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1.
Anticancer Res ; 43(3): 1273-1282, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36854497

RESUMO

BACKGROUND/AIM: Pembrolizumab alone or combined with chemotherapy is now approved in PD-L1-positive patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Since real-world data are pending, our goal was to evaluate the efficacy and safety of immune checkpoint inhibitor (CPI) therapy in an unselected cohort of patients with SCCHN. PATIENTS AND METHODS: We analyzed 78 patients with recurrent or metastatic SCCHN from three Austrian cancer centers that received CPI therapy alone or with chemotherapy as palliative first-line systemic treatment for this retrospective study. Patient characteristics, details on treatment, and survival were analyzed by a chart-based review. RESULTS: Of the 78 patients analyzed, 55 patients were treated with CPI alone (45 with Pembrolizumab, 10 with Nivolumab) and 23 patients received chemotherapy with a platinum and 5-FU in addition to CPI. With a median follow-up of twelve months, the median PFS of all patients was 4 months [95% confidence interval (CI)=2.2-5.8] and the median OS was 11 months (95% CI=7.1-14.9). The overall response and disease control rates were 20.5% and 46.1%, respectively. There was no statistically significant difference in clinical outcome between patient groups with a different combined positive score (CPS). The rate of reported immune related adverse events was comparable to existing data. CONCLUSION: Our findings confirm the results of the KEYNOTE-048 trial that CPI therapy alone or together with chemotherapy is an effective treatment for patients with recurrent or metastatic CPS-positive SCCHN.


Assuntos
Neoplasias de Cabeça e Pescoço , Humanos , Áustria , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Nivolumabe , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico
2.
J Bone Miner Res ; 37(11): 2156-2164, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36056473

RESUMO

Metabolic bone disease is a devastating condition in critically ill patients admitted to an intensive care unit (ICU). We investigated the effects of early administration of the antiresorptive drug denosumab on bone metabolism in previously healthy patients. Fourteen patients with severe intracerebral or subarachnoid hemorrhage were included in a phase 2 trial. Within 72 hours after ICU admission, they were randomized in a 1:1 ratio to receive denosumab 60 mg or placebo subcutaneously. The primary endpoint was group differences in the percentage change of C-terminal telopeptide of type 1 collagen (CTX-1) levels in serum from denosumab/placebo application to 4 weeks thereafter. Changes in serum levels of bone formation markers and urinary calcium excretion were secondary outcome parameters. Regarding serum levels of CTX-1, changes over time averaged -0.45 ng/mL (95% confidence interval [CI] -0.72, -0.18) for the denosumab group and 0.29 ng/mL (95% CI -0.01, 0.58) for the placebo group. The primary endpoint, the group difference in changes between baseline and secondary measurement, adjusted for baseline serum levels and baseline neurological status, averaged -0.74 ng/mL (95% CI -1.14, -0.34; p = 0.002). The group difference in changes between baseline and secondary osteocalcin measurement averaged -5.60 ng/mL (95% CI -11.2, -0.04; p = 0.049). The group difference in averaged change between baseline and secondary measurement of 24-hour urine calcium excretion was significant (-1.77 mmol/L [95% CI -3.48, -0.06; p = 0.044]). No adverse events could be attributed to the study medication. The investigation proved that a single application of denosumab early after admission to an ICU prevents acute immobilization-associated increase in bone resorption among previously healthy individuals. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).


Assuntos
Conservadores da Densidade Óssea , Denosumab , Humanos , Densidade Óssea , Cálcio/farmacologia , Biomarcadores/metabolismo , Remodelação Óssea , Conservadores da Densidade Óssea/uso terapêutico , Minerais
3.
Front Pharmacol ; 13: 875695, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35721106

RESUMO

Background: Extravasation during chemotherapy administration can lead to dangerous adverse effects ranging from pain to tissue necrosis. Evidence-based data about prevention and treatment of extravasation injuries of some clinically used compounds still remains elusive. This work aimed to investigate, in a preclinical mouse model, the effects of extravasation of two chemotherapeutic agents, nanoliposomal irinotecan (nal-Iri) and trabectedin. In addition, we aimed to study treatment options for injuries induced by extravasation of these substances. Methods: Mice were subcutaneously injected with nal-Iri or trabectedin applied in clinically used concentration. Doxorubicin was used as a positive control. In subsequently performed experiments, hyaluronidase, DMSO and tacrolimus were tested as potential treatments against extravasation-induced injuries by trabectedin. Systemic effects were analyzed by observation and documentation of the health status of mice and local reactions were measured and graded. In addition, hematoxylin-eosin stained histological sections of the treated skin areas were analyzed. Results: Of the two tested substances, only trabectedin showed vesicant effects. Subcutaneous injection of trabectedin caused erythema formation in mice by day two that was progressing to skin ulcerations by day five. Furthermore, we found that topical treatment of mice with tacrolimus or DMSO reduced the vesicant effects of trabectedin. The results observed in vivo were supported microscopically by the analysis of histological sections. Conclusions: We recommend classifying trabectedin as a vesicant agent and nal-Iri as a non-vesicant agent. Furthermore, our results obtained in a preclinical model suggest that tacrolimus and DMSO might be suitable treatment options of trabectedin extravasations, a finding that might be further utilized in clinical studies.

4.
Ann Med ; 54(1): 1339-1349, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35535695

RESUMO

BACKGROUND: Immune checkpoint inhibitors (ICI) are regarded as a standard of care in multiple malignancies. We hypothesized that serum parameters are of prognostic value in ICI treated patients suffering from solid tumours. METHODS: Data from 114 patients treated with ICIs for solid malignancies from 2015 to 2019 at the Medical University of Vienna were collected retrospectively. Data included baseline characteristics, cancer type, serum parameters such as lactate dehydrogenase (LDH), C-reactive protein (CRP), albumin (Alb) and lymphocyte counts as well as overall survival (OS) and progression free survival. Additionally, the Gustave Roussy Immune Score (GRIm score) and the Glasgow prognostic score (GPS) were calculated. Cox regression models including time-dependent effects and strata for tumour type were used. Prognostic factors were pre-selected using a relaxed LASSO approach. RESULTS: The majority of patients were male (64.9%). The most common cancer types were non-small cell lung cancer (30.7%) and renal cell carcinoma (21.9%). Increased LDH and CRP were associated with poor 6-month OS (Hazard ratios (HR)=1.16 and 1.06 per 20% LDH/CRP increase; 95% CI 1.07-1.26 and 95% CI 1.03-1.09, respectively; p < .001). Both GRIm Score and GPS had a significant influence on OS (GRIm: HR = 2.84, 95% CI 1.72-4.69; p < .001 for high vs. low; GPS HR 3.57, 95% CI 1.76-7.25; p < .001 for poor vs. good). The proportion of explained variation (PEV) of our full multivariable model was significantly higher compared to the GRIm and GPS (PEV = 29.5% vs. 14.8% and 14.65%). When grouped into quartiles according to the individual 8-weeks change, both increased LDH and CRP correlated with poor OS (LDH (p=.001) and CRP (p < .001)). CONCLUSION: The results of this analysis suggest that serum parameters might have prognostic value for the outcome of cancer patients treated with ICI, regardless of the tumour type.Key messagesIn this retrospective analysis, 114 patients with solid tumours were included. The results of this analysis point out that pre-treatment LDH, CRP and albumin levels are strongly prognostic for a poor 6-month OS.In addition to that, a high GRIm-score and poor GPS were associated with a worse OS (GRIm: HR = 2.84, 95% CI 1.72-4.69; p < .001 for high vs. low; GPS HR = 3.57, 95% CI 1.76-7.25; p < .001 for poor vs. good).Pre-treatment serum parameters might have prognostic value for the outcome of cancer patients treated with ICI, regardless of the tumour type.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Antígeno B7-H1/metabolismo , Biomarcadores , Proteína C-Reativa/metabolismo , Feminino , Humanos , L-Lactato Desidrogenase , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Prognóstico , Estudos Retrospectivos
5.
Oral Oncol ; 124: 105634, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34844042

RESUMO

BACKGROUND: Taxane-based checkpoint inhibitor combination therapy might improve the outcome in recurrent/metastatic (R/M) head and neck cancer (HNSCC) patients. Thus, we investigated the efficacy and safety of docetaxel (DTX) plus pembrolizumab (P) in a prospective phase I/II trial. METHODS: Platinum-resistant R/M HNSCC patients received DTX 75 mg/m^2 plus P 200 mg for up to six cycles followed by P maintenance therapy. The primary endpoint was overall response rate (ORR) and safety. Secondary endpoints comprised disease control rate (DCR), overall survival (OS) and progression free survival (PFS). RESULTS: Twenty-two patients were enrolled. Nine patients (40.9%) had a primary tumor in the oropharynx, 8 (36.4%) in the oral cavity, 3 (13.6%) in the hypopharynx and 2 (9.1%) in the larynx. The ORR was 22.7% (95% CI 10.1%-43.4%) and one (4.5%) complete response was achieved. The DCR was 54.6% (95% 34.7%-73.1%). The median PFS was 5.8 months (95% CI 2.7-11.6) and the median OS 21.3 months (95% CI 6.3-31.1). The 1-year PFS and OS rates were 27.3% and 68.2%, respectively. While the most frequent adverse event (AE) was myelosuppression, which was reported in all 22 patients, 3 (13.6%) patients experienced grade 3 febrile neutropenia. The most common immune-related AEs were grade skin rash (40.9%) and hypothyroidism (40.9%). One patient (4.5%) experienced grade 5 immune thrombocytopenia. CONCLUSION: DXT in combination with P shows promising activity accompanied with a manageable side effect profile in pre-treated R/M HNSCC patients.


Assuntos
Neoplasias de Cabeça e Pescoço , Recidiva Local de Neoplasia , Anticorpos Monoclonais Humanizados , Docetaxel , Neoplasias de Cabeça e Pescoço/induzido quimicamente , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Recidiva Local de Neoplasia/patologia , Estudos Prospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico
6.
Blood ; 137(12): 1669-1678, 2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33067632

RESUMO

The risk of venous thromboembolism (VTE) and arterial thromboembolism (ATE) associated with immune checkpoint inhibitors is currently unclear. Our aim was to quantify the risk of VTE/ATE in patients with cancer treated with immune checkpoint inhibitors, explore clinical impact, and investigate potential clinical risk factors. Patients treated with immune checkpoint inhibitors at the Medical University of Vienna from 2015 to 2018 were identified using in-house pharmacy records (n = 672; most frequent entities: 30.4% melanoma, 24.1% non-small cell lung cancer; 86% stage IV disease). A retrospective chart review was performed to screen for VTE and/or ATE. Cumulative incidences and between-group differences were estimated in competing-risk analysis. The impact of VTE/ATE on mortality was studied by multistate modelling. Over a median follow-up of 8.5 months, 47 VTEs and 9 ATEs were observed. Cumulative incidences of VTE and ATE were 12.9% (95% confidence interval [CI], 8.2-18.5) and 1.8% (95% CI, 0.7-3.6). Occurrence of VTE was associated with increased mortality (transition hazard ratio, 3.09; 95% CI, 2.07-4.60). History of VTE predicted VTE occurrence (subdistribution hazard ratio [SHR], 3.69; 95% CI, 2.00-6.81), and distant metastasis was nonsignificantly associated with VTE risk (SHR, 1.71; 95% CI, 0.62-4.73). No association of VTE with Eastern Cooperative Oncology Group performance status, Charlson comorbidity index, or Khorana score was observed, and rates of VTE were comparable between tumor types and checkpoint-inhibitory agents. In conclusion, patients with cancer under immune checkpoint inhibitor therapy are at high risk of thromboembolism, especially VTE. Furthermore, VTE occurrence was associated with increased mortality.


Assuntos
Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias/tratamento farmacológico , Tromboembolia/induzido quimicamente , Tromboembolia Venosa/induzido quimicamente , Idoso , Feminino , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Tromboembolia/etiologia , Resultado do Tratamento , Tromboembolia Venosa/etiologia
7.
Med Oncol ; 35(3): 32, 2018 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-29411154

RESUMO

Three weekly high-dose chemotherapy regimens in combination with weekly cetuximab are the treatment of choice for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (SCCHN), although the majority of patients suffer from severe side effects. Thus, we investigated the efficacy and safety of an alternative, more convenient and less toxic biweekly modified cisplatin, docetaxel plus cetuximab (TPEx) regimen in this retrospective analysis. Thirty-eight patients receiving off-protocol cisplatin (50 mg/m2) in combination with docetaxel (50 mg/m2) plus cetuximab (500 mg/m2) every other week were included. Data collection included baseline demographic, response rate (ORR) and toxicity data as well as disease control rate, overall survival (OS) and progression-free survival (PFS). The median age was 60 years, and the majority of patients suffered from oral cavity carcinomas (44.7%) followed by oropharyngeal (28.9%) and laryngeal (17.9%) carcinomas. The ORR was 50%, and four (10.5%) patients achieved a complete response, while 15 (39.5%) patients had a partial response. The OS and PFS were 10.8 months (95% CI 6.7-14.2) and 6.3 months (95% CI 5.7-6.8), respectively. The one-year survival rate was 44.7%. The therapy was well tolerated, and the most common grade 3/4 adverse events were myelosuppression (13.2%), hypomagnesaemia (23.7%) and acne-like rash (13.1%). In conclusion, modified biweekly TPEx is of comparable efficacy with conventional TPEx and represents a well-tolerated regimen in R/M SCCHN patients. Further evaluation of this protocol in prospective clinical trials is warranted.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Carcinoma de Células Escamosas/secundário , Cetuximab/administração & dosagem , Cisplatino/administração & dosagem , Docetaxel , Feminino , Seguimentos , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Taxoides/administração & dosagem
8.
J Am Soc Nephrol ; 29(2): 591-605, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29242250

RESUMO

Late antibody-mediated rejection (ABMR) is a leading cause of kidney allograft failure. Uncontrolled studies have suggested efficacy of the proteasome inhibitor bortezomib, but no systematic trial has been undertaken to support its use in ABMR. In this randomized, placebo-controlled trial (the Bortezomib in Late Antibody-Mediated Kidney Transplant Rejection [BORTEJECT] Trial), we investigated whether two cycles of bortezomib (each cycle: 1.3 mg/m2 intravenously on days 1, 4, 8, and 11) prevent GFR decline by halting the progression of late donor-specific antibody (DSA)-positive ABMR. Forty-four DSA-positive kidney transplant recipients with characteristic ABMR morphology (median time after transplant, 5.0 years; pretransplant DSA documented in 19 recipients), who were identified on cross-sectional screening of 741 patients, were randomly assigned to receive bortezomib (n=21) or placebo (n=23). The 0.5-ml/min per 1.73 m2 per year (95% confidence interval, -4.8 to 5.8) difference detected between bortezomib and placebo in eGFR slope (primary end point) was not significant (P=0.86). We detected no significant differences between bortezomib- and placebo-treated groups in median measured GFR at 24 months (33 versus 42 ml/min per 1.73 m2; P=0.31), 2-year graft survival (81% versus 96%; P=0.12), urinary protein concentration, DSA levels, or morphologic or molecular rejection phenotypes in 24-month follow-up biopsy specimens. Bortezomib, however, associated with gastrointestinal and hematologic toxicity. In conclusion, our trial failed to show that bortezomib prevents GFR loss, improves histologic or molecular disease features, or reduces DSA, despite significant toxicity. Our results reinforce the need for systematic trials to dissect the efficiency and safety of new treatments for late ABMR.


Assuntos
Bortezomib/uso terapêutico , Rejeição de Enxerto/prevenção & controle , Rejeição de Enxerto/fisiopatologia , Antígenos HLA/imunologia , Transplante de Rim , Inibidores de Proteassoma/uso terapêutico , Adulto , Aloenxertos/imunologia , Anticorpos/sangue , Bortezomib/efeitos adversos , Progressão da Doença , Método Duplo-Cego , Feminino , Taxa de Filtração Glomerular , Rejeição de Enxerto/complicações , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inibidores de Proteassoma/efeitos adversos , Proteinúria/etiologia , Fatores de Tempo , Falha de Tratamento
9.
Blood ; 130(23): 2499-2503, 2017 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-28972014

RESUMO

T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive T-lymphoid malignancy usually refractory to current treatment strategies and associated with short overall survival. By applying next-generation functional testing of primary patient-derived lymphoma cells using a library of 106 US Food and Drug Administration (FDA)-approved anticancer drugs or compounds currently in clinical development, we set out to identify novel effective treatments for T-PLL patients. We found that the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (ABT-199) demonstrated the strongest T-PLL-specific response when comparing individual ex vivo drug response in 86 patients with refractory hematologic malignancies. Mechanistically, responses to venetoclax correlated with protein expression of BCL-2 but not with expression of the BCL-2 family members myeloid cell leukemia 1 (MCL-1) and BCL-XL in lymphoma cells. BCL-2 expression was inversely correlated with the expression of MCL-1. Based on the ex vivo responses, venetoclax treatment was commenced in 2 late-stage refractory T-PLL patients resulting in clinical responses. Our findings demonstrate first evidence of single-agent activity of venetoclax both ex vivo and in humans, offering a novel agent in T-PLL.


Assuntos
Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Leucemia Prolinfocítica de Células T/tratamento farmacológico , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonamidas/uso terapêutico , Adulto , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Resistencia a Medicamentos Antineoplásicos , Feminino , Ensaios de Triagem em Larga Escala , Humanos , Leucemia Prolinfocítica de Células T/diagnóstico , Leucemia Prolinfocítica de Células T/metabolismo , Masculino , Pessoa de Meia-Idade , Recidiva , Sulfonamidas/farmacologia , Resultado do Tratamento
10.
Sci Rep ; 7(1): 6216, 2017 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-28740204

RESUMO

Developing effective therapies against chronic wound healing deficiencies is a global priority. Thus we evaluated the safety of two different doses of topically administered autologous APOSEC, the secretome of apoptotic peripheral blood mononuclear cells (PBMCs), in healthy male volunteers with artificial dermal wounds. Ten healthy men were enrolled in a single-center, randomized, double-blinded, placebo-controlled phase 1 trial. Two artificial wounds at the upper arm were generated using a 4-mm punch biopsy. Each participant was treated with both topically applied APOSEC and placebo in NuGel for 7 consecutive days. The volunteers were randomized into two groups: a low-dose group (A) receiving the supernatant of 12.5 × 106 PBMCs and a high-dose group (B) receiving an equivalent of 25 × 106 PBMCs resuspended in NuGel Hydrogel. Irradiated medium served as placebo. The primary outcome was the tolerability of the topical application of APOSEC. All adverse events were recorded until 17 days after the biopsy. Local tolerability assessment was measured on a 4-point scale. Secondary outcomes were wound closure and epithelization at day 7. No therapy-related serious adverse events occurred in any of the participants, and both low- and high-dose treatments were well tolerated. Wound closure was not affected by APOSEC therapy.


Assuntos
Apoptose , Proteínas Sanguíneas/metabolismo , Meios de Cultivo Condicionados/farmacologia , Hidrogéis/administração & dosagem , Leucócitos Mononucleares/metabolismo , Pele/efeitos dos fármacos , Cicatrização/fisiologia , Administração Tópica , Adulto , Método Duplo-Cego , Voluntários Saudáveis , Humanos , Masculino , Pele/lesões , Pele/metabolismo , Pele Artificial
11.
Sci Rep ; 6: 32946, 2016 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-27597175

RESUMO

For patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (SCCHN) limited therapeutic options exist. Only a subset of patients is suitable for combination chemotherapy regimens. Biweekly docetaxel plus cetuximab might be an alternative option. Thus, we performed this retrospective analysis in unselected patients in order to investigate the efficacy and safety of this regimen. Thirty-one patients receiving off protocol docetaxel (50 mg/m(2)) plus cetuximab (500 mg/m(2)) biweekly were included. Data collection included baseline demographic, response rate (ORR), disease control rate (DCR), overall survival (OS), progression free survival (PFS) as well as toxicity. OS and PFS were 8.3 months (95% CI 4.8-11.8) and 4.0 months (95% CI 1.0-7.0), respectively. Three (9.7%) patients achieved a complete response and one patient (3.2%) a partial response. The DCR was 41.9% and we observed an ORR of 12.9%. The one-year survival rate was 25.8%. The therapy was well tolerated and the most common grade 3/4 adverse events were neutropenia (19.4%), hypomagnesaemia (12.9%) and acne-like rash (9.7%). Biweekly cetuximab/docetaxel is an effective regimen and well tolerated in R/M SCCHN patients not suitable for platinum doublet treatment. Further evaluation of this regimen in prospective clinical trials is warranted.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Carcinoma de Células Escamosas/secundário , Cetuximab/administração & dosagem , Docetaxel , Feminino , Seguimentos , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/patologia , Prognóstico , Indução de Remissão , Estudos Retrospectivos , Taxa de Sobrevida , Taxoides/administração & dosagem
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