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Metallocenes are well-established compounds in organometallic chemistry, and can exhibit either a coplanar structure or a bent structure according to the nature of the metal center (E) and the cyclopentadienyl ligands (Cp). Herein, we re-examine the chemical bonding to underline the origins of the geometry and stability observed experimentally. To this end, we have analysed a series of group 2 metallocenes [Ae(C5R5)2] (Ae = Be-Ba and R = H, Me, F, Cl, Br, and I) with a combination of computational methods, namely energy decomposition analysis (EDA), polarizability model (PM), and dispersion interaction densities (DIDs). Although the metal-ligand bonding nature is mainly an electrostatic interaction (65-78%), the covalent character is not negligible (33-22%). Notably, the heavier the metal center, the stronger the d-orbital interaction with a 50% contribution to the total covalent interaction. The dispersion interaction between the Cp ligands counts only for 1% of the interaction. Despite that orbital contributions become stronger for heavier metals, they never represent the energy main term. Instead, given the electrostatic nature of the metallocene bonds, we propose a model based on polarizability, which faithfully predicts the bending angle. Although dispersion interactions have a fair contribution to strengthen the bending angle, the polarizability plays a major role.

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Electrophilic AlIII species have long dominated the aluminum reactivity towards arenes. Recently, nucleophilic low-valent AlI aluminyl anions have showcased oxidative additions towards arenes C-C and/or C-H bonds. Herein, we communicate compelling evidence of an AlII radical addition reaction to the benzene ring. The electron reduction of a ligand stabilized precursor with KC8 in benzene furnishes a double addition to the benzene ring instead of a C-H bond activation, producing the corresponding cyclohexa-1,3(orl,4)-dienes as Birch-type reduction product. X-ray crystallographic analysis, EPR spectroscopy, and DFT results suggest this reactivity proceeds through a stable AlII radical intermediate, whose stability is a consequence of a rigid scaffold in combination with strong steric protection.

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Herein, the first stable anions K[SIPrBp ] (4 a-K) and K[IPrBp ] (4 b-K) (SIPrBp =BpC{N(Dipp)CH2 }2 , IPrBp =BpC{N(Dipp)CH}2 ; Bp=4-PhC6 H4 ; Dipp=2,6-iPr2 C6 H3 ) derived from classical N-heterocyclic carbenes (NHCs) (i.e. SIPr and IPr) have been isolated as violet crystalline solids. 4 a-K and 4 b-K are prepared by KC8 reduction of the neutral radicals [SIPrBp ] (3 a) and [IPrBp ] (3 b), respectively. The radicals 3 a and 3 b as well as [Me-IPrBp ] 3 c (Me-IPrBp =BpC{N(Dipp)CMe}2 ) are accessible as crystalline solids on treatment of the respective 1,3-imidazoli(ni)um bromides (SIPrBp )Br (2 a), (IPrBp )Br (2 b), and (Me-IPrBp )Br (2 c) with KC8 . The cyclic voltammograms of 2 a-2 c exhibit two one-electron reversible redox processes in -0.5 to -2.5 V region that correspond to the radicals 3 a-3 c and the anions (4 a-4 c)- . Computational calculations suggest a closed-shell singlet ground state for (4 a-4 c)- with the singlet-triplet energy gap of 17-24 kcal mol-1 .

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INTRODUCTION: The impact of ABO mismatch on outcomes following allo-HSCT remains controversial. In this study, our aim is to define the effect of ABO mismatch on post-transplant outcomes, engraftment kinetics and complications in a large cohort. PATIENTS AND METHODS: We retrospectively identified 1000 patients who underwent allo-HSCT from either bone marrow or peripheral blood stem cells at our center between 1988 and 2016. P<0.05 was considered statistically significant. RESULTS: Five hundred and ninety (59%) patient-donor pairs were ABO matched, 164 (16.4%) were ABO major mismatched (MM), 191 (19.1%) were ABO minor MM, and 55 (5.5%) were ABO bi-directionally MM. ABO matched pairs were more common in transplants from related donors (P<0.001) and using bone marrow as a stem cell source (P<0.001). In minor ABO MM transplantations, mild delayed hemolytic reaction occurred more frequently compared to major and bidirectional ABO MM transplantations (47% vs 35% and 18%, P<0.001). Neutrophil engraftment was slightly delayed in ABO MM patient-donor pairs when compared ABO matched donor pairs according to median engraftment time in all group (167/410, 41% vs 204/590, 35%, P=0.046). Pure red cell aplasia was diagnosed in 6 patients (1%). Higher risk of death was shown in ABO MM transplants compared to ABO matched transplants in overall survival (OS) analysis (HR:1.201, 95% CI:1.004-1.437, P=0.045). The non-relapse mortality (P=0.546) and cumulative incidences of acute graft versus host disease (aGVHD) and chronic (c) GVHD were comparable between ABO MM and ABO matched patient-donor pairs (for aGVHD, P=0.235; for cGVHD, P=0.137). CONCLUSION: ABO MM transplants were associated with decreased OS and slightly delayed neutrophil engraftment. NRM and the risk of GVHD were not related to ABO incompatibility.

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OBJECTIVES: Extracorporeal photo-chemotherapy (ECP, photopheresis) is an approved treatment modality for mycosis fungoides (MF). Our aim is to present our ECP data for MF. METHODS: We retrospectively evaluated 50 MF patients who received ECP for clinical activity, toxicity, and response and outcome rates, and we compared these with combination therapies. RESULTS: The overall response rate (ORR) was 42% (21/50), while the median time to response was 11months (range, 3-48months). Ten of the responders (48%) had 3 or more treatment lines prior to ECP. Eight patients (16%) had adverse events related to ECP. The overall survival (OS) of 50 patients was 72months (range, 3-211). There was no statistically significant difference in the OS in early-stage vs late-stage patients (77 vs 69months, P=0.077). The stage 3 and 4 patients received an average of 31 cycles compared to 55 cycles in stage 1 and 2 patients (P=0.006). The increased extent of ECP was not correlated with the response. Combined treatment with ECP significantly improved the OS (84months vs 62months, P=0.005). DISCUSSION: A low frequency of side effects and improved OS observed in combination therapy makes ECP a favorable option for treating MF.

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Among the novel biological therapeutics that will increase our ability to cure human cancer in years to come, adoptive cellular therapy is one of the most promising approaches. Although this is a complex and challenging field, there have been major advances in basic and translational research resulting in clinical trial activity that is now beginning to confirm this promise. The results obtained with tumor-infiltrating lymphocytes therapy for melanoma, and virus-specific CTLs for EBV-associated malignancies are encouraging in terms of both ability to obtain clinical benefit and limited toxicity profile. In both settings, objective responses were obtained in at least 50% of treated patients. However, improvements to the clinical protocols, in terms of better patient selection and timing of administration, as well as cell product quality and availability, are clearly necessary to further ameliorate outcome, and logistical solutions are warranted to extend T-cell therapy beyond academic centers. In particular, there is a need to simplify cell production, in order to decrease costs and ease preparation. Promising implementations are underway, including harnessing the therapeutic potential of T cells transduced with TCRs directed against shared tumor antigens, and delineating strategies aimed at targeting immune evasion mechanisms exerted by tumor cells.

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In spite of the safety and efficiency of the classical mobilization protocols, recombinant human G-CSF±chemotherapy, there is still a considerable amount of mobilization failures (10-30%), which warrant novel agents and approaches both in an autologous and an allogeneic transplant setting. Attempts to improve CD34+ yields by using several cytokines and growth factors as adjuncts to G-CSF could not change the standard approaches during the last decade, either because of inefficiency or the adverse events encountered with these agents. As a long-acting G-CSF analog, pegfilgrastim has the advantages of an earlier start of apheresis, reduction in the number of apheresis procedures as well as a reduced number of injections as compared with unconjugated G-CSF. However, dosing and cost-effectiveness especially in cytokine-only mobilizations require further investigation. As interactions between hematopoietic stem cells and the BM microenvironment are better understood, new molecules targeting these interactions are emerging. Plerixafor, which started its journey as an anti-HIV drug, recently ended up being a popular stem cell mobilizer with the ability of rapid mobilization and gained approval as an adjunct to G-CSF for poor mobilizers. At present, it is challenging to search for the best approach by using the available drugs with appropriate timing to provide sufficient CD34+ yield after an initial mobilization attempt, and in a cost-effective manner thereby avoiding further mobilization attempts and exposure to chemotherapy. Approaches not only for increasing stem cell yield, but also aiming to improve the quality of graft content and the associated transplantation outcomes are promising areas of research.

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The optimal timing for recombinant human (rh)G-CSF administration after chemotherapy for PBSC mobilization has not yet been determined. In this study, we compared two different time schedules of rhG-CSF; 4th (early) vs 7th day (late), in 48 consecutive patients with multiple myeloma and lymphoma undergoing PBSC mobilization with CE (CY 4 g/m(2) on day 1 and etoposide 200 mg/m(2) on days 1-3). The rhG-CSF dose was 10 microg/kg/day for all patients. Both groups were comparable in terms of sex, age and number of previously given different chemotherapy regimens. Duration of neutropenia, CD34(+) cell count on the first day of apheresis and numbers of aphereses were not statistically different between the two arms. However, the number of doses of rhG-CSF up to the first cycle of apheresis procedures was significantly lower in the late group than in the early group (P=0.005). The median number of total CD34(+) cells collected was 10.54 x 10(6)/kg (range 0.11-37.27) in the early group and 10.81 x 10(6)/kg (range 0.17-49.83) in the late group of rhG-CSF (P=0.781). We conclude that PBSC mobilization after late use of rhG-CSF is an effective approach and therefore, in routine clinical practice, late rhG-CSF may be used for PBSC collections after chemotherapy-based mobilization regimens in this cost-conscious era.

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Between 1978 and 2006, the European Group for Blood and Marrow Transplantation registered 4098 high-dose therapy (HDT) procedures followed by stem cell rescue (SCR) (3974 autologous/124 allogeneic) in patients with neuroblastoma. The 5-year rates for overall (OS) and event-free survival are 37 and 32%, respectively. The median age at diagnosis is 3.9 years (0.3-62 years) with 76 patients older than 18 years. Patients above 10 years carry a 2.5-fold higher risk. Younger patients cure significantly (<0.001) better with OS rates of 40 and 30% for age groups 2-4 years and 4-10 years, respectively. Their risks are about twofold higher than that of patients below 2 years with OS rates of 60%. The better the quality of remission status before HDT/SCT the better are the observed OS rates: 43% in CR1 (1199 patients) and 42% for CR2 (140 patients), and 36% for those in very good partial or partial remission (1413 patients) and 21% for those with sensitive relapse (134 patients). Patients reported with stable disease in first remission still had an OS rate of 30%. Multivariate analysis shows significantly better OS in the age group of less than 2 years (<0.0001), as well as a better quality of remission status before HDT/SCT (P<0.0001), with the use of peripheral stem cells (P=0.014), autologous SCT (P=0.031) and busulphan/melphalan HDT (P<0.001). Busulphan/melphalan HDT/SCT in first remission achieves an OS of 48%, while it is only 35% with other regimens (P<0.001), including melphalan alone, other melphalan-containing regimens, a variety of other drugs given as a single HDT as well as the addition of TBI or sequential HDT/SCT procedures. Further progress in the field may only be expected from large-scale international randomized trials.

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We reviewed 66 women with poor-risk metastatic breast cancer from 15 centers to describe the efficacy of allogeneic hematopoietic cell transplantation (HCT). Median follow-up for survivors was 40 months (range, 3-64). A total of 39 patients (59%) received myeloablative and 27 (41%) reduced-intensity conditioning (RIC) regimens. More patients in the RIC group had poor pretransplant performance status (63 vs 26%, P=0.002). RIC group developed less chronic GVHD (8 vs 36% at 1 year, P=0.003). Treatment-related mortality rates were lower with RIC (7 vs 29% at 100 days, P=0.03). A total of 9 of 33 patients (27%) who underwent immune manipulation for persistent or progressive disease had disease control, suggesting a graft-vs-tumor (GVT) effect. Progression-free survival (PFS) at 1 year was 23% with myeloablative conditioning and 8% with RIC (P=0.09). Women who developed acute GVHD after an RIC regimen had lower risks of relapse or progression than those who did not (relative risk, 3.05: P=0.03), consistent with a GVT effect, but this did not affect PFS. These findings support the need for preclinical and clinical studies that facilitate targeted adoptive immunotherapy for breast cancer to explore the benefit of a GVT effect in breast cancer.

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We report the experience of the EBMT Solid Tumours Working Party (STWP) using high-dose chemotherapy (HDCT) with PBPC support in patients with non-small cell lung cancer (NSCLC). Between 1989 and 2004, 36 NSCLC patients (27 men and 9 women), median age 53.5 years (range: 24-62) were treated with 63 HDCT courses. A high-dose carboplatin-based regimen was used in 53% of the cases. Thirty-two patients had relapsed/metastatic disease, while four classified as stage IIIB received HDCT followed by radiotherapy. No treatment-related death occurred. Of 25 patients who were planned to receive multi-cycle HDCT, 4 cases (16%) interrupted the treatment early due to prolonged severe toxicities and 4 (16%) due to progressive disease. Of 36 evaluable patients, 3 (8%) achieved a complete remission and 13 (36%) had a partial remission at an overall response rate of 44%. Of these, one patient with stage IIIB and one with stage IV are alive disease free at 71+ and 149+ months, respectively. After a median follow-up of 48 months (range: 6-149), median survival was 7 months (range: 1-149). Despite one anecdotal case, HDCT did not show significant activity, but induced relevant morbidity in NSCLC patients.

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BACKGROUND: An allogeneic antitumour effect has been reported for various cancers. We evaluated the experience of allogeneic haematopoietic stem cell transplantation (HSCT) for renal cell carcinoma (RCC) in 124 patients from 21 European centres. PATIENTS AND METHODS: Reduced intensity conditioning and peripheral blood stem cells from an HLA-identical sibling (n = 106), a mismatched related (n = 5), or an unrelated (n = 13) donor were used. Immunosuppression was cyclosporine alone, or combined with methotrexate or mycophenolate mofetil. Donor lymphocyte infusions (DLI) were given to 42 patients. The median follow-up was 15 (range 3-41) months. RESULTS: All but three patients engrafted. The cumulative incidence of moderate to severe, grades II-IV acute GVHD was 40% and for chronic GVHD it was 33%. Transplant-related mortality was 16% at one year. Complete (n = 4) or partial (n = 24) responses, median 150 (range 42-600) days post-transplant, were associated with time from diagnosis to HSCT, mismatched donor and acute GVHD II-IV. Factors associated with survival included chronic GVHD (hazards ratio, HR 4.12, P < 0.001), DLI (HR 3.39, P < 0.001), <3 metastatic sites (HR 2.61, P = 0.002) and a Karnofsky score >70 (HR 2.33, P = 0.03). Patients (n = 17) with chronic GVHD and given DLI had a 2-year survival of 70%. CONCLUSION: Patients with metastatic RCC, less than three metastatic locations and a Karnofsky score >70% can be considered for HSCT. Posttransplant DLI and limited chronic GVHD improved the patient survival.

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Since the early 1980s high dose chemotherapy with autologous hematopoietic stem cell support was adopted by many oncologists as a potentially curative option for solid tumors, supported by a strong rationale from laboratory studies and apparently convincing results of early phase II studies. As a result, the number and size of randomized trials comparing this approach with conventional chemotherapy initiated (and often abandoned before completion) to prove or disprove its value was largely insufficient. In fact, with the possible exception of breast carcinoma, the benefit of a greater escalation of dose of chemotherapy with stem cell support in solid tumors is still unsettled and many oncologists believe that this approach should cease. In this article, we critically review and comment on the data from studies of high dose chemotherapy so far reported in adult patients with small cell lung cancer, ovarian cancer, germ cell tumors and sarcomas.

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The Accreditation Subcommittee of the EBMT regularly publishes special reports on current practice of haemopoietic stem cell transplantation for haematological diseases, solid tumours and immune disorders in Europe. Major changes have occurred since the first report was published in 1996. Haemopoietic stem cell transplantation today includes grafting with allogeneic and autologous stem cells derived from bone marrow, peripheral blood and cord blood. With reduced intensity conditioning regimens in allogeneic transplantation, the age limit has increased, permitting the inclusion of older patients. New indications have emerged such as autoimmune disorders and AL amyloidosis for autologous, and solid tumours for allogeneic transplants. The introduction of alternative therapies has challenged well-established indications such as imatinib for chronic myeloid leukaemia. An updated report with revised tables and operating definitions is presented here.

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We reviewed the European Group for Blood and Marrow Transplantation (EBMT) experience with salvage high-dose chemotherapy (HDC) in paediatric patients with extragonadal germ-cell tumour (GCT). A total of 23 children with extragonadal GCT, median age 12 years (range 1-20), were treated with salvage HDC with haematopoietic progenitor cell support. The GCT primary location was intracranial site in nine cases, sacrococcyx in eight, retroperitoneum in four, and mediastinum in two. In all, 22 patients had a nongerminomatous GCT and one germinoma. Nine patients received HDC in first- and 14 in second- or third-relapse situation. No toxic deaths occurred. Overall, 16 of 23 patients (70%) achieved a complete remission. With a median follow-up of 66 months (range 31-173 months), 10 (43%) are continuously disease-free. Of six patients who had a disease recurrence after HDC, one achieved a disease-free status with surgical resection followed by chemotherapy and radiotherapy. In total, 11 patients (48%) are currently disease-free. Eight of 14 patients (57%) with extracranial primary and three of nine patients (33%) with intracranial primary GCT are currently disease-free. HDC induced impressive long-term remissions as salvage treatment in children with extragonadal extracranial GCTs. Salvage HDC should be investigated in prospective trials in these patients.

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The majority of advanced ovarian cancer patients achieve an objective response following chemotherapy; however, only 20-30% are in remission after 5 years. Intraperitoneal or high-dose chemotherapy (HDC) may prolong disease-free and overall survival (OS) in patients with platinum-sensitive, small volume disease. To better define the subsets of patients who might benefit from HDC, we performed a retrospective analysis on 91 patients in 1st complete remission (CR) treated from 21 centres of the EBMT group. At a median follow-up of 48 months, median time-to-progression (TTP) and OS were 21.2 and 44.4 months, respectively. Tumour grade, stage, residual disease, disease status before HDC, type and year of transplant, source of haemopoietic progenitors and use of haemopoietic growth factors (HGF) after transplant were analysed for TTP and OS. The only significant parameter was the use of HGF: median OS for patients receiving or not receiving HGF was 46.2 vs 17.8 months, respectively (P: 0.035); this difference was maintained after multivariate analysis (P: 0.02). Our analysis does not identify any subgroup of patients in 1st CR who can benefit from HDC; however, median survival of patient with no residual disease has not been reached. The role of HGF after HDC deserves further investigation.

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BACKGROUND: Results of second-line chemotherapy in patients with extragonadal non-seminomatous germ cell tumor (NSGCT) appear inferior to results in testicular NSGCT. Patients with retroperitoneal NSGCT achieve a comparable long-term survival rate of 30%, but the salvage rates of patients with mediastinal primary are less than 10%. We conducted a retrospective analysis on patients with mediastinal and retroperitoneal NSGCT treated with second-line high-dose chemotherapy (HDCT) registered with the European Group for Blood and Marrow Transplantation (EBMT). PATIENTS AND METHODS: Between 1987 and 1999, 59 registered patients with retroperitoneal (n=37) and mediastinal (n=22) primary NSGCT, median age 28 years (range 18-60), were treated with second-line HDCT. All had received cisplatin-containing chemotherapy as first-line treatment. RESULTS: Toxic death occurred in three cases (5%). With a median follow-up of 58 months (range 14-114), 18/59 patients (30%) continue to be disease-free. Of three patients who had a disease recurrence after HDCT, one patient achieved a disease-free status with further chemotherapy and surgery. In total, 19 patients (32%) are currently disease-free. Sixteen of 37 patients (43%) with retroperitoneal NSGCT, and three of 22 patients (14%) with mediastinal NSGCT are currently alive and disease-free. CONCLUSIONS: Second-line HDCT might represent a possible option for patients with retroperitoneal primary NSGCT. New salvage strategies are needed for patients with mediastinal NSGCT.

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Extragonadal germ cell tumors are classified according to the staging system of the International Germ Cell Cancer Collaborative Group (IGCCCG). The 5-year overall and disease-free survival rates for poor prognosis patients are 41 and 48%, respectively after standard-dose chemotherapy. We report the experience of the EBMT Solid Tumours Working Party (STWP) with first-line HDCT with hematopoietic progenitor cell support (HPCS) in patients with poor prognosis extragonadal nonseminomatous germ cell tumor (NSGCT). Between 1990 and 2001, 22 extragonadal NSGCT patients (21 M, 1 F), median age 30 years (range 17-52) were treated with first-line HDCT with HPCS. Primary site was mediastinum in 11 patients, retroperitoneum in 10, and unknown in one. The Carbopec regimen, consisting of high doses of carboplatin, etoposide, and cyclophosphamide, was used in most cases (12 patients). No treatment-related deaths occurred. No patient developed myelodysplasia or a secondary leukemia. In total, 17 of 22 patients (77%) achieved complete remission. At a median follow-up of 50 months (range 26-132), 15 patients (68%) are alive disease-free. The survival rates of patients with poor prognosis extragonadal NSGCT treated with first-line HDCT in the EBMT STWP experience appear higher than that expected according to the IGCCCG classification.

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The purpose of this evaluation was to investigate the efficacy of high-dose chemotherapy with thiotepa, melphalan, and carboplatin (TMCb), and of autologous peripheral blood stem cell (PBSC) infusion in patients with aggressive non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD). A total of 42 patients, 23 with intermediate-grade NHL and 19 with HD, received thiotepa (500 mg/m2), melphalan (100 mg/m2), and carboplatin (1050-1350 mg/m2) followed by autologous PBSC infusion. Of 21 patients with more advanced disease, four had primary refractory disease, one was in complete remission (CR)-2, 11 were in first refractory relapse, and five were beyond first relapse. Of 21 patients with less advanced disease, two were in CR-1, four were in CR-2, and 15 were in first responding relapse. In all, 14 patients (33%) had received prior radiotherapy prohibiting a total-body irradiation (TBI)-based conditioning regimen. The projected 2-year probabilities of survival, event-free survival (EFS), and relapse for all patients were 0.65, 0.60, and 0.21 (0.85, 0.80, and 0.10 for patients with less advanced disease and 0.47, 0.42, and 0.33 for patients with more advanced disease). The probability of nonrelapse mortality in the first 100 days was 0.12. Grade 3-4 regimen-related toxicities (RRT) occurred in five of 42 (12%) patients and death due to grade-4 RRT occurred in only one (2.5%) patient. These preliminary data suggest that 0.42% EFS in this study for advanced disease patients is highly encouraging and high-dose TMCb followed by autologous PBSC transplantation is well tolerated as well as an effective regimen in patients with intermediate-grade NHL or HD, and may be comparable to some previously used regimens including TBI-based regimens.

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