Heidelberg University

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.

Plastic and reconstructive surgery (PRS) encompasses a wide range of procedures, and postoperative complications remain a persistentchallenge. While preoperative laboratory values (PLVs) are routinely assessed, their predictive value for postoperative outcomes inPRS is unclear. This study evaluates the association between PLVs and postoperative morbidity to enhance risk stratification. The ACS-NSQIP database (2008-2022) was analyzed for PRS patients. PLVs included sodium, blood urea nitrogen, creatinine, albumin, bilirubin, SGOT, alkaline phosphatase, white blood cell count, hematocrit, platelets, partial thromboplastin time, international normalized ratio, and prothrombin time (PT). Multivariate logistic regression identified independent predictors of complications, while decision tree analysis established risk thresholds, validated through cross-validation. A total of 200,015 patients with a mean age of 50.3±14.5 years and a mean BMI of 29.1±6.8 kg/m2 were included in this study. Albumin levels emerged as the strongest predictor for the occurrence of any complications. Patients with albumin ≤ 3.3 g/dL had a 36.5% risk for the occurrence of any complication compared to 10.4% in those with higher levels. In the high-risk group, prolonged PT (> 16.2s) further increased risk for the occurrence of any complications. Also, in the lower-risk group (albumin > 3.3 g/dL), prolonged PT (> 13.7 s) were found to significantly influence complication occurrence. Further, multivariate analysis confirmed reduced albumin (OR 0.460) as the strongest independent predictors for any complication occurrence. Albumin and PT are key predictors of 30-day postoperativecomplications in PRS. Preoperative optimization of these values can enhance patient safety and surgical outcomes. Findings support integrating targeted preoperative evaluations into clinical practice. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

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.

Brl1 and Brr6 are integral membrane proteins of the yeast nuclear envelope (NE) that transiently associate with nuclear pore complexes (NPCs). The exact roles of Brl1 and Brr6 during NPC assembly are unclear. Here, we demonstrate that Brr6 operates at both early and late stages of NPC assembly. Its early function is supported by amphipathic α-helix mutants, which impact nucleoporin recruitment without nuclear envelope deformation, whereas mutations in conserved cysteine residues result in NE deformation accompanied by defective NE fusion. The N-terminus of Brl1 interacts with the nucleoporin Nic96, promoting Nic96 recruitment to early assembly sites. AlphaFold predictions, the essential role of the conserved PAL motif, and the inhibition of NE fusion upon overexpression of PAL mutants together suggest that the perinuclear domains of Brl1 and Brr6 interact across the perinuclear space. Extending the length of the perinuclear-space regions of Brl1 and Brr6 causes uncontrolled NE fusion, as indicated by nuclear envelope disintegration dependent on the conserved cysteine residues. Together, Brl1 and Brr6 promote NE fusion by bridging the perinuclear space through PAL motif interactions, followed by nuclear envelope fusion and NPC insertion.

Systolic blood pressure (SBP) variability has been associated with an increase in rates of death or disability in patients with intracerebral hemorrhage (ICH). We analyzed data from the Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH)-2 trial to determine whether the association between SBP variability and death or disability at 90days is dependent on the time from randomization. The difference between maximum and minimum SBP (hourly SBP range) for the first 24h after enrollment was used to calculate the hourly SBP variability. The effect of hourly SBP variability was evaluated in logistic regression models on: (1) death or disability (modified Rankin scale score of 4-6 at 90days), (2) hematoma expansion (increase of > 33% in volume on the computed tomography scan obtained at 24h) within 24h, (3) neurological deterioration within 24h, and (4) acute kidney injury within 72h after enrollment. We adjusted for age, baseline Glasgow Coma Scale score, intraventricular hemorrhage, hematoma volume, and maximum SBP values for each time window. A total of 961 patients (mean age ± standard deviation [SD], 62 ± 13years; 61.9% were men) who were enrolled at a mean ± SD time of 184 ± 56min from symptom onset were analyzed. The mean ± SD hourly SBP variability was 15.6 ± 16mm Hg. The hourly SBP variability became significantly lower with increasing time intervals from randomization (ranging from 41.8 ± 23.3 at hour 1 to 12.4 ± 14.0 at hour 24, P < 0.0001). SBP variability at five hours (P = 0.014) and six hours (P = 0.014) after enrollment was significantly associated with death or disability at 90days, with positive but not statistically significant associations observed at all other points up to eight hours after randomization. Risk of neurological deterioration within 24h was highly associated with SBP variability, with the largest association observed between one (P < 0.001) and five (P < 0.001) hours following randomization, with significant associations observed up to 22h following randomization. Risk of hematoma expansion was associated with SBP variability between three (P = 0.015) and eight (P = 0.002) hours after randomization. Statistically significant associations between SPB variability and risk of acute kidney injury were not observed. Reduced SBP variability within the first eight hours following randomization appears most impactful on both short-term and long-term outcomes in patients with ICH, and the first eight hours may represent a time window for future interventions directed at reducing SBP variability in patients with ICH.

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.