect penicillin allergy diagnoses, implementation of programmatic delabeling strategies is important for successful antibiotic stewardship. This systematic review evaluates the effectiveness of different delabeling strategies and highlights elements and settings that facilitate or constrict their implementation. Following the PRISMA-statement PubMed/MEDLINE, EMBASE, Cochrane Library, and grey literature databases "Worldcat" and "OpenGrey" were searched for studies reporting on interventions to identify, evaluate, or rule out incorrect penicillin allergy in hospitalized adults. Data extraction included settings, intervention types, and their effectiveness, barriers, facilitators, and regulatory factors. This review included 42 studies, involving 6269 patients undergoing penicillin allergy delabeling, with 5017 (80%) successfully delabeled. Effectiveness varied from 32% to 99%. Skin testing had the highest success rate at 87%, followed by a combination of skin testing and oral challenge (84%), and direct oral challenges (77%). Direct delabeling alone had a lower effectiveness (67%), which improved to 80% when paired with oral challenges. Key facilitators included standardized algorithms and involvement of interdisciplinary teams. Barriers included patient refusal, staff resistance, time constraints, and financial limitations, particularly in smaller hospitals. Dependent on financial and staffing resources, oral challenges and direct delabeling after risk stratification may be alternatives to resource-intensive methods, such as skin testing, for successful delabeling. To address barriers to widespread delabeling implementation, patient and provider education must be improved, interprofessional collaboration enhanced, and standardized protocols developed.

Minimally invasive liver surgery has rapidly evolved in recent years. In addition to the laparoscopic liver resection (LLR), robot-assisted liver resection (RLR) is increasingly gaining in importance; however, although the robotic-assisted approach offers clinical benefits, particularly in complex procedures, it remains amatter of debate. The aim of this study was to present the development, perioperative outcomes, key challenges, and insights from over 500 minimally invasive liver resections performed at aspecialized high-volume center. It focused on the comparison between LLR and RLR based on the IWATE difficulty score. Aretrospective single-center analysis of 526 consecutive elective minimally invasive liver resections (2018-2024) was conducted. All cases were stratified using the IWATE score. The LLR and RLR were compared in terms of operative parameters, conversion rate and postoperative complications. Additionally, the annual procedural development was analyzed. The RLR was established in 2021 and accounted for over 50% of all minimally invasive liver resections by 2024. Compared to LLR, RLR was associated with significantly reduced intraoperative blood loss as well as lower conversion and complication rates, particularly in technically demanding resections. Despite an increasing proportion of advanced/expert resections, the rate of major complications could be reduced over time. Minimally invasive liver resections can be safely performed at high-volume centers. The robotic-assisted technique offers specific advantages especially in complex resections, with respect to complication rates, reduced conversion rates and decreased blood loss. Akey success factor in the implementation of robotic liver surgery is the pre-existing expertise in laparoscopic techniques, which significantly shortened the learning curve. The use of standardized techniques such as the scissor hepatectomy may have contributed to the comparatively low rate of bile leaks observed in RLR.

To assess variability of maximum diameter measurements of prostate lesions in MRI assessing patient repositioning, rater and sequence effects. Forty-two patients were included retrospectively, who received a clinical bi-/multiparametric prostate MRI examination and agreed to have the T2-weighted (T2WI) and diffusion weighted-imaging (DWI) sequences scanned twice. Maximum diameter measurements of prostate lesions mentioned in the clinical radiologist reports were performed by four readers in multiple reading sessions for determination of inter-sequence (between two DWI sequences), inter-scan (between clinical and additional scan), intra-rater and inter-rater variability. The primary calculated metrics were the repeatability and reproducibility coefficient (RC/RDC), including pooled RC/RDC. Variability measured by RCs/RDCs was lowest for measurements obtained within the same reading session, with inter-scan RCs up to 5.6mm/6.5mm for T2WI/DWI, pooled RCs of 4.8mm/5.8mm, respectively, and inter-sequence RDCs of 5.4mm-5.9mm, pooled RDC 5.8mm. Measurements performed in separate reading sessions demonstrated significantly higher variability for both settings in the majority of cases (RCs: up to 10.9mm/11.7mm/10.2mm for T2WI/DWI/inter-sequence, p≤0.002), pooled RCs/RDCs 9.2mm-9.9mm. Measurements necessarily generated in different reading sessions, i.e., intra-rater or inter-rater, demonstrated high variability (RCs/RDCs up to 11.4mm/11.5mm for T2WI/DWI). Prostate lesion measurements demonstrate considerable variability. When measured in one reading session by one rater, lesion diameter differences below the pooled RCs of 4.8mm, 95%-CI [3.9, 5.6] for T2WI and 5.8mm, 95%-CI [4.7, 7.1] for DWI should not necessarily assumed to be true biological change, as these differences may result from measurement- or repositioning-based variability alone. Caution needs to be taken assessing size changes.

Non-unions (NU) after fractures, especially in cases with the need of surgical intervention, represent one of the most severe complications in traumatology. As previous studies estimate post-fracture NU risk between 2% and 10% data inconsistencies persist. In particular, the data on the influence of different anatomical regions, age and sex on fracture associated NU is scarce. Therefore, this study aims to provide a comprehensive descriptively assessment of the ratio of surgically treated tibia and femur NU to tibia and femur fractures based on a nationwide dataset, with a specific focus on differences across anatomical regions. This retrospective, population-based, cross-sectional analysis of the German InEK database (2019-2023) was conducted, including 888,442 fractures and 3,017 NU cases. The study focused on ICD- (International Statistical Classification of Diseases and Related Health Problems-) coded diagnoses of femur and tibia NU and their associated fractures. To enhance precision, fracture and NU sites were grouped according to different anatomical regions assessed by documented OPS- (Operation and Procedure Classification System) codes. Subgroup analyses were performed for age and sex. Surgically treated femoral shaft NU had the highest incidence (0.18 cases per 100,000 residents and year), followed closely by tibial shaft NU (0.16). The highest NU/100-fractures ratio was observed in tibial shaft (1.277), followed by distal tibia (1.095) and distal femur (0.996). Across all localisations, men had clearly higher NU/100-fractures ratios than women. NU/100-fractures ratios also varied with age, with highest ratio in the economically active population, followed by a generally decline in older patients. This nationwide database study indicates that surgically treated NU/fracture ratios of femur and tibia are generally low. The proportion of NU to fracture differ between different anatomical regions. In general, proximal localisations showed lower NU/100-fractures ratios than distal localisations within the femur and in comparison of femur and tibia. Independently of the anatomical localisation men had a higher NU/100-fractures ratio than women. As highest NU/100-fractures ratios were detected in the economically active population, this highlights the substantial socioeconomic burden associated with this condition.

Neurological recovery following spinal cord injury (SCI) is commonly studied through changes in high-level descriptors of injury severity, such as the American Spinal Injury Association Impairment Scale (AIS) grade, or total upper and/or lower extremity motor scores. More recently, the analysis of segmental motor scores has attracted interest as it provides a more detailed understanding of the exact location and extent of changes occurring during recovery. We propose to augment the analysis of segmental motor recovery with a qualitative descriptor of local motor score patterns, which is defined for all upper and lower extremity myotomes below the neurological level of injury (NLI) and based on a categorization of the changes along the rostrocaudal motor score sequence. Our hypothesis is that recovery of segmental motor scores depends on the residual function as described by the newly proposed descriptors of local motor score patterns. Using data of 1385 patients from the European Multicenter Study about SCI, we analyze differences in recovery at approximately 6 months after injury between local motor score patterns and find an increased probability of full motor recovery for myotomes associated with increased motor scores in the caudal direction. We further use an aggregated descriptor of motor score patterns focusing on increases of motor scores in the caudal direction as an alternative or complementary feature to the AIS grade in prediction models for segmental motor scores at recovery. We observe equivalent predictive performance as measured by the root mean square error between actual and predicted motor scores below the NLI for models using the same set of features and additionally either the AIS grade (median = 0.79) or local pattern (median = 0.80). This is noteworthy as the definition of local motor score patterns requires only the examination of the 10 key muscles of the International Standards for Neurological Classification of SCI on each side of the body, while the AIS grade can only be reliably determined if extensive sensory testing is performed in addition. These results indicate the potential benefits of considering information inherent to the rostrocaudal sequence of motor scores for a better understanding of motor recovery. Furthermore, it supports the development and use of abbreviated sensorimotor examinations specifically in the early phase after SCI.

Handheld ultrasound (HHUS) devices are increasingly used in clinical practice due to their portability and cost-effectiveness. However, HHUS image quality remains variable, and a standardized expert-based evaluation protocol is lacking. This study compares the image quality of B-mode recordings of five HHUS models with a high-end reference system (HEUS) using a blinded assessment to identify differences, covariates, offering a standardized evaluation framework.In this blinded, multi-center study, video sequences of the liver, pancreas, and sigmoid colon were recorded in ten volunteers using 5 HHUS devices - Vscan Air, Butterfly iQ+, Philips Lumify, Clarius C3, and Clarius C3 HD3 - and one HEUS (GE Logiq E10). Twenty-two physicians with many years of abdominal ultrasound experience rated blinded clips for 5 image quality parameters.The HEUS consistently received the highest ratings. Image quality differed significantly between HHUS devices. Clarius systems showed the smallest deviation from the reference, followed by Vscan Air and Philips Lumify. All image parameters significantly correlated with the overall impression, without a single dominant factor. The patients' BMI had no relevant influence. Examiner experience was less impactful than device familiarity and personal preference.The image quality of HEUS remained superior to all tested HHUS devices. Further subdivision of image quality aspects did not provide additional information. Furthermore, we could not identify significant covariates in our setup. These findings could justify simplified setups with reduced questionnaires and requirements for examiners.