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Magnetic resonance imaging (MRI) misses a proportion of "clinically significant" prostate cancers (csPC) as defined by histopathology criteria. The aim of this study was to analyze whether long-term oncologic outcomes differ between MRI-detectable and MRI-occult csPC.Retrospective analysis of 1449 patients with pre-prostatectomy MRI and csPC on prostatectomy specimens (ie, Grade group ≥2 or extraprostatic spread) between 2001-2006. T2-weighted MRIs were classified according to the Prostate Imaging Reporting and Data System into MRI-occult (categories 1, 2), MRI-equivocal (category 3), and MRI-detectable (categories 4, 5). Cumulative incidence of biochemical recurrence (BCR), metastatic disease, and cancer-specific mortality, estimated with competing risk models. The median follow-up in survivors was 11.0 years (IQR: 8.9-13.1).In 188 (13%) cases, csPC was MRI-occult, 435 (30%) MRIs were equivocal, and 826 (57%) csPC were MRI-detectable. The 15-year cumulative incidence [95% CI] of BCR was 8.3% [2.2, 19.5] for MRI-occult cases, 17.4% [11.1, 24.8] for MRI-equivocal cases, and 43.3% [38.7, 47.8] for MRI-detectable cases (P.001). The cumulative incidences of metastases were 0.61% [0.06, 3.1], 3.5% [1.5, 6.9], and 19.6% [15.4, 24.2] for MRI-occult, MRI-equivocal, and MRI-detectable cases, respectively (P.001). There were no deaths from prostate cancer observed in patients with MRI-occult csPC, compared to an estimated 1.9% [0.54, 4.9], and 7.1 % [4.5, 10.6] for patients with MRI-equivocal and MRI-detectable cancer, respectively (P.001).Oncologic outcomes after prostatectomy for csPC differ between MRI-occult and MRI-detectable lesions. Judging the clinical significance of a negative prostate MRI based on histopathologic surrogates alone might be misleading.Among 1449 patients with pre-prostatectomy MRI and clinically significant prostate cancer on prostatectomy histopathology, MRI-occult cancers (n = 188, 13%) were less likely to recur biochemically (8% vs. 43%, P.001), metastasize (0.6% vs. 20%, P.001), or lead to prostate cancer mortality (0% vs. 7%, P.001) than MRI-detectable cancers (n = 826, 57%). MRI-occult cancers constitute a prognostically distinct subgroup among higher-grade prostate cancers.

Shifting runoff dynamics and highly intensified geomorphic processes are immediate consequences of the evident glacier mass loss in high-alpine headwater catchments. Rapidly retreating glaciers expose unconsolidated sediments to erosion in the proximity of meltwater-fed mountain streams impacting the catchment-scale sediment dynamics. Altering sediment fluxes can have considerable implications for the operation and management of water infrastructure, especially hydro-electric power facilities in otherwise non-regulated glaciated catchments. Bedload-rich outwash plains with typical braided channel networks serve as a deposition area for glacier debris under average runoff conditions. During flood flow conditions, the proglacial areas connect with the downstream catchment, delivering subglacial sediments to lower stream sections.As such, they represent key elements in high-alpine river systems when considering future discharge and sediment yield from deglaciating catchments. Establishing a numerical model of this important component of the headwater catchment illuminates a data scarce fluvial process domain. Yet, model parametrization and setting boundary conditions for a glacier forefield are challenging. Direct measurements in the paraglacial transition zone of retreating glaciers are usually complicated to achieve, especially since outwash plains are frequently subject to intensive geomorphic processes. Therefore, innovative methods, minimizing labour-intensive and time-consuming manual surveying, are needed to overcome data scarcity in paraglacial environments.A combined methodological approach to parameterize key boundary conditions of an Alpine proglacial outwash plain (Jamtal valley, Austria) with an area of 0.035 km2 and an average channel inclination of 4.8 % is presented. Measuring discharge in situ is difficult since the braided riverbed is not stable due to frequent relocation of sediment. Therefore, close range sensing techniques based on RGB imagery from hand-held and fixed time-lapse cameras used in combination with maximum water level gauges are used directly in the outwash plain to monitor flood runoff events. A conventional discharge gauge (non-contact flow velocity and water level sensor) was realized 3 km further downstream covering the recent hydrologic summers (2019-2022). UAV-borne RGB imagery was used to detect changes in topography, sediment budget and composition.We present results on key parameters, essential for numerical modelling of hydraulic flood flow conditions, including: (i) multi-annual high-resolution topographic 3-D models of the frequently changing channel geometry, (ii) hydraulic roughness of surface sediments derived from areal grain size distribution maps (i.e., D50, D84) and (iii) spatio-temporal flood flow maps indicating the annual variability in the surveyed proglacial outwash plain. These interrelated survey results are then used to parameterize and calibrate a 2-D numerical model (TELEMAC 2-D) to simulate hydraulic base and flood flow conditions, demonstrating the applicability and robustness of the presented multi-method approach.

Purpose: Oncogenic alterations of the PI3K/AKT pathway occur in >40% of patients with metastatic castration-resistant prostate cancer, predominantly via PTEN loss. The significance of other PI3K pathway components in prostate cancer is largely unknown. Experimental Design: Patients in this study underwent tumor sequencing using the MSK-IMPACT clinical assay to capture single-nucleotide variants, insertions, and deletions; copy-number alterations; and structural rearrangements, or were profiled through The Cancer Genome Atlas. The association between PIK3R1 alteration/expression and survival was evaluated using univariable and multivariable Cox proportional-hazards regression models. We used the siRNA-based knockdown of PIK3R1 for functional studies. FDG-PET/CT examinations were performed with a hybrid positron emission tomography (PET)/CT scanner for some prostate cancer patients in the MSK-IMPACT cohort. Results: Analyzing 1,417 human prostate cancers, we found a significant enrichment of PIK3R1 alterations in metastatic cancers compared with primary cancers. PIK3R1 alterations or reduced mRNA expression tended to be associated with worse clinical outcomes in prostate cancer, particularly in primary disease, as well as in breast, gastric, and several other cancers. In prostate cancer cell lines, PIK3R1 knockdown resulted in increased cell proliferation and AKT activity, including insulin-stimulated AKT activity. In cell lines and organoids, PIK3R1 loss/mutation was associated with increased sensitivity to AKT inhibitors. PIK3R1-altered patient prostate tumors had increased uptake of the glucose analogue 18F-fluorodeoxyglucose in PET imaging, suggesting increased glycolysis. Conclusions: Our findings describe a novel genomic feature in metastatic prostate cancer and suggest that PIK3R1 alteration may be a key event for insulin–PI3K–glycolytic pathway regulation in prostate cancer.

BACKGROUND: It is unknown how the imperfect accuracy of MRI for local staging of prostate cancer relates to oncologic outcomes. PURPOSE: To analyze how staging discordances between MRI and histopathologic evaluation relate to recurrence and survival after radical prostatectomy. MATERIALS AND METHODS: Health Insurance Portability and Accountability Act–compliant retrospective analysis of preprostatectomy T2-weighted prostate MRI (January 2001 to December 2006). Extraprostatic extension and seminal vesicle invasion were assessed by using five-point Likert scales; scores of 4 or higher were classified as positive. Biochemical recurrence (BCR), metastases, and prostate cancer–specific mortality rates were estimated with Kaplan-Meier and Cox models. RESULTS: A total of 2160 patients (median age, 60 years; interquartile range, 55–64 years) were evaluated. Among patients with histopathologic extraprostatic (pT3) disease (683 of 2160; 32%), those with organ-confined disease at MRI (384 of 683; 56%) experienced better outcomes than those with concordant extraprostatic disease at MRI and pathologic analysis: 15-year risk for BCR, 30% (95% CI: 22, 40) versus 68% (95% CI: 60, 75); risk for metastases, 14% (95% CI: 8.4, 24) versus 32% (95% CI: 26, 39); risk for prostate cancer–specific mortality, 3% (95% CI: 1, 6) versus 15% (95% CI: 9.5, 23) (P < .001 for all comparisons). Among patients with histopathologic organ-confined disease (pT2) (1477 of 2160; 68%), those with extraprostatic disease at MRI (102 of 1477; 7%) were at higher risk for BCR (27% [95% CI: 19, 37] vs 10% [95% CI: 8, 14]; P < .001), metastases (19% [95% CI: 6, 48] vs 3% [95% CI: 1, 6]; P < .001), and prostate cancer–specific mortality (2% [95% CI: 1, 9] vs 1% [95% CI: 0, 5]; P = .009) than those with concordant organ-confined disease at MRI and pathologic analysis. At multivariable analyses, tumor extent at MRI (hazard ratio range, 4.1–5.2) and histopathologic evaluation (hazard ratio range, 3.6–6.7) was associated with the risk for BCR, metastases, and prostate cancer–specific mortality (P < .001 for all analyses). CONCLUSION: The local extent of prostate cancer at MRI is associated with oncologic outcomes after prostatectomy, independent of pathologic tumor stage. This might inform a strategy on how to integrate MRI into a clinical staging algorithm. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Gottlieb in this issue.

The semiconductor supply chain is characterized by a global and complex production network in a competitive market. The time when work at one location ends and can be resumed at another is defined as Transit Time (TT). Therefore, planning Transit Time accurately and minimizing delays is crucial as it is used in the execution system to determine the Available to Promise (ATP) and thus important for daily order confirmation. By determining the ATP, the customer receives a response to the resource availability and a due date to the customer requests. Due to tool inherent differences, we choose semantic integration via Knowledge Graph (KG) to match the planned TT used in the execution system and the actual TT measured in the monitoring tool. KnowGraph-TT thereby serves as a role model for further matching and alignment tasks using KG. It connects actual and planned TT, highlights the gaps via applied queries, and enables an optimized update of planned TT. With our solution, deviations of actual and planned TT can be minimized and confirmations of unrealizable deliverable times are avoided.

All tumor-level alteration data with OncoKB annotation (mutations, copy number changes, fusions)

Supplementary Table from The Impact of PIK3R1 Mutations and Insulin–PI3K–Glycolytic Pathway Regulation in Prostate Cancer

Purpose:The genomic underpinning of clinical phenotypes and outcomes in metastatic castration-sensitive prostate cancer is unclear.Experimental Design:In patients with metastatic castration-sensitive prostate cancer at a tertiary referral center, clinical-grade targeted tumor sequencing was performed to quantify tumor DNA copy number alterations and alterations in predefined oncogenic signaling pathways. Disease volume was classified as high volume (≥4 bone metastases or visceral metastases) versus low volume.Results:Among 424 patients (88% white), 213 (50%) had high-volume disease and 211 (50%) had low-volume disease, 275 (65%) had de novo metastatic disease, and 149 (35%) had metastatic recurrence of nonmetastatic disease. Rates of castration resistance [adjusted hazard ratio, 1.84; 95% confidence interval (CI), 1.40–2.41] and death (adjusted hazard ratio, 3.71; 95% CI, 2.28–6.02) were higher in high-volume disease. Tumors from high-volume disease had more copy number alterations. The NOTCH, cell cycle, and epigenetic modifier pathways were the highest-ranking pathways enriched in high-volume disease. De novo metastatic disease differed from metastatic recurrences in the prevalence of CDK12 alterations but had similar prognosis. Rates of castration resistance differed 1.5-fold to 5-fold according to alterations in AR, SPOP (inverse), and TP53, and the cell cycle, WNT (inverse), and MYC pathways, adjusting for disease volume and other genomic pathways. Overall survival rates differed 2-fold to 4-fold according to AR, SPOP (inverse), WNT (inverse), and cell-cycle alterations. PI3K pathway alterations were not associated with prognosis once adjusted for other factors.Conclusions:This study identified genomic features associated with prognosis in metastatic castration-sensitive disease that may aid in molecular classification and treatment selection.

Purpose:Oncogenic alterations of the PI3K/AKT pathway occur in >40% of patients with metastatic castration-resistant prostate cancer, predominantly via PTEN loss. The significance of other PI3K pathway components in prostate cancer is largely unknown.Experimental Design:Patients in this study underwent tumor sequencing using the MSK-IMPACT clinical assay to capture single-nucleotide variants, insertions, and deletions; copy-number alterations; and structural rearrangements, or were profiled through The Cancer Genome Atlas. The association between PIK3R1 alteration/expression and survival was evaluated using univariable and multivariable Cox proportional-hazards regression models. We used the siRNA-based knockdown of PIK3R1 for functional studies. FDG‐PET/CT examinations were performed with a hybrid positron emission tomography (PET)/CT scanner for some prostate cancer patients in the MSK-IMPACT cohort.Results:Analyzing 1,417 human prostate cancers, we found a significant enrichment of PIK3R1 alterations in metastatic cancers compared with primary cancers. PIK3R1 alterations or reduced mRNA expression tended to be associated with worse clinical outcomes in prostate cancer, particularly in primary disease, as well as in breast, gastric, and several other cancers. In prostate cancer cell lines, PIK3R1 knockdown resulted in increased cell proliferation and AKT activity, including insulin-stimulated AKT activity. In cell lines and organoids, PIK3R1 loss/mutation was associated with increased sensitivity to AKT inhibitors. PIK3R1-altered patient prostate tumors had increased uptake of the glucose analogue 18F‐fluorodeoxyglucose in PET imaging, suggesting increased glycolysis.Conclusions:Our findings describe a novel genomic feature in metastatic prostate cancer and suggest that PIK3R1 alteration may be a key event for insulin–PI3K–glycolytic pathway regulation in prostate cancer.

Supplementary Figure from The Impact of PIK3R1 Mutations and Insulin–PI3K–Glycolytic Pathway Regulation in Prostate Cancer

In den letzten drei Jahren hat sich die Verletzlichkeit internationaler effektivitätsgetriebener Wertschöpfungsnetzwerke in einer hyperglobalisierten Welt offenbart. Beispielsweise kam es im Verlauf der COVID-19-Pandemie oder des anhaltenden Ukraine-Konfliktes zu Versorgungsengpässen kritischer Güter, die für die moderne Gesellschaft unerlässlich sind. Zu diesen zählen Medikamente, Hygieneartikel, Verpackungsmaterialien sowie Erdgas und Halbleiter, besser bekannt als Mikrochips. Deshalb beschäftigt sich die vorliegende Forschungsarbeit mit der Identifikation, Analyse und Bewertung von kritischen Knotenpunkten solcher Netzwerke sowie deren Risiken am Beispiel der Halbleiterindustrie. Diesbezüglich wurden auf Grundlage einer umfassenden Literaturrecherche neue Methoden gesucht, die es ermöglichen, die Komplexität der Zielsysteme greifbar zu machen und deren Schwach-stellen zu identifizieren. Im Zuge der Recherche fiel die Wahl auf die Process Analysis Method, eine Methode aus dem Nachhaltigkeitsmanagement, die bereits zur Risikobeurteilung der Energieversorgung Großbritanniens verwendet wurde. Dazu wird die folgende Forschungsfrage gestellt: Wie kann die Process Analysis Method zur Analyse und Bewertung kritischer Knotenpunkte innerhalb des Wertschöpfungsnetzwerkes der Halbleiterindustrie angewendet werden? Die systemorientiere Adaptierung dieser Methode wurde anhand von vier Expert*innen-Workshops durchgeführt. Diesen sind vier explorative Gespräche mit Expert*innen aus der Halbleiterindustrie und der Rohstoffpolitik vorausgegangen. Um die Anpassung der Methode sowie die Ergebnisse zu validieren, fand eine halbstrukturierte Fokusgruppendiskussion mit Expert*innen aus der Halbleiterindustrie, der Logistik sowie der Forschung aus dem Supply Chain Risk Management statt. Die empirische Untersuchung hat gezeigt, dass bei der Nutzung der Process Analysis Method die holistische Systembetrachtung, die Implementierung weiterer Kritikalitätsparameter sowie das stringente Ursache-Wirkungs-bezogene Vorgehen die wesentlichen Anwendungsparadigmen und zentralen Werttreiber darstellen. Deshalb könnte sich die weiterführende Forschung mit der Integration von Risiko-management-Simulationsmodellen in die Process Analysis Method beschäftigen. In the last three years, the vulnerability of international efficiency-driven value networks in a hyperglobalised world has become apparent. For example, in the course of the COVID-19-pandemic or the ongoing Ukraine conflict, supply shortages of critical goods that are essential for modern society have occurred. These goods include medicines, hygiene products, packaging materials, as well as natural gas and semiconductors, which are better known as microchips. For this reason, this research addresses the identification, analysis and evaluation of the critical nodes of such networks, along with their risks, by means of the semi-conductor industry. To this end, new methods were sought, based on a compre-hensive literature view, which make it possible to distinguish the complexity of the target systems and to identify their vulnerable points. In the course of the research, the process analysis method was chosen for the assessment. This method derives from sustainability management and has already been used for the risk assess-ment of the energy supply chain the United Kingdom. Hence, the following research question arises: How can the process analysis method be applied to the analysis and assessment of critical nodes within the value network of the semiconductor industry? The system-oriented adaptation of this method was carried out on the basis of four expert workshops. These were preceded by four exploratory interviews with experts from the semiconductor industry and raw materials policy. To validate the adapta-tion of the method and the results, a semi-structured focus group discussion took place with experts from the semiconductor industry and from the fields of logistics and supply chain risk management research. The empirical study showed that the holistic system view, the implementation of further criticality parameters and the stringent cause-effect approach represent es-sential application paradigms and central value drivers when using the process analysis method. Therefore, future research could address the integration of risk management simu-lation models into the process analysis method.