Other malignancies in the history of CLL: an international multicenter study conducted by ERIC, the European Research Initiative on CLL, in HARMONY

Chronic lymphocytic leukemiaLeucèmia limfocítica crònicaLeucemia linfocítica crónicaBackground Patients with chronic lymphocytic leukemia (CLL) have a higher risk of developing other malignancies (OMs) compared to the general population. However, the impact of CLL-related risk factors and CLL-directed treatment is still unclear and represents the focus of this work. Methods We conducted a retrospective international multicenter study to assess the incidence of OMs and detect potential risk factors in 19,705 patients with CLL, small lymphocytic lymphoma, or high-count CLL-like monoclonal B-cell lymphocytosis, diagnosed between 2000 and 2016. Data collection took place between October 2020 and March 2022. Findings In 129,254 years of follow-up after CLL diagnosis, 3513 OMs were diagnosed (27.2 OMs/1000 person-years). The most common hematological OMs were Richter transformation, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Non-melanoma skin (NMSC) and prostate cancers were the most common solid tumors (STs). The only predictor for MDS and AML development was treatment with fludarabine and cyclophosphamide with/without rituximab (FC ± R) (OR = 3.7; 95% CI = 2.79–4.91; p < 0.001). STs were more frequent in males and patients with unmutated immunoglobulin heavy variable genes (OR = 1.77; 95% CI = 1.49–2.11; p < 0.001/OR = 1.89; 95% CI = 1.6–2.24; p < 0.001). CLL-directed treatment was associated with non-melanoma skin and prostate cancers (OR = 1.8; 95% CI = 1.36–2.41; p < 0.001/OR = 2.11; 95% CI = 1.12–3.97; p = 0.021). In contrast, breast cancers were more frequent in untreated patients (OR = 0.17; 95% CI = 0.08–0.33; p < 0.001). Patients with CLL and an OM had inferior overall survival (OS) than those without. AML and MDS conferred the worst OS (p < 0.001). Interpretation OMs in CLL impact on OS. Treatment for CLL increased the risk for AML/MDS, prostate cancer, and NMSC. FCR was associated with increased risk for AML/MDS.This project was supported in part by AbbVie; EU/EFPIA Innovative Medicines Initiative [2] Joint Undertaking HARMONY grant n° 116026; the Hellenic Precision Medicine Network in Oncology; MH-CZ_AZV_NU23-03-00401; MH CZ DRO (FNBr, 65269705); MH CZ DRO (FNOl, 00098892), program COOPERATIO (research area ONCO), and NPO-NUVR LX22NPO5102. Munci Yagci was provided with study materials

COVID-19 severity and mortality in patients with CLL: an update of the international ERIC and Campus CLL study

Chronic lymphocytic leukemia; Coronavirus infections; MortalityLeucemia linfocítica crónica; Infecciones por coronavirus; MortalidadLeucèmia limfocítica crònica; Infeccions per coronavirus; MortalitatPatients with chronic lymphocytic leukemia (CLL) may be more susceptible to Coronavirus disease 2019 (COVID-19) due to age, disease, and treatment-related immunosuppression. We aimed to assess risk factors of outcome and elucidate the impact of CLL-directed treatments on the course of COVID-19. We conducted a retrospective, international study, collectively including 941 patients with CLL and confirmed COVID-19. Data from the beginning of the pandemic until March 16, 2021, were collected from 91 centers. The risk factors of case fatality rate (CFR), disease severity, and overall survival (OS) were investigated. OS analysis was restricted to patients with severe COVID-19 (definition: hospitalization with need of oxygen or admission into an intensive care unit). CFR in patients with severe COVID-19 was 38.4%. OS was inferior for patients in all treatment categories compared to untreated (p < 0.001). Untreated patients had a lower risk of death (HR = 0.54, 95% CI:0.41-0.72). The risk of death was higher for older patients and those suffering from cardiac failure (HR = 1.03, 95% CI:1.02-1.04; HR = 1.79, 95% CI:1.04-3.07, respectively). Age, CLL-directed treatment, and cardiac failure were significant risk factors of OS. Untreated patients had a better chance of survival than those on treatment or recently treated

Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY

Cancer genetics; Genetics researchGenètica del càncer; Recerca genèticaGenética del cáncer; Investigación genéticaRecent evidence suggests that the prognostic impact of gene mutations in patients with chronic lymphocytic leukemia (CLL) may differ depending on the immunoglobulin heavy variable (IGHV) gene somatic hypermutation (SHM) status. In this study, we assessed the impact of nine recurrently mutated genes (BIRC3, EGR2, MYD88, NFKBIE, NOTCH1, POT1, SF3B1, TP53, and XPO1) in pre-treatment samples from 4580 patients with CLL, using time-to-first-treatment (TTFT) as the primary end-point in relation to IGHV gene SHM status. Mutations were detected in 1588 (34.7%) patients at frequencies ranging from 2.3–9.8% with mutations in NOTCH1 being the most frequent. In both univariate and multivariate analyses, mutations in all genes except MYD88 were associated with a significantly shorter TTFT. In multivariate analysis of Binet stage A patients, performed separately for IGHV-mutated (M-CLL) and unmutated CLL (U-CLL), a different spectrum of gene alterations independently predicted short TTFT within the two subgroups. While SF3B1 and XPO1 mutations were independent prognostic variables in both U-CLL and M-CLL, TP53, BIRC3 and EGR2 aberrations were significant predictors only in U-CLL, and NOTCH1 and NFKBIE only in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management.The European Research Initiative on CLL (ERIC) is a partner in the HARMONY Alliance, the EHA Scientific Working group on CLL and the ELN Workpackage 7 on CLL. This work was in part supported by; Associazione Italiana per la Ricerca sul Cancro—AIRC, Milano, Italy (Investigator Grant #20246 and Special Program on Metastatic Disease—5 per mille #21198); ERA NET TRANSCAN-2 Joint Transnational Call for Proposals: JTC 2014 (project #143 GCH-CLL) and JTC 2016 (project #179 NOVEL), project code (MIS) 5041673; Bando della Ricerca Finalizzata 2018, Ministero della Salute, Roma, Italy (progetto RF-2018–12368231); “la Caixa” Foundation (Health Research 2017 Program HR17-00221); the American Association for Cancer Research (2021 AACR-Amgen Fellowship in Clinical/Translational Cancer Research, 21-40-11-NADE), the European Hematology Association (EHA Junior Research Grant 2021, RG-202012-00245), and the Lady Tata Memorial Trust (International Award for Research in Leukaemia 2021-2022, LADY_TATA_21_3223); the Hellenic Precision Medicine Network in Oncology; project ODYSSEAS (Intelligent and Automated Systems for enabling the Design, Simulation and Development of Integrated Processes and Products) implemented under the “Action for the Strategic Development on the Research and Technological Sector”, funded by the Operational Programme “Competitiveness, Entrepreneurship and Innovation” (NSRF 2014-2020) and co-financed by Greece and the European Union, with grant agreement no: MIS 5002462”; MH CZ—DRO (FNBr, 65269705), NV19-03-00091 and the project National Institute for Cancer Research (Programme EXCELES, ID Project No. LX22NPO5102)—Funded by the European Union—Next-Generation EU; Instituto de Salud Carlos III (ISCIII), “PI21/00983”, co-funded by the European Union; the EU’s Horizon 2020 research and innovation program under grant agreement No. 739593, by the Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund, financed under the K21_137948, FK20_134253, TKP2021-EGA-24 and TKP2021-NVA-15 funding schemes, and Elixir Hungary; Instituto de Salud Carlos III (ISCIII), “PI21/00983”, co-funded by the European Union; Fondo di Ateneo per la Ricerca (FAR) 2019, 2020 and 2021 of the University of Ferrara (GMR; AC), Associazione Italiana contro le Leucemie-Linfomi e Mieloma ONLUS Ferrara (AC; GMR), BEAT Leukemia Foundation Milan Italy (AC); the Danish Cancer Society and the CLL-CLUE project under the frame of ERA PerMed; Cancer Research UK (ECRIN-M3 accelerator award C42023/A29370, Southampton Experimental Cancer Medicine Centre grant C24563/A15581, Cancer Research UK Southampton Centre grant C34999/A18087, and programme C2750/A23669); the Swedish Cancer Society (19 0425 Pj 01 H), the Swedish Research Council (2020-01750), the Knut and Alice Wallenberg Foundation (2016.0373), Region Stockholm (ALF/FoUI-962423), and Radiumhemmets Forskningsfonder (194133), Stockholm; and Lion’s Cancer Research Foundation, Uppsala

Evidence of somatic hypermutation in the antigen binding sites of patients with CLL harboring IGHV genes with 100% germline identity

Classification of patients with chronic lymphocytic leukemia (CLL) based on the somatic hypermutation (SHM) status of the clonotypic immunoglobulin heavy variable (IGHV) gene has established predictive and prognostic relevance. The SHM status is assessed based on the number of mutations within the IG heavy variable domain sequence, albeit only over the rearranged IGHV gene excluding the variable heavy complementarity determining region 3 (VH CDR3). This may lead to an underestimation of the actual impact of SHM, in fact overlooking the most critical region for antigen-antibody interactions, i.e. the VH CDR3. Here we investigated whether SHM may be present within the VH CDR3 of cases bearing ‘truly unmutated’ IGHV genes (i.e. 100% germline identity across VH FR1-VH FR3) employing Next Generation Sequencing. We studied 16 patients bearing a ‘truly unmutated’ CLL clone assigned to stereotyped subsets #1 (n=12) and #6 (n=4). We report the existence of SHM within the germline-encoded 3’IGHV, IGHD, 5’IGHJ regions of the VH CDR3 in both the main IGHV-IGHD-IGHJ gene clonotype and its variants. Recurrent somatic mutations were identified between different patients of the same subset, supporting the notion that they represent true mutational events rather than technical artefacts; moreover, they were located adjacent to/within AID hotspots, pointing to SHM as the underlying mechanism. In conclusion, we provide immunogenetic evidence for intra-VH CDR3 variations, attributed to SHM, in CLL patients carrying ‘truly unmutated’ IGHV genes. Although the clinical implications of this observation remain to be defined, our findings offer a new perspective into the immunobiology of CLL, alluding to the operation of VH CDR3-restricted SHM in U-CLL

Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY

Recent evidence suggests that the prognostic impact of gene mutations in patients with chronic lymphocytic leukemia (CLL) may differ depending on the immunoglobulin heavy variable (IGHV) gene somatic hypermutation (SHM) status. In this study, we assessed the impact of nine recurrently mutated genes (BIRC3, EGR2, MYD88, NFKBIE, NOTCH1, POT1, SF3B1, TP53, and XPO1) in pre-treatment samples from 4580 patients with CLL, using time-to-first-treatment (TTFT) as the primary end-point in relation to IGHV gene SHM status. Mutations were detected in 1588 (34.7%) patients at frequencies ranging from 2.3-9.8% with mutations in NOTCH1 being the most frequent. In both univariate and multivariate analyses, mutations in all genes except MYD88 were associated with a significantly shorter TTFT. In multivariate analysis of Binet stage A patients, performed separately for IGHV-mutated (M-CLL) and unmutated CLL (U-CLL), a different spectrum of gene alterations independently predicted short TTFT within the two subgroups. While SF3B1 and XPO1 mutations were independent prognostic variables in both U-CLL and M-CLL, TP53, BIRC3 and EGR2 aberrations were significant predictors only in U-CLL, and NOTCH1 and NFKBIE only in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management

COVID-19 severity and mortality in patients with CLL: an update of the international ERIC and Campus CLL study

Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to Coronavirus disease 2019 (COVID-19) due to age, disease, and treatment-related immunosuppression. We aimed to assess risk factors of outcome and elucidate the impact of CLL-directed treatments on the course of COVID-19. We conducted a retrospective, international study, collectively including 941 patients with CLL and confirmed COVID-19. Data from the beginning of the pandemic until March 16, 2021, were collected from 91 centers. The risk factors of case fatality rate (CFR), disease severity, and overall survival (OS) were investigated. OS analysis was restricted to patients with severe COVID-19 (definition: hospitalization with need of oxygen or admission into an intensive care unit). CFR in patients with severe COVID-19 was 38.4%. OS was inferior for patients in all treatment categories compared to untreated (p < 0.001). Untreated patients had a lower risk of death (HR = 0.54, 95% CI:0.41–0.72). The risk of death was higher for older patients and those suffering from cardiac failure (HR = 1.03, 95% CI:1.02–1.04; HR = 1.79, 95% CI:1.04–3.07, respectively). Age, CLL-directed treatment, and cardiac failure were significant risk factors of OS. Untreated patients had a better chance of survival than those on treatment or recently treated

The evolving landscape of COVID‐19 and post‐COVID condition in patients with chronic lymphocytic leukemia: A study by ERIC, the European research initiative on CLL

In this retrospective international multicenter study, we describe the clinical characteristics and outcomes of patients with chronic lymphocytic leukemia (CLL) and related disorders (small lymphocytic lymphoma and high-count monoclonal B lymphocytosis) infected by SARS-CoV-2, including the development of post-COVID condition. Data from 1540 patients with CLL infected by SARS-CoV-2 from January 2020 to May 2022 were included in the analysis and assigned to four phases based on cases disposition and SARS-CoV-2 variants emergence. Post-COVID condition was defined according to the WHO criteria. Patients infected during the most recent phases of the pandemic, though carrying a higher comorbidity burden, were less often hospitalized, rarely needed intensive care unit admission, or died compared to patients infected during the initial phases. The 4-month overall survival (OS) improved through the phases, from 68% to 83%, p = .0015. Age, comorbidity, CLL-directed treatment, but not vaccination status, emerged as risk factors for mortality. Among survivors, 6.65% patients had a reinfection, usually milder than the initial one, and 16.5% developed post-COVID condition. The latter was characterized by fatigue, dyspnea, lasting cough, and impaired concentration. Infection severity was the only risk factor for developing post-COVID. The median time to resolution of the post-COVID condition was 4.7 months. OS in patients with CLL improved during the different phases of the pandemic, likely due to the improvement of prophylactic and therapeutic measures against SARS-CoV-2 as well as the emergence of milder variants. However, mortality remained relevant and a significant number of patients developed post-COVID conditions, warranting further investigations

Συστήματα διαχείρισης αποθεμάτων υπό διαφορετικές μορφές αβεβαιότητας στον ανεφοδιασμό

Due to the stochasticity not only of real demand, but also supply processes, inventory management deals with uncertain environments. Supply uncertainty is a diachronic and perhaps unavoidable phenomenon. It can be distinguished into two main categories: lead-time and yield uncertainty. The former concerns situations in which the exact delivery time is a random variable, whereas the latter is met when the batch received may differ from the order placed. Yield uncertainty can be further distinguished in four types: (1) random yield, in which the amount delivered does not equal to the quantity ordered; (2) random capacity, in which the supplier provides either the quantity ordered (if available) or the maximum available stock; (3) random quality, in which a batch received may contain imperfect items; (4) supply disruption, in which a placed order may fail to materialize. Some of the causes leading to supply uncertainty include complex production runs, machine breakdowns, inadequate raw materials, damage in transit, extreme adverse weather events, strikes, pandemics, or even just an unreliable supplier. Consequently, the firm is exposed to inefficient inventory management and so unplanned shortages, hence reduction of customer service, firm reputation and profit. In this thesis, consideration is given to systems facing either quality uncertainty or supply disruptions. More specifically, in the context of quality uncertainty, we study a continuous review inventory system in which each batch received is subject to a time-consuming screening process in order to detect any imperfect quality item. Concerning the supply disruptions, we study two periodic review inventory systems; one examines the impact of the disruption profile (combination of time until disruption occurrence and recovery), and one evaluates the benefits of advance delivery information sharing. In the existing literature, several mitigation and contingency strategies have been investigated to deal with quality uncertainty and supply disruptions, with the most commonly used being the safety stock. Although the safety stock reduces the unplanned shortages and improves the overall system performance, it is not always efficient. A higher one results in holding cost increase, whereas a lower one may not protect the system against unplanned shortages. In order to determine the optimal safety stock, the decision maker should take advantage of any inherent knowledge or available information about the outcome of the supply process. Regarding the quality uncertainty, the main hitherto action against unplanned shortages is to use a safety stock equal to the total demand during the screening process. The proposed safety stock is independent of the shortage cost, a result that is intuitively unappealing. Hence, in this dissertation, adopting the reorder level - order quantity (r,Q) policy, we appropriately formulate the shortage cost and determine the optimal safety stock that minimize the long-run average cost per unit time. Furthermore, we propose a new safety stock that effectively prevents any unplanned shortage and results in significantly lower costs compared to the one suggested in the literature. Yet, there is still a cost increase compared to systems with quality reliability, which becomes more intense as the proportion of imperfect quality items increases. As for supply disruptions, although the disruption profile has been considered in continuous review inventory systems, it is ignored in the periodic review. Instead, only the limiting disruption probabilities are taken into account. However, two systems may have the same limiting disruption probabilities but completely different disruption profiles (ranging from frequent-short to rare-long). Hence, in the existing literature, such systems are treated in the same way. By obtaining full insight of the supply process and operating under the order-up-to level - reorder interval (S,T) policy, we build a mathematical formulation that effectively distinguishes the systems with the same limiting disruption probabilities but different profiles. We determine the policy variables that minimize the long-run average cost per unit time and, also, propose an approximated solution for the reorder interval. Theoretical and numerical results demonstrate that systems facing rare but long disruptions are associated with inventory cycles of higher variance, although the expected length is kept constant, need higher safety stocks, and are more costly than systems facing frequent but short. This result indicates that a different strategy (such as the use of a backup supplier) may be more efficient against rare but long disruptions. As for the performance of the approximated solution, it performs quite well, opposite to the solution that ignores the disruption profile. Besides, we study a periodic review inventory system under endogenous disruptions (described by Bernoulli as a stationary process) in which the supplier provides the buyer advance delivery information. Two extreme regimes are considered: full delivery information (FDI) where the timing of the next delivery is always known, and partial delivery information (PDI) where the timing of the next delivery is only known if it coincides with the next planned delivery. For both regimes, a natural adaptation of the base stock policy is used, having multiple order-up-to levels, each corresponding to a particular level of information available when ordering. For both models, we determine the optimal policy variables that minimize the long-run average cost per unit time. The solution is obtained in closed-form, directly analogous to the classical EOQ. Numerical results show that advance information directly reduces operating costs, with the magnitude of the reduction being positively associated with the amount of information. However, since even under full information the costs remain high, the decision makers should always seek reliable suppliers aiming at ensuring disruption-free operation.Η διαχείριση αποθεμάτων πραγματοποιείται σε ένα περιβάλλον με αβεβαιότητα εξαιτίας της στοχαστικότητας όχι μόνο της ζήτησης, αλλά και της διαδικασίας εφοδιασμού. Η αβεβαιότητα στον εφοδιασμό είναι ένα διαχρονικό και ίσως αναπό-φευκτο φαινόμενο. Μπορεί να διακριθεί σε δύο κύριες κατηγορίες: αβεβαιότητα ως προς το χρόνο παράδοσης και αβεβαιότητα ως προς την απόδοση της τοποθετειθήσας παραγγελίας. Η πρώτη αφορά καταστάσεις στις οποίες ο ακριβής χρόνος παράδοσης είναι τυχαίος, ενώ η δεύτερη συναντάται όταν η παρτίδα που παραλαμβάνεται μπορεί να διαφέρει από την τοποθετούμενη παραγγελία. Περαιτέρω, η δεύτερη κατηγορία αβεβαιότητας μπορεί να διακριθεί σε τέσσερις τύπους: (1) η ποσότητα που παραλαμβάνεται δεν ισούται με την ποσότητα παραγγελίας, (2) ο προμηθευτής παρέχει είτε την παραγγελθείσα ποσότητα (εάν είναι διαθέσιμη) είτε το μέγιστο διαθέσιμο απόθεμα, (3) η ποσότητα που παραλαμβάνεται μπορεί να περιέχει προϊόντα χαμηλότερης ποιότητας, (4) μια παραγγελία που έχει τοποθετηθεί μπορεί να μην διεκπεραιωθεί. Μερικές από τις αιτίες που οδηγούν σε αβεβαιότητα εφοδιασμού περιλαμβάνουν πολύπλοκες διαδικασίες παραγωγής, βλάβες μηχανών, ανεπαρκείς πρώτες ύλες, ζημιές κατά τη μεταφορά, ακραία καιρικά φαινόμενα, απεργίες, πανδημίες ή ακόμα και κάποιον αναξιόπιστο προμηθευτή. Συνέπεια των παραπάνω είναι η μη αποτελεσματική διαχείριση των αποθεμάτων, αφού οδηγούν σε μη προγραμματισμένες ελλείψεις και συνακόλουθα σε μείωση του επιπέδου εξυπηρέτησης των πελατών, απώλεια της αξιοπιστίας της εταιρείας και εν τέλει σε μείωση των κερδών της. Σε αυτή τη διατριβή, μελετώνται συστήματα στα οποία είτε η ποσότητα που παραλαμβάνεται μπορεί να περιέχει προϊόντα χαμηλότερης ποιότητας είτε η παραγγελία ενδέχεται να μην διεκπεραιωθεί. Πιο συγκεκριμένα, μελετάμε ένα σύστημα αποθεμάτων συνεχούς επιθεώρησης, στο οποίο κάθε παρτίδα που παραλαμβάνεται υπόκειται σε μια χρονοβόρα διαδικασία ελέγχου προκειμένου να εντοπιστούν τα προϊόντα χαμηλότερης ποιότητας. Σχετικά με τις διακοπές προμήθειας, μελετάμε δύο συστήματα αποθεμάτων περιοδικής επιθεώρησης στα οποία αξιοποιούνται είτε εγγενής γνώση της διαδικασίας διακοπής είτε πληροφορία που παρέχεται από τον προμηθευτή. Ως προς το πρώτο σύστημα, διερευνάται η επίδραση του προφίλ διακοπής (συνδυασμός χρόνου μέχρι τη διακοπή και χρόνου μέχρι την επαναφορά). Ως προς το δεύτερο σύστημα, αξιολογούνται τα οφέλη της χρήσης εκ των προτέρων πληροφοριών σχετικά με την παράδοση. Στην υπάρχουσα βιβλιογραφία, έχουν διερευνηθεί αρκετές στρατηγικές πρόληψης και αποκατάστασης για την αντιμετώπιση καταστάσεων στις οποίες είτε μία παραλαμβανόμενη ποσότητα περιέχει προϊόντα χαμηλότερης ποιότητας είτε μία παραγγελία δεν πραγματοποιείται. Πιο συχνά χρησιμοποιούμενη στρατηγική είναι το απόθεμα ασφαλείας. Αν και το απόθεμα ασφαλείας μειώνει τις μη προγραμματισμένες ελλείψεις και βελτιώνει τη συνολική απόδοση του συστήματος, δεν είναι πάντα αποτελεσματικό. Ένα υψηλότερο οδηγεί σε αύξηση του κόστους διατήρησης, ενώ ένα χαμηλότερο μπορεί να μην προστατεύει το σύστημα από τις μη προγραμματισμένες ελλείψεις. Έτσι, προκειμένου να καθοριστεί το βέλτιστο απόθεμα ασφάλειας, η αξιοποίηση οποιασδήποτε γνώσης ή διαθέσιμης εκ των προτέρων πληροφορίας σχετικά με το αποτέλεσμα της διαδικασίας εφοδιασμού μπορεί να αποδειχθεί χρήσιμη. Όσον αφορά την αβεβαιότητα ποιότητας, η κύρια μέχρι τώρα ενέργεια ενάντια στις μη προγραμματισμένες ελλείψεις είναι η χρήση αποθέματος ασφαλείας ίσου με τη συνολική ζήτηση κατά τη διαδικασία ελέγχου. Το προτεινόμενο απόθεμα ασφαλείας είναι ανεξάρτητο από το κόστος έλλειψης, ένα αποτέλεσμα που είναι διαισθητικά μη ελκυστικό. Ως εκ τούτου, σε αυτή τη διατριβή, υιοθετώντας την πολιτική επιπέδου αναπαραγγελίας - ποσότητας παραγγελίας (r,Q), μοντελοποιούμε κατάλληλα το κόστος έλλειψης και προσδιορίζουμε το βέλτιστο απόθεμα ασφαλείας που ελαχιστοποιεί το μακροπρόθεσμο μέσο κόστος ανά μονάδα χρόνου. Επιπλέον, προσδιορίζουμε ένα απόθεμα ασφαλείας που αποτρέπει οποιαδήποτε μη προγραμματισμένη έλλειψη και οδηγεί σε σημαντικά χαμηλότερο κόστος σε σύγκριση με αυτό που προτείνεται στη βιβλιογραφία. Ωστόσο, εξακολουθεί να υπάρχει αύξηση του κόστους σε σύγκριση με συστήματα στα οποία δεν τίθεται ζήτημα ποιότητας, η οποία γίνεται εντονότερη καθώς αυξάνεται το ποσοστό των προϊόντων χαμηλότερης ποιότητας. Όσο αφορά τις διακοπές εφοδιασμού, αν και το προφίλ διακοπής έχει ληφθεί υπόψη στα συστήματα αποθεμάτων συνεχούς επιθεώρησης, παραβλέπεται στην περιοδική επιθεώρηση. Αντίθετα, λαμβάνονται υπόψη μόνο οι οριακές πιθανότητες διακοπής εφοδιασμού. Ωστόσο, δύο συστήματα μπορεί να έχουν τις ίδιες οριακές πιθανότητες διακοπής αλλά εντελώς διαφορετικά προφίλ διακοπής (που ευρύνονται από συχνές-μικρής διάρκειας έως σπάνιες-μακράς διάρκειας). Κατά συνέπεια, στην υπάρχουσα βιβλιογραφία, τέτοια συστήματα αντιμετωπίζονται με τον ίδιο τρόπο. Αποκτώντας πλήρη εικόνα της διαδικασίας προμήθειας και λειτουργώντας σύμφωνα με την (S,T) πολιτική, προτείνουμε ένα μαθηματικό μοντέλο που μπορεί να διακρίνει αποτελεσματικά συστήματα με τις ίδιες οριακές πιθανότητες διακοπής αλλά διαφορετικά προφίλ. Προσδιορίζουμε τις μεταβλητές απόφασης που ελαχιστοποιούν το μακροπρόθεσμο μέσο κόστος ανά μονάδα χρόνου και, επίσης, προτείνουμε μια προσεγγιστική λύση για το διάστημα αναπαραγγελίας. Θεωρητικά και αριθμητικά αποτελέσματα υποδεικνύουν ότι οι σπάνιες αλλά μακροχρόνιες διακοπές σχετίζονται με κύκλους αποθεμάτων υψηλότερης διακύμανσης (μολονότι το αναμενόμενο μήκος διατηρείται σταθερό) απαιτούν υψηλότερα επίπεδα αποθεμάτων ασφαλείας και είναι πιο κοστοβόρες από τις συχνές αλλά σύντομες διακοπές εφοδιασμού. Αυτό το αποτέλεσμα δείχνει ότι μια διαφορετική στρατηγική (όπως η χρήση εφεδρικού προμηθευτή) μπορεί να είναι πιο αποτελεσματική έναντι σπάνιων αλλά μακροχρόνιων διακοπών. Όσον αφορά την απόδοση της προσεγγιστικής λύσης, αποδίδει καλά, αντίθετα με τη λύση που αγνοεί το προφίλ διακοπής. Επιπλέον, μελετάμε ένα σύστημα περιοδικής επιθεώρησης κάτω από ενδογενείς διακοπές (που περιγράφονται από τη διαδικασία Bernoulli), στο οποίο ο προμηθευτής παρέχει στον αγοραστή εκ των προτέρων πληροφορίες σχετικά με την παράδοση της παραγγελίας. Δύο ακραίες περιπτώσεις μελετώνται: πλήρης πληροφορία χρόνου παράδοσης (FDI) όπου ο χρόνος της επόμενης παράδοσης είναι πάντα γνωστός, και μερική πληροφορία χρόνου παράδοσης (PDI), όπου ο χρόνος της επόμενης παράδοσης είναι γνωστός μόνο εάν συμπίπτει με την επόμενη προγραμματισμένη παράδοση. Και για τις δύο περιπτώσεις, χρησιμοποιείται μια παραλλαγή της (S,T) πολιτικής, με πολλαπλά order up to levels, καθένα από τα οποία αντιστοιχεί σε ένα συγκεκριμένο επίπεδο πληροφορίας κατά την παραγγελία. Και για τα δύο μοντέλα, προσδιορίζουμε τις βέλτιστες μεταβλητές απόφασης που ελαχιστοποιούν το μακροπρόθεσμο μέσο κόστος ανά μονάδα χρόνου. Αριθμητικά αποτελέσματα υποδεικνύουν ότι η εκ των προτέρων πληροφορία μειώνει το μέσο μακροπρόθεσμο κόστος, με το μέγεθος της μείωσης να αυξάνεται με την ποσότητα της διαθέσιμης πληροφορίας. Ωστόσο, δεδομένου ότι ακόμη και με πλήρη πληροφορία το κόστος παραμένει υψηλό, θα πρέπει πάντα να αναζητούνται αξιόπιστοι προμηθευτές με στόχο τη διασφάλιση της λειτουργίας του συστήματος χωρίς διακοπές προμήθειας

Concordance between Three Homologous Recombination Deficiency (HRD) Assays in Patients with High-Grade Epithelial Ovarian Cancer

Our aim was to evaluate the concordance between the Myriad MyChoice and two alternative homologous recombination deficiency (HRD) assays (AmoyDx HRD Focus NGS Panel and OncoScan™) in patients with epithelial ovarian cancer (EOC). Tissue samples from 50 patients with newly diagnosed EOC and known Myriad MyChoice HRD status were included. DNA aliquots from tumor samples, previously evaluated with Myriad MyChoice and centrally reassessed, were distributed to laboratories to assess their HRD status using the two platforms, after being blinded for the Myriad MyChoice CDx HRD status. The primary endpoint was the concordance between Myriad MyChoice and each alternative assay. Tumor samples were evaluated with an AmoyDx® HRD Focus Panel (n = 50) and with OncoScan™ (n = 43). Both platforms provided results for all tumors. Analysis showed that correlation was high for the Myriad MyChoice GI score and AmoyDx® HRD Focus Panel (r = 0.79) or OncoScan™ (r = 0.87) (continuous variable). The overall percent agreement (OPA) between Myriad MyChoice GI status (categorical variable) and each alternative assay was 83.3% (68.6–93.3%) with AmoyDx and 77.5% (61.5–89.2%) with OncoScan™. The OPA in HRD status between Myriad MyChoice and AmoyDx was 88.6% (75.4–96.2). False-positive rates were 31.6% (6/19) for AmoyDx GI status and 31.9% (7/22) for OncoScan™, while false-negative rates were 0% (0/28, AmoyDx) and 11.1% (2/18, OncoScan™) compared with the Myriad MyChoice GI status. While substantial concordance between Myriad MyChoice and alternative assays was demonstrated, prospective validation of the analytical performance and clinical relevance of these assays is warranted