Application of the 5th WHO Guidelines for the Diagnosis of Lung Carcinoma in Small Lung Biopsies in a Tertiary Care Center: Is Insecurity of Pathologists for the Accurate Diagnosis Justified?

BACKGROUND/OBJECTIVES: The diagnosis of lung carcinoma (LC) is currently performed in small biopsies and according to the WHO classification by using limited stains to spare tissue for molecular testing. This procedure, however, often causes diagnostic uncertainty among pathologists. METHODS: In this retrospective analysis, we compared the diagnosis made by these guidelines in 288 lung biopsies with that using more stains, as retrieved from our archive. We also compared the results of p63 and p40 immunoexpression and investigated the diagnostic role of p53/Rb1. RESULTS: In our investigation, we reached a definite diagnosis with a mean number of one stain compared with six stains in the original diagnostic procedure, with a 97.3% concordance rate. Only in the case of metastases, a clear advantage is proven in the use of more stains, especially in the absence of clinical information. We also found a comparable utility of p40 and p63 for the diagnosis of squamous cell carcinoma, despite the higher p63 expression in other histological types. Moreover, normal p53/Rb1 expression could be utilized for the exclusion of small-cell LC. CONCLUSIONS: Our study confirms the diagnostic certainty achieved by the suggestions of the WHO classification and justifies the potential insecurity in the absence of adequate communication with the treating clinician.

Interactions of contact force, impedance and power during repeat atrial arrhythmia ablation after previous atrial fibrillation ablation.

BACKGROUND: Acutely effective repeat radiofrequency catheter ablation (RFCA) after previous atrial fibrillation ablation depends on several parameters including local impedance (LI), contact force (CF) and power. OBJECTIVE: To investigate the relationship of LI, CF and power to the LI drop in a repeat atrial RFCA environment. METHODS: Consecutive patients undergoing repeat atrial RFCA were studied. High-quality local electrograms (EGMs) were analyzed regarding morphology changes indicating effective RFCA and associated LI dynamics. The influence of baseline LI, mean CF and power on the LI drop was analyzed. Investigated power levels included ≤25 W, 30 W and ≥40 W. RESULTS: 1390 RFCA points from 48 patients (48 % female, median age 70 years) were analyzed. 40.5% of 309 analyzed EGMs showed effective RFCA morphology changes with a higher median LI drop (effective 19.7 Ω vs partially effective 14.1 Ω, p<0.001). CF showed the highest correlation to the LI drop within high baseline LI and when applying ≥40 W (low baseline LI, R=0.39; intermediate, R=0.66; high, R=0.72). Within low baseline LI regions, CF levels showed a lower correlation to the LI drop (≤25 W, R=0.30; 30 W, R=0.35; ≥40 W, R=0.39). A mean CF ≥10 g resulted in elevated LI drops with higher power compared to lower power within all baseline LI tertiles (p<0.001 each). CONCLUSION: Within rather high baseline LI regions, CF plays a greater role for the maximum LI drop when higher power is chosen. A mean CF ≥10 g ensures increased LI drops with increasing power levels.

Early detection of malignant and pre-malignant peripheral nerve tumors using cell-free DNA fragmentomics.

PURPOSE: Early detection of neurofibromatosis type 1 (NF1) associated peripheral nerve sheath tumors (PNST) informs clinical decision-making, enabling early definitive treatment and potentially averting deadly outcomes. Here, we describe a cell-free DNA (cfDNA) fragmentomic approach which distinguishes non-malignant, pre-malignant and malignant forms of PNST in cancer predisposition syndrome NF1. EXPERIMENTAL DESIGN: cfDNA was isolated from plasma samples of a novel cohort of 101 NF1 patients and 21 healthy controls and underwent whole genome sequencing. We investigated diagnosis-specific signatures of copy number alterations (CNA) with in silico size selection as well as well as fragment profiles. Fragmentomics were analyzed using complementary feature types: bin-wise fragment size ratios, end-motifs, and fragment non-negative matrix factorization (NMF) signatures. RESULTS: The novel cohort of NF1 patients validated that our previous cfDNA CNA-based approach identifies malignant peripheral nerve sheath tumor (MPNST) but cannot distinguish among benign and premalignant states. Fragmentomic methods were able to differentiate pre-malignant states including atypical neurofibromas (AN). Fragmentomics also adjudicated AN cases suspicious for MPNST, correctly diagnosing samples noninvasively, which could have informed clinical management. CONCLUSIONS: Novel cfDNA fragmentomic signatures distinguish atypical neurofibromas from benign plexiform neurofibromas and malignant peripheral nerve sheath tumors, enabling more precise clinical diagnosis and management. This study pioneers the early detection of malignant and premalignant peripheral nerve sheath tumors in NF1 and provides a blueprint for de-centralizing non-invasive cancer surveillance in hereditary cancer syndromes.

Context-sensitivity and context-productivity: notions of "practice" and "practicality" in ethnomethodology and conversation analysis.

The text reconstructs the concepts of practice and practicality used in ethnomethodology and conversation analysis and examines their internal similarities and differences as well as similarities and differences to other practice theories. After a description of the characteristics of practice theories, the ethnomethodological perspective on practice and practicality is presented. Then, the use of the terms in conversation analysis is examined. Ethnomethodology uses the notions of "practice" and "practicality" to outline a non-metaphysical theory of social order in which the sharedness of rules or meanings is not presupposed. "Practical" here means that social action, and social order more generally, are practically grounded as well as temporally and situationally constrained. The fact that practical action is fundamentally situated and can only be understood "from within" establishes an essentially indexical character of practical action. In conversation analysis, "practices" are viewed as "context-free" but "context-sensitive" components that constitute action and as such become the objects of investigation. While some have diagnosed a departure of conversation analysis from its ethnomethodological roots, I argue that "context-freeness" and "context-sensitivity" should be complemented by "context-productivity" by reference to Garfinkel's interpretation of Aron Gurwitsch's gestalt phenomenology in order to formulate a more encompassing concept of practice.

Outcomes After Definitive Surgery for Spinal and Sacral Chordoma in 101 Patients Over 20 Years.

BACKGROUND AND OBJECTIVES: Spinal chordomas are primary bone tumors where surgery remains the primary treatment. However, their low incidence, lack of evidence, and late disease presentation make them challenging to manage. Here, we report the postoperative outcomes of a large cohort of patients after surgical resection, investigate predictors for overall survival (OS) and local recurrence-free survival (LRFS) times, and trend functional outcomes over multiple time periods. METHODS: Retrospective review of all patients followed for spinal chordoma at a quaternary spinal oncology center from 2003 to 2023 was included. Data were collected regarding demographics, preoperative and perioperative management, and follow-up since initial definitive surgery. Primary outcomes were OS and LRFS, whereas secondary outcomes were functional deficits. RESULTS: One hundred one patients had an average follow-up of 6.0 ± 4.2 years. At the time of census, 25/101 (24.8%) had experienced a recurrence and 10/101 (9.9%) had died. After surgery, patients experienced a significant decrease in pain over time, but rates of sensory deficits, weakness, and bowel/bladder dysfunction remained static. Tumors ≥100 cm3 (hazard ratio (HR) = 5.89, 95% CI 1.72-20.18, P = .005) and mobile spine chordomas (HR = 7.73, 95% CI 2.09-28.59, P = .002) are related to worse LRFS, whereas having neoadjuvant radiotherapy is associated with improved LRFS (HR = 0.09, 95% CI 0.01-0.88, P = .038). On the other hand, being age ≥65 years was associated with decreased OS (HR = 16.70, 95% CI 1.54-181.28, P = .021). CONCLUSION: Surgeons must often weigh the pros and cons of en bloc resection and sacrificing important but affected native tissues. Our findings can provide a benchmark for counseling patients with spinal chordoma. Tumors ≥100 cm3 appear to have a 5.89-times higher risk of recurrence, mobile spine chordomas have a 7.73 times higher risk, and neoadjuvant radiotherapy confers an 11.1 times lower risk for local recurrence. Patients age ≥65 years at surgery have a 16.70 times higher risk of mortality than those <65 years.

Expanded profiling of WD repeat domain 5 inhibitors reveals actionable strategies for the treatment of hematologic malignancies.

WD40 Repeat Domain 5 (WDR5) is a highly conserved nuclear protein that recruits MYC oncoprotein transcription factors to chromatin to stimulate ribosomal protein gene expression. WDR5 is tethered to chromatin via an arginine-binding cavity known as the "WIN" site. Multiple pharmacological inhibitors of the WDR5-interaction site of WDR5 (WINi) have been described, including those with picomolar affinity and oral bioavailability in mice. Thus far, however, WINi have only been shown to be effective against a number of rare cancer types retaining wild-type p53. To explore the full potential of WINi for cancer therapy, we systematically profiled WINi across a panel of cancer cells, alone and in combination with other agents. We report that WINi are unexpectedly active against cells derived from both solid and blood-borne cancers, including those with mutant p53. Among hematologic malignancies, we find that WINi are effective as a single agent against leukemia and diffuse large B cell lymphoma xenograft models, and can be combined with the approved drug venetoclax to suppress disseminated acute myeloid leukemia in vivo. These studies reveal actionable strategies for the application of WINi to treat blood-borne cancers and forecast expanded utility of WINi against other cancer types.

[Long-term courses of alcohol dependence]. / Langzeitverläufe der Alkoholabhängigkeit.

BACKGROUND: Descriptions of long-term histories of alcohol dependence provide insight into the etiology, prevention and care. OBJECTIVE: Report of empirical findings about the development into and remission from alcohol dependence. METHOD: Narrative literature review, analysis of findings from cohort studies in the general population. RESULTS: Risk factors provide the opportunity to estimate increased probabilities of developing an alcohol dependence. Adolescents disclosed symptoms of alcohol dependence within 8 years after the first alcohol consumption. Alcohol dependence is related to a life expectancy 17.6 years fewer than in the general population. Data of a general population sample revealed a risk of early death 2.8 times higher than among people without mental disorders. The severity of alcohol dependence was shown to be a predictor of premature death. Nicotine dependence can add to the shortening of life in addition to alcohol dependence. Among the alcohol dependent residents in a general population sample, 90.2% did not have utilized detoxification treatment that included motivational treatment and 78.4% did not have utilized standard detoxification treatment in a psychiatric treatment facility. Remission without formal help has been proven. It is the main route of remission. CONCLUSION: To reduce unfavorable courses of alcohol dependence, prevention and treatment should be focused more on the needs in the general population. In psychiatric and other medical routine care, screening and an appropriate brief intervention should be carried out.

[Sex-specific differences in surgical confidence: results of the Endo Workshop of the German Society of Residents in Urology 2022]. / Geschlechtsspezifische Unterschiede im chirurgischen Selbstvertrauen: Ergebnisse des Endo-Workshops der German Society of Residents in Urology 2022.

BACKGROUND: Simulation-based training is gaining importance in urologic residents training. OBJECTIVES: This prospective study evaluated the influence of the Endo Workshop of the German Society of Residents in Urology e. V. (GeSRU) on surgical confidence. MATERIALS AND METHODS: GeSRU Endo Workshop 2022 included 1 h simulation-based training sessions on stone removal using ureteroscopy (URS) and transurethral resection of the bladder (TURB). Using an online questionnaire, surgical confidence was assessed before and after the workshop. Surgical assessment relied on the global rating scale (GRS). RESULTS: Overall, 40 residents participated: 25 (62.5%) men and 15 (37.5%) women. In URS assessment, men vs. women achieved an average of 26.6 vs. 26.1/35 points on the GRS (p = 0.7) and completed the task in 8.1 ± 1.9 vs. 9.9 ± 0.4 min (p < 0.001). In TURB assessment, men vs. women achieved an average of 26.0 vs. 27.3/35 points on the GRS (p = 0.3) and required 7.6 ± 1.9 vs. 7.7 ± 2.2 min (p = 0.9), respectively. Among participants who answered the baseline survey and the evaluation (n = 33), 16 (80%) men vs. 3 (23%) women had surgical confidence to perform URS before (p = 0.01), and 19 (95%) men vs. 7 (54%) women after the workshop (p = 0.03). Regarding the performance of TURB, 10 (50%) men vs. 7 (54%) women reported surgical confidence before (p = 0.1), and 15 (75%) men vs. 10 (77%) women after the workshop (p = 1.0). An increase in surgical confidence to perform URS and TURB was reported by 9 (45%) and 10 (50%) men and 9 (69%) and 8 (62%) women, respectively. CONCLUSIONS: Endourologic simulation-based training increases surgical confidence of both female and male residents. Despite comparable surgical outcomes, women approach URS with lower surgical confidence compared to their male counterparts.

Ocular adnexal sebaceous carcinoma in a patient with Li-Fraumeni syndrome.

Li-Fraumeni syndrome (LFS) is caused by a pathogenic germline variant at the TP53 locus and is associated with an increased predisposition to a variety of cancers. The neoplasms most frequently associated with LFS are sarcomas, breast cancer, brain tumors, and adrenocortical carcinomas. In this case report, we present a 43-year-old male diagnosed with an ocular adnexal sebaceous carcinoma of the right upper eyelid who was confirmed to have LFS with subsequent genetic testing. The mutational profile of both the patient's genetic screen and tumor sequencing were congruent, demonstrating the same pathogenic loss-of-function TP53 variant. This case report highlights the importance of pursuing genetic testing in patients with a history of multiple tumor types, particularly those with uncommon diagnoses. In this case, confirmation of LFS had important implications for personalized patient care, including identification of contraindicated treatment interventions and the imaging modalities necessary for vigilant follow-up screening.

The predictive validity of MCAT scores and undergraduate GPA for COMLEX-USA licensure exam performance of students enrolled in osteopathic medical schools.

CONTEXT: Osteopathic (Doctor of Osteopathic Medicine [DO]) medical students account for more than 25 % of all medical students in the United States. OBJECTIVES: This study examined the predictive validity of Medical College Admission Test (MCAT) total scores and cumulative undergraduate grade point averages (UGPAs) for performance on the Comprehensive Osteopathic Medical Licensing Examination of the United States (COMLEX-USA) Level 1 and Level 2-CE (Cognitive Evaluation) licensure examinations administered by the National Board of Osteopathic Medical Examiners (NBOME). Additionally, the study examined the degree to which MCAT total scores and UGPAs provide comparable prediction of student performance by key sociodemographic variables. METHODS: This study involved a collaborative effort between the Association of American Medical Colleges (AAMC), the American Association of Colleges of Osteopathic Medicine (AACOM) and the NBOME. Data were examined for 39 accredited DO-granting medical schools in the United States during the 2017 application cycle. Researchers utilized three regression models that included MCAT total scores, cumulative UGPA, and combined MCAT total scores and cumulative UGPA to determine predictive validity. Researchers also examined the comparability of prediction for sociodemographic variables by examining the differences between observed and predicted error for both scores and pass/fail success rates. RESULTS: Medium to large correlations were discernible between MCAT total scores, UGPA, and COMLEX-USA examination outcomes. For both COMLEX-USA Level 1 and Level 2-CE scores and pass/fail outcomes, MCAT scores alone provided superior predictive value to UGPA alone. However, MCAT scores and UGPA utilized in conjunction provided the best predictive value. When predicting both licensure examination scores and pass/fail outcomes by sociodemographic variables, all three models provided comparable predictive accuracy. CONCLUSIONS: Findings from this comprehensive study of DO-granting medical schools provide evidence for the value-added benefit of taking MCAT scores and UGPA into consideration, particularly when these measures are utilized in conjunction. Further, findings provide evidence indicating that individuals from different sociodemographic backgrounds who enter medical school with similar MCAT scores and UGPA perform similarly on licensure examination outcome measures.

App-Based Addiction Prevention at German Vocational Schools: Implementation and Reach for a Cluster-Randomized Controlled Trial.

This article examines the implementation, participation rates, and potential determinants of participation in the digital addiction prevention program "ready4life." A two-arm cluster-randomized trial recruited German vocational students via class-based strategies. Intervention group received 16 weeks of in-app coaching; the control group received health behavior information, with coaching offered after 12 months. Potential determinants of participation were analyzed based on class and individual characteristics. Out of 525 contacted schools, 35 participated, enrolling 376 classes. Implementation during the pandemic required flexible adjustments, with 49.7% of introductions conducted in person, 43.1% digitally via online streaming, and 7.2% received a video link via email. Despite challenges, 72.3% of the vocational students downloaded the app, and 46.7% gave informed consent. Participation rates were highest among (associate) professionals, vocational grammar school classes, classes introduced by females, younger individuals, members of the project team, and classes introduced face-to-face. Female gender, lower social competencies, lifetime cannabis use, higher problematic internet use, and higher perceived stress were associated with higher individual participation. The study highlights the importance of proactive outreach and personalized interventions for addiction prevention programs in vocational schools. While reached students aligned with the aims of the app, tailored recruitment strategies could enhance engagement among under-represented groups. The trial was registered in the German Clinical Trials Register (DRKS): DRKS00022328; registration date 09.10.2020.

Pulmonary Vein Isolation or Pace and Ablate in Elderly Patients With Persistent Atrial Fibrillation (ABLATE Versus PACE)-Rationale, Methods, and Design.

Age is a major risk-factor for atrial fibrillation (AF) and associated hospitalisations. With increasing emphasis on rhythm control, pulmonary vein isolation (PVI) is often suggested, even to elderly patients (≥ 75 years of age). Efficacy of PVI aiming at rhythm control is limited in persistent AF. Pacemaker implantation with atrioventricular node (AVN) ablation may represent a reasonable alternative, with the aim of controlling symptoms and improving quality of life in elderly patients. In this investigator-initiated, randomised, multicentre trial, we test the hypothesis that pacemaker implantation and AVN ablation provides superior symptom control over PVI in elderly patients with symptomatic persistent AF, without any increase in adverse event profile. In the ABLATE Versus PACE (NCT04906668) prospective open-label superiority trial, 196 elderly patients with normal ejection fraction and symptomatic persistent AF despite guideline-indicated medical therapy will be randomised to either cryoballoon PVI (ABLATE) or dual-chamber pacemaker implantation with subsequent AVN ablation (PACE), and followed for a minimum of 12 months. The primary efficacy outcome is a composite end point of rehospitalisation for atrial arrhythmia or cardiac decompensation/heart failure, (outpatient) electrical cardioversion, or upgrade to cardiac resynchronisation therapy owing to worsening of left ventricular ejection fraction to ≤ 35%. Secondary end points include death from any cause, stroke, quality of life, and procedure-related complications. Sample size is designed to achieve 80% power for the primary end point (2-tailed alpha of 5%). ABLATE Versus PACE will determine whether pacemaker implantation and AVN ablation can improve symptom-control in elderly patients with persistent AF over PVI without increasing safety end points.

Cardioneuroablation for the treatment of reflex syncope and functional bradyarrhythmias: A Scientific Statement of the European Heart Rhythm Association (EHRA) of the ESC, the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS) and the Latin American Heart Rhythm Society (LAHRS).

Cardioneuroablation has emerged as a potential alternative to cardiac pacing in selected cases with vasovagal reflex syncope, extrinsic vagally induced sinus bradycardia-arrest or atrioventricular block. The technique was first introduced decades ago, and its use has risen over the past decade. However, as with any intervention, proper patient selection and technique are a prerequisite for a safe and effective use of cardioneuroablation therapy. This document aims to review and interpret available scientific evidence and provide a summary position on the topic.

Posttranslational regulation of photosynthetic activity via the TOR kinase in plants.

Chloroplasts are the powerhouse of the plant cell, and their activity must be matched to plant growth to avoid photooxidative damage. We have identified a posttranslational mechanism linking the eukaryotic target of rapamycin (TOR) kinase that promotes growth and the guanosine tetraphosphate (ppGpp) signaling pathway of prokaryotic origins that regulates chloroplast activity and photosynthesis in particular. We find that RelA SpoT homolog 3 (RSH3), a nuclear-encoded enzyme responsible for ppGpp biosynthesis, interacts directly with the TOR complex via a plant-specific amino-terminal region which is phosphorylated in a TOR-dependent manner. Down-regulating TOR activity causes a rapid increase in ppGpp synthesis in RSH3 overexpressors and reduces photosynthetic capacity in an RSH-dependent manner in wild-type plants. The TOR-RSH3 signaling axis therefore regulates the equilibrium between chloroplast activity and plant growth, setting a precedent for the regulation of organellar function by TOR.

Resistance to Spindle Inhibitors in Glioblastoma Depends on STAT3 and Therapy Induced Senescence.

While mitotic spindle inhibitors specifically kill proliferating tumor cells without the toxicities of microtubule poisons, resistance has limited their clinical utility. Treating glioblastomas with the spindle inhibitors ispinesib, alisertib, or volasertib creates a subpopulation of therapy induced senescent cells that resist these drugs by relying upon the anti-apoptotic and metabolic effects of activated STAT3. Furthermore, these senescent cells expand the repertoire of cells resistant to these drugs by secreting an array of factors, including TGFß, which induce proliferating cells to exit mitosis and become quiescent-a state that also resists spindle inhibitors. Targeting STAT3 restores sensitivity to each of these drugs by depleting the senescent subpopulation and inducing quiescent cells to enter the mitotic cycle. These results support a therapeutic strategy of targeting STAT3-dependent therapy-induced senescence to enhance the efficacy of spindle inhibitors for the treatment of glioblastoma. Highlights: • Resistance to non-microtubule spindle inhibitors limits their efficacy in glioblastoma and depends on STAT3.• Resistance goes hand in hand with development of therapy induced senescence (TIS).• Spindle inhibitor resistant glioblastomas consist of three cell subpopulations-proliferative, quiescent, and TIS-with proliferative cells sensitive and quiescent and TIS cells resistant.• TIS cells secrete TGFß, which induces proliferative cells to become quiescent, thereby expanding the population of resistant cells in a spindle inhibitor resistant glioblastoma• Treatment with a STAT3 inhibitor kills TIS cells and restores sensitivity to spindle inhibitors.

Primary Tumor Resection in Leiomyosarcoma Patients With Synchronous Isolated Lung Metastases: A National Cancer Database Study.

INTRODUCTION: Up to half of patients with leiomyosarcoma (LMS) present with distant metastases, most commonly in the lungs. Despite guidelines around managing metachronous oligometastatic disease, limited evidence exists for synchronous isolated lung metastases (SILMs). Our histology-specific study describes management patterns and outcomes for patients with LMS and SILM across disease sites. METHODS: We used the National Cancer Database to analyze patients with LMS of the retroperitoneum, extremity, trunk/chest/abdominal wall, and pelvis with SILM. Patients with extra-pulmonary metastases were excluded. We identified factors associated with primary tumor resection and receipt of metastasectomy. Outcomes included median, 1-year, and 5-year overall survival (OS) across treatment approaches using log-rank tests, Kaplan-Meier curves, and Cox proportional hazard models. RESULTS: We identified 629 LMS patients with SILM from 2004 to 2017. Patients were more likely to have resection of their primary tumor or lung metastases if treated at an academic center compared to a community cancer center. Five year OS for patients undergoing both primary tumor resection and metastasectomy was 20.9% versus 9.2% for primary tumor resection alone, and 2.6% for nonsurgical patients. Median OS for all-comers was 15.5 mo. Community treatment site, comorbidity score, and larger primary tumors were associated with worse survival. Chemotherapy, primary resection, and curative intent surgery predicted improved survival on multivariate Cox regression. CONCLUSIONS: An aggressive surgical approach to primary LMS with SILM was undertaken for select patients in our population and found to be associated with improved OS. This approach should be considered for suitable patients at high-volume centers.

Natural variation in response to combined water and nitrogen deficiencies in Arabidopsis.

Understanding plant responses to individual stresses does not mean that we understand real-world situations, where stresses usually combine and interact. These interactions arise at different levels, from stress exposure to the molecular networks of the stress response. Here, we built an in-depth multiomic description of plant responses to mild water (W) and nitrogen (N) limitations, either individually or combined, among 5 genetically different Arabidopsis (Arabidopsis thaliana) accessions. We highlight the different dynamics in stress response through integrative traits such as rosette growth and the physiological status of the plants. We also used transcriptomic and metabolomic profiling during a stage when the plant response was stabilized to determine the wide diversity in stress-induced changes among accessions, highlighting the limited reality of a "universal" stress response. The main effect of the W × N interaction was an attenuation of the N-deficiency syndrome when combined with mild drought, but to a variable extent depending on the accession. Other traits subject to W × N interactions are often accession specific. Multiomic analyses identified a subset of transcript-metabolite clusters that are critical to stress responses but essentially variable according to the genotype factor. Including intraspecific diversity in our descriptions of plant stress response places our findings in perspective.

Value-Based Health Care for Prostate Cancer Centers by Implementing Specific Key Performance Indicators Using a Balanced Score Card.

BACKGROUND: Prostate cancer (PC) is the most common cancer in men in 112 countries, and accounts for 15% of cancers. Because it cannot be prevented, the rise in cases is inevitable, and improvements in diagnostic pathways and treatments are needed, as there is still a shortage of cost-effective diagnostics and widespread oncologically safe treatment options with measurable quality. As part of the implementation of a Full Cycle of Care, instruments have been developed to achieve value-based medicine, such as consistent commitment to measurability. One of these instruments is the Balanced Scorecard (BSC). Here, we propose the first BSC for prostate cancer (PC) treatment. METHODS: BSCs are used to assess performance in healthcare organizations across four dimensions: financial, patient and referrer, process, and learning and development. This study aimed to identify Key Performance Indicators (KPIs) for each perspective. A systematic literature search was conducted according to PRISMA guidelines using multiple databases and specific search terms to identify KPIs for PC care, excluding case reports and conference abstracts. In total, 44 reports were included in analyses and development of the PC-specific BSC. RESULTS: In the present study, a PC-specific BSC and KPIs were defined for the four classic perspectives, as well as for a newly developed PC-Specific Disease and Outcome perspective, including patient-related parameters from the German Cancer Society and the International Consortium for Health Outcomes Measurement. In addition, the Process perspective includes KPIs of fulfillment of continuing education of residents and the metrics of structured training of the radical prostatectomy procedure in the Learning and Development perspective. CONCLUSIONS: The developed BSC provides a comprehensive set of perspectives for an Integrated Practice Unit or center in PC care, ensuring that the indicators remain manageable and applicable. The BSC facilitates value creation in line with Porter's Full Cycle of Care by systematically collecting and providing economic, personnel, and medical results, actions, and indicators. In particular, this BSC includes KPIs of structured training of practitioners and metrics of the German Cancer Society, that recently proved to improve PC patients outcomes.

MT-125 Inhibits Non-Muscle Myosin IIA and IIB, Synergizes with Oncogenic Kinase Inhibitors, and Prolongs Survival in Glioblastoma.

We have identified a NMIIA and IIB-specific small molecule inhibitor, MT-125, and have studied its effects in GBM. MT-125 has high brain penetrance and retention and an excellent safety profile; blocks GBM invasion and cytokinesis, consistent with the known roles of NMII; and prolongs survival as a single agent in murine GBM models. MT-125 increases signaling along both the PDGFR- and MAPK-driven pathways through a mechanism that involves the upregulation of reactive oxygen species, and it synergizes with FDA-approved PDGFR and mTOR inhibitors in vitro . Combining MT-125 with sunitinib, a PDGFR inhibitor, or paxalisib, a combined PI3 Kinase/mTOR inhibitor significantly improves survival in orthotopic GBM models over either drug alone, and in the case of sunitinib, markedly prolongs survival in ∼40% of mice. Our results provide a powerful rationale for developing NMII targeting strategies to treat cancer and demonstrate that MT-125 has strong clinical potential for the treatment of GBM. Highlights: MT-125 is a highly specific small molecule inhibitor of non-muscle myosin IIA and IIB, is well-tolerated, and achieves therapeutic concentrations in the brain with systemic dosing.Treating preclinical models of glioblastoma with MT-125 produces durable improvements in survival.MT-125 stimulates PDGFR- and MAPK-driven signaling in glioblastoma and increases dependency on these pathways.Combining MT-125 with an FDA-approved PDGFR inhibitor in a mouse GBM model synergizes to improve median survival over either drug alone, and produces tumor free, prolonged survival in over 40% of mice.