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1. Sepsis in cancer patients residing in Zimbabwe: spectrum of bacterial and fungal aetiologies and their antimicrobial susceptibility patterns

Author

Frank Chinowaita, Wendy Chaka, Tinashe K. Nyazika, Tendai C. Maboreke, Emmanuel Tizauone, Prichard Mapondera, Inam Chitsike, Andrew Z. Cakana, and Rooyen T. Mavenyengwa

Subjects
Sepsis, Cancer, Aetiology, Antimicrobial resistance, ESBL, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background Cancer and sepsis comorbidity is a major public health problem in most parts of the world including Zimbabwe. The microbial aetiologies of sepsis and their antibiograms vary with time and locations. Knowledge on local microbial aetiologies of sepsis and their susceptibility patterns is critical in guiding empirical antimicrobial treatment choices. Methods This was a descriptive cross-sectional study which determined the microbial aetiologies of sepsis from blood cultures of paediatric and adult cancer patients obtained between July 2016 and June 2017. The TDR-X120 blood culture system and TDR 300B auto identification machine were used for incubation of blood culture bottles and identification plus antimicrobial susceptibility testing, respectively. Results A total of 142 participants were enrolled; 50 (35.2%) had positive blood cultures, with 56.0% Gram positive, 42.0% Gram-negative bacteria and 2.0% yeast isolated. Common species isolated included coagulase negative Staphylococcus spp. (CoNS) (22.0%), E. coli (16.0%), K. pneumoniae (14.0%), E. faecalis (14.0%) and S. aureus (8.0%). Gram-negative isolates exhibited high resistance to gentamicin (61.9%) and ceftriaxone (71.4%) which are the empiric antimicrobial agents used in our setting. Amikacin and meropenem showed 85.7 and 95.2% activity respectively against all Gram-negative isolates, whilst vancomycin and linezolid were effective against 96.2 and 100.0% of all Gram-positive isolates respectively. We isolated 10 (66.7%) extended spectrum β-lactamase (ESBL) amongst the E. coli and K. pneumoniae isolates. Ten (66.7%) of the Staphylococcus spp. were methicillin resistant. Conclusions CoNS, E. coli, K. pneumoniae, E. faecalis and S. aureus were the major microbial drivers of sepsis amongst cancer patients in Zimbabwe. Most isolates were found to be resistant to commonly used empirical antibiotics, with isolates exhibiting high levels of ESBL and methicillin resistance carriage. A nationwide survey on microbial aetiologies of sepsis and their susceptibility patterns would assist in the guidance of effective sepsis empiric antimicrobial treatment among patients with cancer.

Published
2020
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2. Excessive neutrophil recruitment promotes typical T-helper 17 responses in Coronavirus disease 2019 patients.

Author

Tanaka Arthur Choto, Ian Makupe, Andrew Zolani Cakana, Elopy Nimele Sibanda, and Takafira Mduluza

Subjects
Medicine, Science
Abstract

Coronavirus disease 2019 (COVID-19) is caused by a recently identified virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the disease is a pandemic. Although the hallmarks of severe COVID-19 have been established, the underlying mechanisms that promote severe pathology have not been thoroughly studied. A better understanding of the immune response in severe COVID-19 patients may help guide the development of therapeutic strategies and predict immuno-pathogenicity. This study was set to determine the lymphocyte and cytokine profiles associated with COVID-19 severity. A total of 43 hospitalised COVID-19 patients were recruited for the study and whole blood samples were drawn from each patient. Complete blood counts, lymphocyte subset profiles and C-reactive protein statuses of patients were determined. Cytometric bead array was performed to analyse the cytokine profiles of each patient. The demographic characteristics showed that the median age of the patients was 48.72 years, with an interquartile range from 40 to 60 years, and 69.77% of the patients were male. COVID-19 patients exhibited significantly low CD4+ lymphocyte expansion and leucocytosis augmented by elevated neutrophil and immature granulocytes. Stratification analysis revealed that reduced monocytes and elevated basophils and immature granulocytes are implicated in severe pathology. Additionally, cytokine results were noted to have significant incidences of interleukin 17A (IL-17A) expression associated with severe disease. Results from this study suggest that a systemic neutrophilic environment may preferentially skew CD4+ lymphocytes towards T-helper 17 and IL-17A promotion, thus, aggravating inflammation. Consequently, results from this study suggest broad activity immunomodulation and targeting neutrophils and blocking IL-17 production as therapeutic strategies against severe COVID-19.

Published
2022
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4. Supplementary Table 2 from Prespecified Candidate Biomarkers Identify Follicular Lymphoma Patients Who Achieved Longer Progression-Free Survival with Bortezomib–Rituximab Versus Rituximab

Author

Coiffier, Bertrand, primary, Li, Weimin, primary, Henitz, Erin D., primary, Karkera, Jayaprakash D., primary, Favis, Reyna, primary, Gaffney, Dana, primary, Shapiro, Alice, primary, Theocharous, Panteli, primary, Elsayed, Yusri A., primary, van de Velde, Helgi, primary, Schaffer, Michael E., primary, Osmanov, Evgenii A., primary, Hong, Xiaonan, primary, Scheliga, Adriana, primary, Mayer, Jiri, primary, Offner, Fritz, primary, Rule, Simon, primary, Teixeira, Adriana, primary, Romejko-Jarosinska, Joanna, primary, de Vos, Sven, primary, Crump, Michael, primary, Shpilberg, Ofer, primary, Zinzani, Pier Luigi, primary, Cakana, Andrew, primary, Esseltine, Dixie-Lee, primary, Mulligan, George, primary, and Ricci, Deborah, primary

Published
2023
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5. Supplemental Table S3 from Loss of RASSF4 Expression in Multiple Myeloma Promotes RAS-Driven Malignant Progression

Author

De Smedt, Eva, primary, Maes, Ken, primary, Verhulst, Stefaan, primary, Lui, Hui, primary, Kassambara, Alboukadel, primary, Maes, Anke, primary, Robert, Nicolas, primary, Heirman, Carlo, primary, Cakana, Andrew, primary, Hose, Dirk, primary, Breckpot, Karine, primary, van Grunsven, Leo A., primary, De Veirman, Kim, primary, Menu, Eline, primary, Vanderkerken, Karin, primary, Moreaux, Jérôme, primary, and De Bruyne, Elke, primary

Published
2023
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6. Supplemental Figures S1-S7 from Loss of RASSF4 Expression in Multiple Myeloma Promotes RAS-Driven Malignant Progression

Author

De Smedt, Eva, primary, Maes, Ken, primary, Verhulst, Stefaan, primary, Lui, Hui, primary, Kassambara, Alboukadel, primary, Maes, Anke, primary, Robert, Nicolas, primary, Heirman, Carlo, primary, Cakana, Andrew, primary, Hose, Dirk, primary, Breckpot, Karine, primary, van Grunsven, Leo A., primary, De Veirman, Kim, primary, Menu, Eline, primary, Vanderkerken, Karin, primary, Moreaux, Jérôme, primary, and De Bruyne, Elke, primary

Published
2023
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7. Data from Loss of RASSF4 Expression in Multiple Myeloma Promotes RAS-Driven Malignant Progression

Author

De Smedt, Eva, primary, Maes, Ken, primary, Verhulst, Stefaan, primary, Lui, Hui, primary, Kassambara, Alboukadel, primary, Maes, Anke, primary, Robert, Nicolas, primary, Heirman, Carlo, primary, Cakana, Andrew, primary, Hose, Dirk, primary, Breckpot, Karine, primary, van Grunsven, Leo A., primary, De Veirman, Kim, primary, Menu, Eline, primary, Vanderkerken, Karin, primary, Moreaux, Jérôme, primary, and De Bruyne, Elke, primary

Published
2023
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8. Supplementary Figure 3 from Prespecified Candidate Biomarkers Identify Follicular Lymphoma Patients Who Achieved Longer Progression-Free Survival with Bortezomib–Rituximab Versus Rituximab

Author

Coiffier, Bertrand, primary, Li, Weimin, primary, Henitz, Erin D., primary, Karkera, Jayaprakash D., primary, Favis, Reyna, primary, Gaffney, Dana, primary, Shapiro, Alice, primary, Theocharous, Panteli, primary, Elsayed, Yusri A., primary, van de Velde, Helgi, primary, Schaffer, Michael E., primary, Osmanov, Evgenii A., primary, Hong, Xiaonan, primary, Scheliga, Adriana, primary, Mayer, Jiri, primary, Offner, Fritz, primary, Rule, Simon, primary, Teixeira, Adriana, primary, Romejko-Jarosinska, Joanna, primary, de Vos, Sven, primary, Crump, Michael, primary, Shpilberg, Ofer, primary, Zinzani, Pier Luigi, primary, Cakana, Andrew, primary, Esseltine, Dixie-Lee, primary, Mulligan, George, primary, and Ricci, Deborah, primary

Published
2023
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9. Supplementary Figure 1 from Prespecified Candidate Biomarkers Identify Follicular Lymphoma Patients Who Achieved Longer Progression-Free Survival with Bortezomib–Rituximab Versus Rituximab

Author

Coiffier, Bertrand, primary, Li, Weimin, primary, Henitz, Erin D., primary, Karkera, Jayaprakash D., primary, Favis, Reyna, primary, Gaffney, Dana, primary, Shapiro, Alice, primary, Theocharous, Panteli, primary, Elsayed, Yusri A., primary, van de Velde, Helgi, primary, Schaffer, Michael E., primary, Osmanov, Evgenii A., primary, Hong, Xiaonan, primary, Scheliga, Adriana, primary, Mayer, Jiri, primary, Offner, Fritz, primary, Rule, Simon, primary, Teixeira, Adriana, primary, Romejko-Jarosinska, Joanna, primary, de Vos, Sven, primary, Crump, Michael, primary, Shpilberg, Ofer, primary, Zinzani, Pier Luigi, primary, Cakana, Andrew, primary, Esseltine, Dixie-Lee, primary, Mulligan, George, primary, and Ricci, Deborah, primary

Published
2023
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10. Supplementary Table 1 from Prespecified Candidate Biomarkers Identify Follicular Lymphoma Patients Who Achieved Longer Progression-Free Survival with Bortezomib–Rituximab Versus Rituximab

Author

Coiffier, Bertrand, primary, Li, Weimin, primary, Henitz, Erin D., primary, Karkera, Jayaprakash D., primary, Favis, Reyna, primary, Gaffney, Dana, primary, Shapiro, Alice, primary, Theocharous, Panteli, primary, Elsayed, Yusri A., primary, van de Velde, Helgi, primary, Schaffer, Michael E., primary, Osmanov, Evgenii A., primary, Hong, Xiaonan, primary, Scheliga, Adriana, primary, Mayer, Jiri, primary, Offner, Fritz, primary, Rule, Simon, primary, Teixeira, Adriana, primary, Romejko-Jarosinska, Joanna, primary, de Vos, Sven, primary, Crump, Michael, primary, Shpilberg, Ofer, primary, Zinzani, Pier Luigi, primary, Cakana, Andrew, primary, Esseltine, Dixie-Lee, primary, Mulligan, George, primary, and Ricci, Deborah, primary

Published
2023
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11. Supplemental materials and methods, supplemental references and supplemental figure legends from Loss of RASSF4 Expression in Multiple Myeloma Promotes RAS-Driven Malignant Progression

Author

De Smedt, Eva, primary, Maes, Ken, primary, Verhulst, Stefaan, primary, Lui, Hui, primary, Kassambara, Alboukadel, primary, Maes, Anke, primary, Robert, Nicolas, primary, Heirman, Carlo, primary, Cakana, Andrew, primary, Hose, Dirk, primary, Breckpot, Karine, primary, van Grunsven, Leo A., primary, De Veirman, Kim, primary, Menu, Eline, primary, Vanderkerken, Karin, primary, Moreaux, Jérôme, primary, and De Bruyne, Elke, primary

Published
2023
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12. Supplementary Figure 2 from Prespecified Candidate Biomarkers Identify Follicular Lymphoma Patients Who Achieved Longer Progression-Free Survival with Bortezomib–Rituximab Versus Rituximab

Author

Coiffier, Bertrand, primary, Li, Weimin, primary, Henitz, Erin D., primary, Karkera, Jayaprakash D., primary, Favis, Reyna, primary, Gaffney, Dana, primary, Shapiro, Alice, primary, Theocharous, Panteli, primary, Elsayed, Yusri A., primary, van de Velde, Helgi, primary, Schaffer, Michael E., primary, Osmanov, Evgenii A., primary, Hong, Xiaonan, primary, Scheliga, Adriana, primary, Mayer, Jiri, primary, Offner, Fritz, primary, Rule, Simon, primary, Teixeira, Adriana, primary, Romejko-Jarosinska, Joanna, primary, de Vos, Sven, primary, Crump, Michael, primary, Shpilberg, Ofer, primary, Zinzani, Pier Luigi, primary, Cakana, Andrew, primary, Esseltine, Dixie-Lee, primary, Mulligan, George, primary, and Ricci, Deborah, primary

Published
2023
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13. Supplementary Table 3 from Prespecified Candidate Biomarkers Identify Follicular Lymphoma Patients Who Achieved Longer Progression-Free Survival with Bortezomib–Rituximab Versus Rituximab

Author

Coiffier, Bertrand, primary, Li, Weimin, primary, Henitz, Erin D., primary, Karkera, Jayaprakash D., primary, Favis, Reyna, primary, Gaffney, Dana, primary, Shapiro, Alice, primary, Theocharous, Panteli, primary, Elsayed, Yusri A., primary, van de Velde, Helgi, primary, Schaffer, Michael E., primary, Osmanov, Evgenii A., primary, Hong, Xiaonan, primary, Scheliga, Adriana, primary, Mayer, Jiri, primary, Offner, Fritz, primary, Rule, Simon, primary, Teixeira, Adriana, primary, Romejko-Jarosinska, Joanna, primary, de Vos, Sven, primary, Crump, Michael, primary, Shpilberg, Ofer, primary, Zinzani, Pier Luigi, primary, Cakana, Andrew, primary, Esseltine, Dixie-Lee, primary, Mulligan, George, primary, and Ricci, Deborah, primary

Published
2023
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14. Supplemental Tables S1, S4 and S5 from Loss of RASSF4 Expression in Multiple Myeloma Promotes RAS-Driven Malignant Progression

Author

De Smedt, Eva, primary, Maes, Ken, primary, Verhulst, Stefaan, primary, Lui, Hui, primary, Kassambara, Alboukadel, primary, Maes, Anke, primary, Robert, Nicolas, primary, Heirman, Carlo, primary, Cakana, Andrew, primary, Hose, Dirk, primary, Breckpot, Karine, primary, van Grunsven, Leo A., primary, De Veirman, Kim, primary, Menu, Eline, primary, Vanderkerken, Karin, primary, Moreaux, Jérôme, primary, and De Bruyne, Elke, primary

Published
2023
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15. Supplementary Table 4 from Prespecified Candidate Biomarkers Identify Follicular Lymphoma Patients Who Achieved Longer Progression-Free Survival with Bortezomib–Rituximab Versus Rituximab

Author

Coiffier, Bertrand, primary, Li, Weimin, primary, Henitz, Erin D., primary, Karkera, Jayaprakash D., primary, Favis, Reyna, primary, Gaffney, Dana, primary, Shapiro, Alice, primary, Theocharous, Panteli, primary, Elsayed, Yusri A., primary, van de Velde, Helgi, primary, Schaffer, Michael E., primary, Osmanov, Evgenii A., primary, Hong, Xiaonan, primary, Scheliga, Adriana, primary, Mayer, Jiri, primary, Offner, Fritz, primary, Rule, Simon, primary, Teixeira, Adriana, primary, Romejko-Jarosinska, Joanna, primary, de Vos, Sven, primary, Crump, Michael, primary, Shpilberg, Ofer, primary, Zinzani, Pier Luigi, primary, Cakana, Andrew, primary, Esseltine, Dixie-Lee, primary, Mulligan, George, primary, and Ricci, Deborah, primary

Published
2023
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16. Supplementary Methods from Prespecified Candidate Biomarkers Identify Follicular Lymphoma Patients Who Achieved Longer Progression-Free Survival with Bortezomib–Rituximab Versus Rituximab

Author

Coiffier, Bertrand, primary, Li, Weimin, primary, Henitz, Erin D., primary, Karkera, Jayaprakash D., primary, Favis, Reyna, primary, Gaffney, Dana, primary, Shapiro, Alice, primary, Theocharous, Panteli, primary, Elsayed, Yusri A., primary, van de Velde, Helgi, primary, Schaffer, Michael E., primary, Osmanov, Evgenii A., primary, Hong, Xiaonan, primary, Scheliga, Adriana, primary, Mayer, Jiri, primary, Offner, Fritz, primary, Rule, Simon, primary, Teixeira, Adriana, primary, Romejko-Jarosinska, Joanna, primary, de Vos, Sven, primary, Crump, Michael, primary, Shpilberg, Ofer, primary, Zinzani, Pier Luigi, primary, Cakana, Andrew, primary, Esseltine, Dixie-Lee, primary, Mulligan, George, primary, and Ricci, Deborah, primary

Published
2023
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17. Supplemental Figures S1-S7 from Loss of RASSF4 Expression in Multiple Myeloma Promotes RAS-Driven Malignant Progression

Author

Elke De Bruyne, Jérôme Moreaux, Karin Vanderkerken, Eline Menu, Kim De Veirman, Leo A. van Grunsven, Karine Breckpot, Dirk Hose, Andrew Cakana, Carlo Heirman, Nicolas Robert, Anke Maes, Alboukadel Kassambara, Hui Lui, Stefaan Verhulst, Ken Maes, and Eva De Smedt

Abstract

Supplemental Figure 1 shows the prognostic value of the classical RASSF proteins RASSF1, RASSF3, RASSF5 and RASSF6 in MM patients. Supplemental Figure S2 shows the cellular localization of RASSF4. Supplemental Figure S3 demonstrates the inducible doxycycline-dependent overexpression of human RASSF4 and provides additional evidence for the anti-myeloma activity of RASSF4 overexpression in human cell lines. Supplemental Figure S4 provides a comparison of the RASSF4 expression levels of the primary MM cells (n=10) and a selected panel of HMCL (n=9) obtained through microarray analysis. Supplemental Figure S5 shows additional data on the effect of RASSF4 overexpression on tumor development and the confirmation of RASSF4 overexpression on protein level. Supplemental Figure S6 provides an overview of the top 20 differentially expressed genes between all control and RASSF4 overexpressing human multiple myeloma cell lines and subsequent pathway enrichment analysis of the genes downregulated after RASSF4 overexpression. Supplemental Figure S7 provides additional evidence for the anti-myeloma activity of trametinib in combination with the HDACi quisinostat or panobinostat and shows the effect of the HDACi panobinostat and/or the MEK1/2 inhibitor trametinib on RASSF4 mRNA expression.

Published
2023
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18. Data from Loss of RASSF4 Expression in Multiple Myeloma Promotes RAS-Driven Malignant Progression

Author

Elke De Bruyne, Jérôme Moreaux, Karin Vanderkerken, Eline Menu, Kim De Veirman, Leo A. van Grunsven, Karine Breckpot, Dirk Hose, Andrew Cakana, Carlo Heirman, Nicolas Robert, Anke Maes, Alboukadel Kassambara, Hui Lui, Stefaan Verhulst, Ken Maes, and Eva De Smedt

Abstract

RAS mutations occur frequently in multiple myeloma (MM), but apart from driving progression, they can also stimulate antitumor effects by activating tumor-suppressive RASSF proteins. Although this family of death effector molecules are often silenced in cancers, functional data about RASSF proteins in MM are lacking. Here, we report that RASSF4 is downregulated during MM progression and correlates with a poor prognosis. Promoter methylation analysis in human cell lines revealed an inverse correlation between RASSF4 mRNA levels and methylation status. Epigenetic modulating agents restored RASSF4 expression. Enforced expression of RASSF4 induced G2-phase cell-cycle arrest and apoptosis in human cell lines, reduced primary MM cell viability, and blocked MM growth in vivo. Mechanistic investigations showed that RASSF4 linked RAS to several pro-death pathways, including those regulated by the kinases MST1, JNK, and p38. By activating MST1 and the JNK/c-Jun pathway, RASSF4 sensitized MM cells to bortezomib. Genetic or pharmacological elevation of RASSF4 levels increased the anti-MM effects of the clinical relevant MEK1/2 inhibitor trametinib. Kinome analysis revealed that this effect was mediated by concomitant activation of the JNK/c-Jun pathway along with inactivation of the MEK/ERK and PI3K/mTOR/Akt pathways. Overall, our findings establish RASSF4 as a tumor-suppressive hub in MM and provide a mechanistic rationale for combining trametinib with HDAC inhibitors or bortezomib to treat patients with tumors exhibiting low RASSF4 expression.Significance: These findings provide a mechanistic rationale for combining trametinib with HDAC inhibitors or bortezomib in patients with multiple myeloma whose tumors exhibit low RASSF4 expression. Cancer Res; 78(5); 1155–68. ©2017 AACR.

Published
2023
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19. Supplementary Table 1 from Prespecified Candidate Biomarkers Identify Follicular Lymphoma Patients Who Achieved Longer Progression-Free Survival with Bortezomib–Rituximab Versus Rituximab

Author

Deborah Ricci, George Mulligan, Dixie-Lee Esseltine, Andrew Cakana, Pier Luigi Zinzani, Ofer Shpilberg, Michael Crump, Sven de Vos, Joanna Romejko-Jarosinska, Adriana Teixeira, Simon Rule, Fritz Offner, Jiri Mayer, Adriana Scheliga, Xiaonan Hong, Evgenii A. Osmanov, Michael E. Schaffer, Helgi van de Velde, Yusri A. Elsayed, Panteli Theocharous, Alice Shapiro, Dana Gaffney, Reyna Favis, Jayaprakash D. Karkera, Erin D. Henitz, Weimin Li, and Bertrand Coiffier

Abstract

Supplementary Table 1 PDF file 55K, Cut-points for protein markers used in different analyses. Cut-points selected for pair-wise comparisons were chosen to reduce the total number of comparisons that would be done. Cut-points for the discovery/confirmation analyses (see Supplementary Methods) were optimized based on enrichment of responders versus non-responders and reasonable population size

Published
2023
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20. Supplementary Figure 1 from Prespecified Candidate Biomarkers Identify Follicular Lymphoma Patients Who Achieved Longer Progression-Free Survival with Bortezomib–Rituximab Versus Rituximab

Author

Deborah Ricci, George Mulligan, Dixie-Lee Esseltine, Andrew Cakana, Pier Luigi Zinzani, Ofer Shpilberg, Michael Crump, Sven de Vos, Joanna Romejko-Jarosinska, Adriana Teixeira, Simon Rule, Fritz Offner, Jiri Mayer, Adriana Scheliga, Xiaonan Hong, Evgenii A. Osmanov, Michael E. Schaffer, Helgi van de Velde, Yusri A. Elsayed, Panteli Theocharous, Alice Shapiro, Dana Gaffney, Reyna Favis, Jayaprakash D. Karkera, Erin D. Henitz, Weimin Li, and Bertrand Coiffier

Abstract

Supplementary Figure 1 PDF file 77K, Biomarker sample collection from the LYM-3001 intent-to-treat population

Published
2023
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21. Supplementary Table 4 from Prespecified Candidate Biomarkers Identify Follicular Lymphoma Patients Who Achieved Longer Progression-Free Survival with Bortezomib–Rituximab Versus Rituximab

Author

Deborah Ricci, George Mulligan, Dixie-Lee Esseltine, Andrew Cakana, Pier Luigi Zinzani, Ofer Shpilberg, Michael Crump, Sven de Vos, Joanna Romejko-Jarosinska, Adriana Teixeira, Simon Rule, Fritz Offner, Jiri Mayer, Adriana Scheliga, Xiaonan Hong, Evgenii A. Osmanov, Michael E. Schaffer, Helgi van de Velde, Yusri A. Elsayed, Panteli Theocharous, Alice Shapiro, Dana Gaffney, Reyna Favis, Jayaprakash D. Karkera, Erin D. Henitz, Weimin Li, and Bertrand Coiffier

Abstract

Supplementary Table 4 PDF file 69K, OS, ORR, CR rate, and TTNT in all patients in the cross-validation model (see Supplementary Methods) who were positive or negative for the biomarker pair PSMB1 P11A (G allele) and low CD68 expression (≤50 CD68-positive cells). Among all biomarker-positive patients there was a significantly longer OS with bortezomib-rituximab versus rituximab, a significantly higher ORR, a higher CR rate, and a significantly longer TTNT. No significant differences were seen for biomarker-negative patients

Published
2023
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22. Supplementary Table 3 from Prespecified Candidate Biomarkers Identify Follicular Lymphoma Patients Who Achieved Longer Progression-Free Survival with Bortezomib–Rituximab Versus Rituximab

Author

Deborah Ricci, George Mulligan, Dixie-Lee Esseltine, Andrew Cakana, Pier Luigi Zinzani, Ofer Shpilberg, Michael Crump, Sven de Vos, Joanna Romejko-Jarosinska, Adriana Teixeira, Simon Rule, Fritz Offner, Jiri Mayer, Adriana Scheliga, Xiaonan Hong, Evgenii A. Osmanov, Michael E. Schaffer, Helgi van de Velde, Yusri A. Elsayed, Panteli Theocharous, Alice Shapiro, Dana Gaffney, Reyna Favis, Jayaprakash D. Karkera, Erin D. Henitz, Weimin Li, and Bertrand Coiffier

Abstract

Supplementary Table 3 PDF file 70K, Median PFS for patients in the discovery and confirmation sets, and in all patients, in the cross-validation model (see Supplementary Materials) who were positive or negative for the biomarker pair PSMB1 P11A (G allele) and low CD68 expression (≤50 CD68-positive cells). Presence of the biomarker pair was associated with a significant PFS benefit in patients treated with bortezomib-rituximab versus rituximab in the discovery set, a positive trend in the smaller confirmation sets, and a significant benefit among all patients. No significant differences were seen for biomarker-negative patients

Published
2023
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23. Data from Prespecified Candidate Biomarkers Identify Follicular Lymphoma Patients Who Achieved Longer Progression-Free Survival with Bortezomib–Rituximab Versus Rituximab

Author

Deborah Ricci, George Mulligan, Dixie-Lee Esseltine, Andrew Cakana, Pier Luigi Zinzani, Ofer Shpilberg, Michael Crump, Sven de Vos, Joanna Romejko-Jarosinska, Adriana Teixeira, Simon Rule, Fritz Offner, Jiri Mayer, Adriana Scheliga, Xiaonan Hong, Evgenii A. Osmanov, Michael E. Schaffer, Helgi van de Velde, Yusri A. Elsayed, Panteli Theocharous, Alice Shapiro, Dana Gaffney, Reyna Favis, Jayaprakash D. Karkera, Erin D. Henitz, Weimin Li, and Bertrand Coiffier

Abstract

Purpose: Identify subgroups of patients with relapsed/refractory follicular lymphoma deriving substantial progression-free survival (PFS) benefit with bortezomib–rituximab versus rituximab in the phase III LYM-3001 study.Experimental Design: A total of 676 patients were randomized to five 5-week cycles of bortezomib–rituximab or rituximab. The primary end point was PFS; this prespecified analysis of candidate protein biomarkers and genes was an exploratory objective. Archived tumor tissue and whole blood samples were collected at baseline. Immunohistochemistry and genetic analyses were completed for 4 proteins and 8 genes.Results: In initial pairwise analyses, using individual single-nucleotide polymorphism genotypes, one biomarker pair (PSMB1 P11A C/G heterozygote, low CD68 expression) was associated with a significant PFS benefit with bortezomib–rituximab versus rituximab, controlling for multiple comparison corrections. The pair was analyzed under dominant, recessive, and additive genetic models, with significant association with PFS seen under the dominant model (G/G+C/G). In patients carrying this biomarker pair [PSMB1 P11A G allele, low CD68 expression (≤50 CD68-positive cells), population frequency: 43.6%], median PFS was 14.2 months with bortezomib–rituximab versus 9.1 months with rituximab (HR 0.47, P < 0.0001), and there was a significant overall survival benefit (HR 0.49, P = 0.0461). Response rates were higher and time to next antilymphoma therapy was longer in the bortezomib–rituximab group. In biomarker-negative patients, no significant efficacy differences were seen between treatment groups. Similar proportions of patients had high-risk features in the biomarker-positive and biomarker-negative subsets.Conclusions: Patients with PSMB1 P11A (G allele) and low CD68 expression seemed to have significantly longer PFS and greater clinical benefit with bortezomib–rituximab versus rituximab. Clin Cancer Res; 19(9); 2551–61. ©2013 AACR.

Published
2023
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24. Supplementary Figure 2 from Prespecified Candidate Biomarkers Identify Follicular Lymphoma Patients Who Achieved Longer Progression-Free Survival with Bortezomib–Rituximab Versus Rituximab

Author

Deborah Ricci, George Mulligan, Dixie-Lee Esseltine, Andrew Cakana, Pier Luigi Zinzani, Ofer Shpilberg, Michael Crump, Sven de Vos, Joanna Romejko-Jarosinska, Adriana Teixeira, Simon Rule, Fritz Offner, Jiri Mayer, Adriana Scheliga, Xiaonan Hong, Evgenii A. Osmanov, Michael E. Schaffer, Helgi van de Velde, Yusri A. Elsayed, Panteli Theocharous, Alice Shapiro, Dana Gaffney, Reyna Favis, Jayaprakash D. Karkera, Erin D. Henitz, Weimin Li, and Bertrand Coiffier

Abstract

Supplementary Figure 2 PDF file 135K, Forest plot for single marker (A) protein and (B) germ-line DNA biomarker analyses

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2023
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25. Supplemental Tables S1, S4 and S5 from Loss of RASSF4 Expression in Multiple Myeloma Promotes RAS-Driven Malignant Progression

Author

Elke De Bruyne, Jérôme Moreaux, Karin Vanderkerken, Eline Menu, Kim De Veirman, Leo A. van Grunsven, Karine Breckpot, Dirk Hose, Andrew Cakana, Carlo Heirman, Nicolas Robert, Anke Maes, Alboukadel Kassambara, Hui Lui, Stefaan Verhulst, Ken Maes, and Eva De Smedt

Abstract

Supplemental Table S1 summarizes the patient characteristics. Supplemental Table S4 provides an overview of all kinases differentially phosphorylated in RASSF4 overexpressing cells treated with trametinib compared to parental cells treated with trametinib and/or RASSF4 overexpressing cells. Supplemental Table S5 summarizes significance and combination index (CI) values calculated for the different drug concentrations used in the combination experiments.

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2023
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26. Supplemental materials and methods, supplemental references and supplemental figure legends from Loss of RASSF4 Expression in Multiple Myeloma Promotes RAS-Driven Malignant Progression

Author

Elke De Bruyne, Jérôme Moreaux, Karin Vanderkerken, Eline Menu, Kim De Veirman, Leo A. van Grunsven, Karine Breckpot, Dirk Hose, Andrew Cakana, Carlo Heirman, Nicolas Robert, Anke Maes, Alboukadel Kassambara, Hui Lui, Stefaan Verhulst, Ken Maes, and Eva De Smedt

Abstract

Information about material and methods, that further support the date described in this article. Additional references and legends to the supplmental figures are also provided.

Published
2023
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27. Supplementary Methods from Prespecified Candidate Biomarkers Identify Follicular Lymphoma Patients Who Achieved Longer Progression-Free Survival with Bortezomib–Rituximab Versus Rituximab

Author

Deborah Ricci, George Mulligan, Dixie-Lee Esseltine, Andrew Cakana, Pier Luigi Zinzani, Ofer Shpilberg, Michael Crump, Sven de Vos, Joanna Romejko-Jarosinska, Adriana Teixeira, Simon Rule, Fritz Offner, Jiri Mayer, Adriana Scheliga, Xiaonan Hong, Evgenii A. Osmanov, Michael E. Schaffer, Helgi van de Velde, Yusri A. Elsayed, Panteli Theocharous, Alice Shapiro, Dana Gaffney, Reyna Favis, Jayaprakash D. Karkera, Erin D. Henitz, Weimin Li, and Bertrand Coiffier

Abstract

Supplementary Methods PDF file 64K, TaqMan SNP Genoytping Assays and Ligation-based Multiplexed Genotyping Assays

Published
2023
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28. Supplementary Table 2 from Prespecified Candidate Biomarkers Identify Follicular Lymphoma Patients Who Achieved Longer Progression-Free Survival with Bortezomib–Rituximab Versus Rituximab

Author

Deborah Ricci, George Mulligan, Dixie-Lee Esseltine, Andrew Cakana, Pier Luigi Zinzani, Ofer Shpilberg, Michael Crump, Sven de Vos, Joanna Romejko-Jarosinska, Adriana Teixeira, Simon Rule, Fritz Offner, Jiri Mayer, Adriana Scheliga, Xiaonan Hong, Evgenii A. Osmanov, Michael E. Schaffer, Helgi van de Velde, Yusri A. Elsayed, Panteli Theocharous, Alice Shapiro, Dana Gaffney, Reyna Favis, Jayaprakash D. Karkera, Erin D. Henitz, Weimin Li, and Bertrand Coiffier

Abstract

Supplementary Table 2 PDF file 78K, Evaluation of PFS and OS under the G-dominant genetic model for PSMB1 P11A among all patients evaluable for the biomarker pair of PSMB1 P11A genotype and CD68 expression who had low (≤50 CD68-positive cells) CD68 expression

Published
2023
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29. Supplementary Figure 3 from Prespecified Candidate Biomarkers Identify Follicular Lymphoma Patients Who Achieved Longer Progression-Free Survival with Bortezomib–Rituximab Versus Rituximab

Author

Deborah Ricci, George Mulligan, Dixie-Lee Esseltine, Andrew Cakana, Pier Luigi Zinzani, Ofer Shpilberg, Michael Crump, Sven de Vos, Joanna Romejko-Jarosinska, Adriana Teixeira, Simon Rule, Fritz Offner, Jiri Mayer, Adriana Scheliga, Xiaonan Hong, Evgenii A. Osmanov, Michael E. Schaffer, Helgi van de Velde, Yusri A. Elsayed, Panteli Theocharous, Alice Shapiro, Dana Gaffney, Reyna Favis, Jayaprakash D. Karkera, Erin D. Henitz, Weimin Li, and Bertrand Coiffier

Abstract

Supplementary Figure 3 PDF file 78K, Kaplan-Meier distributions of A) PFS and B) OS under the G-dominant genetic model for PSMB1 P11A among all patients evaluable for the biomarker pair of PSMB1 P11A genotype and CD68 expression who had low (≤50 CD68-positive cells) CD68 expression

Published
2023
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30. Supplemental Table S2 from Loss of RASSF4 Expression in Multiple Myeloma Promotes RAS-Driven Malignant Progression

Author

Elke De Bruyne, Jérôme Moreaux, Karin Vanderkerken, Eline Menu, Kim De Veirman, Leo A. van Grunsven, Karine Breckpot, Dirk Hose, Andrew Cakana, Carlo Heirman, Nicolas Robert, Anke Maes, Alboukadel Kassambara, Hui Lui, Stefaan Verhulst, Ken Maes, and Eva De Smedt

Abstract

List of differentially expressed genes between all control and RASSF4 overexpressing human multiple myeloma cell lines

Published
2023
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32. Association between quality of response and outcomes in patients with newly diagnosed mantle cell lymphoma receiving VR-CAP versus R-CHOP in the phase 3 LYM-3002 study

Author

Gregor Verhoef, Tadeusz Robak, Huiqiang Huang, Halyna Pylypenko, Noppadol Siritanaratkul, Juliana Pereira, Johannes Drach, Jiri Mayer, Rumiko Okamoto, Lixia Pei, Brendan Rooney, Andrew Cakana, Helgi van de Velde, and Franco Cavalli

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

In the phase 3 LYM-3002 study comparing intravenous VR-CAP with R-CHOP in patients with newly-diagnosed, measurable stage II-IV mantle cell lymphoma, not considered or ineligible for transplant, the median progression-free survival was significantly improved with VR-CAP (24.7 versus 14.4 months with R-CHOP; P

Published
2017
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33. Outcomes with two different schedules of bortezomib, melphalan, and prednisone (VMP) for previously untreated multiple myeloma: matched pair analysis using long-term follow-up data from the phase 3 VISTA and PETHEMA/GEM05 trials

Author

Mateos, Maria-Victoria, Oriol, Albert, Martínez-López, Joaquín, Teruel, Ana-Isabel, Bengoechea, Enrique, Palomera, Luis, de Arriba, Felipe, Esseltine, Dixie-Lee, Cakana, Andrew, Pei, Lixia, van de Velde, Helgi, and Miguel, Jesus San

Published
2016
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36. Superior outcomes associated with complete response in newly diagnosed multiple myeloma patients treated with nonintensive therapy: analysis of the phase 3 VISTA study of bortezomib plus melphalan-prednisone versus melphalan-prednisone

Author

Harousseau, Jean-Luc, Palumbo, Antonio, Richardson, Paul G., Schlag, Rudolf, Dimopoulos, Meletios A., Shpilberg, Ofer, Kropff, Martin, Kentos, Alain, Cavo, Michele, Golenkov, Anatoly, Komarnicki, Mieczyslaw, Mateos, Maria-Victoria, Esseltine, Dixie-Lee, Cakana, Andrew, Liu, Kevin, Deraedt, William, van de Velde, Helgi, and San Miguel, Jesús F.

Published
2010
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38. Pharmacokinetic, Pharmacodynamic and Covariate Analysis of Subcutaneous Versus Intravenous Administration of Bortezomib in Patients with Relapsed Multiple Myeloma

Author

Moreau, Philippe, Karamanesht, Ievgenii I., Domnikova, Natalia, Kyselyova, Maryna Y., Vilchevska, Kateryna V., Doronin, Vadim A., Schmidt, Alexander, Hulin, Cyrille, Leleu, Xavier, Esseltine, Dixie-Lee, Venkatakrishnan, Karthik, Skee, Donna, Feng, Huaibao, Girgis, Suzette, Cakana, Andrew, van de Velde, Helgi, Deraedt, William, and Facon, Thierry

Published
2012
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39. Bortezomib plus melphalan and prednisone for initial treatment of multiple Myeloma

Author

San Miguel, Jesus F., Schlag, Rudolf, Khuageva, Nuriet K., Dimopoulos, Meletios A., Shpilberg, Ofer, Kropff, Martin, Spicka, Ivan, Petrucci, Maria T., Palumbo, Antonio, Samoilova, Olga S., Dmoszynska, Anna, Abdulkadyrov, Kudrat M., Schots, Rik, Bin Jiang, Mateos, Maria-Victoria, Anderson, Kenneth C., Esseltine, Dixie L., Liu, Kevin, Cakana, Andrew, van de Velde, Helgi, and Richardson, Paul G.

Subjects
Multiple myeloma -- Diagnosis, Multiple myeloma -- Risk factors, Multiple myeloma -- Care and treatment, Bortezomib -- Dosage and administration, Bortezomib -- Complications and side effects, Prednisone -- Dosage and administration, Prednisone -- Complications and side effects, Melphalan -- Dosage and administration, Melphalan -- Complications and side effects
Abstract

The study aims to establish the efficacy of bortezomib plus melphalan-prednisone as compared to melphalan-prednisone alone in patients with newly diagnosed multiple myeloma that was ineligible for high-dose therapy is presented. The results indicate that bortezomib plus melphalan-prednisone was more effective in treatment as compared to melphalan-prednisone alone.

Published
2008

40. Sepsis in cancer patients residing in Zimbabwe: spectrum of bacterial and fungal aetiologies and their antimicrobial susceptibility patterns

Author

Andrew Z. Cakana, Emmanuel Tizauone, Rooyen T. Mavenyengwa, Tinashe K. Nyazika, Inam Chitsike, Frank Chinowaita, Prichard T. Mapondera, Tendai C. Maboreke, and Wendy Chaka

Subjects
0301 basic medicine, Male, Antimicrobial resistance, 0302 clinical medicine, Neoplasms, Medicine, Blood culture, 030212 general & internal medicine, Aetiology, Child, Cancer, Aged, 80 and over, medicine.diagnostic_test, Drug Resistance, Microbial, Middle Aged, Antimicrobial, 3. Good health, Anti-Bacterial Agents, Infectious Diseases, Amikacin, Child, Preschool, Vancomycin, Gentamicin, Female, Coagulase, medicine.drug, Research Article, Adult, Zimbabwe, wc_240, Adolescent, 030106 microbiology, wa_395, Microbial Sensitivity Tests, Microbiology, lcsh:Infectious and parasitic diseases, Sepsis, 03 medical and health sciences, Young Adult, Antibiotic resistance, Humans, lcsh:RC109-216, Aged, qw_4, Bacteria, business.industry, Fungi, Infant, medicine.disease, Cross-Sectional Studies, ESBL, business
Abstract

Background Cancer and sepsis comorbidity is a major public health problem in most parts of the world including Zimbabwe. The microbial aetiologies of sepsis and their antibiograms vary with time and locations. Knowledge on local microbial aetiologies of sepsis and their susceptibility patterns is critical in guiding empirical antimicrobial treatment choices. Methods This was a descriptive cross-sectional study which determined the microbial aetiologies of sepsis from blood cultures of paediatric and adult cancer patients obtained between July 2016 and June 2017. The TDR-X120 blood culture system and TDR 300B auto identification machine were used for incubation of blood culture bottles and identification plus antimicrobial susceptibility testing, respectively. Results A total of 142 participants were enrolled; 50 (35.2%) had positive blood cultures, with 56.0% Gram positive, 42.0% Gram-negative bacteria and 2.0% yeast isolated. Common species isolated included coagulase negative Staphylococcus spp. (CoNS) (22.0%), E. coli (16.0%), K. pneumoniae (14.0%), E. faecalis (14.0%) and S. aureus (8.0%). Gram-negative isolates exhibited high resistance to gentamicin (61.9%) and ceftriaxone (71.4%) which are the empiric antimicrobial agents used in our setting. Amikacin and meropenem showed 85.7 and 95.2% activity respectively against all Gram-negative isolates, whilst vancomycin and linezolid were effective against 96.2 and 100.0% of all Gram-positive isolates respectively. We isolated 10 (66.7%) extended spectrum β-lactamase (ESBL) amongst the E. coli and K. pneumoniae isolates. Ten (66.7%) of the Staphylococcus spp. were methicillin resistant. Conclusions CoNS, E. coli, K. pneumoniae, E. faecalis and S. aureus were the major microbial drivers of sepsis amongst cancer patients in Zimbabwe. Most isolates were found to be resistant to commonly used empirical antibiotics, with isolates exhibiting high levels of ESBL and methicillin resistance carriage. A nationwide survey on microbial aetiologies of sepsis and their susceptibility patterns would assist in the guidance of effective sepsis empiric antimicrobial treatment among patients with cancer.

Published
2020

41. Updated survival analysis of a randomized phase III study of subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma

Author

Bertrand Arnulf, Halyna Pylypenko, Sebastian Grosicki, Ievgenii Karamanesht, Xavier Leleu, Helgi van de Velde, Huaibao Feng, Andrew Cakana, William Deraedt, and Philippe Moreau

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

The phase III MMY-3021 study compared safety and efficacy of subcutaneous versus intravenous administration of the proteasome inhibitor bortezomib in patients with relapsed myeloma. The initial report demonstrated non-inferior efficacy with subcutaneous versus intravenous bortezomib for the primary end point: overall response rate after four cycles of single-agent bortezomib. We report updated outcome analyses after prolonged follow up. Best response rate (after up to ten cycles of bortezomib ± dexamethasone) remained 52% in each arm, including 23% and 22% complete or near-complete responses with subcutaneous and intravenous bortezomib, respectively. Time to progression (median 9.7 vs. 9.6 months; hazard ratio 0.872, P=0.462), progression-free survival (median 9.3 vs. 8.4 months; hazard ratio 0.846, P=0.319), and overall survival (1-year: 76.4% vs. 78.0%, P=0.788) were comparable with subcutaneous versus intravenous bortezomib. Peripheral neuropathy rates remained significantly lower with subcutaneous versus intravenous bortezomib, with increased rates of improvement/resolution at the time of this analysis.

Published
2012
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42. Complete response correlates with long-term survival and progression-free survival in high-dose therapy in multiple myeloma

Author

Helgi J.K. van de Velde, Xiangyang Liu, Gang Chen, Andrew Cakana, William Deraedt, and Martine Bayssas

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

There are a number of reports in literature data on the long-term outcomes of patients with multiple myeloma treated with high-dose therapy and autologous stem cell transplantation (HDT/SCT). While in general these data support the association between maximal tumor response and overall survival or progression-free survival after HDT/SCT, some trials have failed to find such correlation and there is no recent comprehensive literature analysis of this issue. We, therefore, performed a comprehensive literature review to identify prospective and retrospective studies on HDT/SCT in frontline multiple myeloma in which long-term outcomes were reported according to best tumor response observed. Following a prospectively defined search strategy we identified 21 studies (10 prospective and 11 retrospective studies) in which outcomes of 4,990 HDT/SCT patients according to their best tumor response were reported. The majority of these studies indicated a correlation between maximal response during or after HDT/SCT and long-term outcomes (overall survival and event-free/progression-free survival). The conclusions in individual studis report on the association between maximal response following induction therapy and long-term outcomes were more heterogeneous, possibly due to the low rate of complete response after standard induction therapy in each individual study. We, therefore, performed two types of meta-analyses, one based on the p-values reported for these associations in the individual studies, and one based on the primary response and outcome data provided in the individual studies. Both meta-analyses indicated highly significant associations between maximal response (complete response/near complete response/very good partial response) during or after HDT/SCT and long-term outcomes (overall survival and event-free/progression-free survival). Both meta-analyses also provided evidence of highly significant associations between maximal response following induction therapy and long-term outcomes (overall survival and event-free/progression-free survival).

Published
2007
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46. Fewer bone disease events, improvement in bone remodeling, and evidence of bone healing with bortezomib plus melphalan-prednisone vs. melphalan-prednisone in the phase III VISTA trial in multiple myeloma

Author

Delforge, Michel, Terpos, Evangelos, Richardson, Paul G., Shpilberg, Ofer, Khuageva, Nuriet K., Schlag, Rudolf, Dimopoulos, Meletios A., Kropff, Martin, Spicka, Ivan, Petrucci, Maria T., Samoilova, Olga S., Mateos, Maria-Victoria, Magen-Nativ, Hila, Goldschmidt, Hartmut, Esseltine, Dixie-Lee, Ricci, Deborah S., Liu, Kevin, Deraedt, William, Cakana, Andrew, van de Velde, Helgi, and San Miguel, Jesús F.

Published
2011
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47. Characterization of haematological parameters with bortezomib–melphalan–prednisone versus melphalan–prednisone in newly diagnosed myeloma, with evaluation of long-term outcomes and risk of thromboembolic events with use of erythropoiesis-stimulating agents: analysis of the VISTA trial

Author

Richardson, Paul, Schlag, Rudolf, Khuageva, Nuriet, Dimopoulos, Meletios, Shpilberg, Ofer, Kropff, Martin, Vekemans, Marie-Christiane, Petrucci, Maria Teresa, Rossiev, Viktor, Hou, Jian, Robak, Tadeusz, Mateos, Maria-Victoria, Anderson, Kenneth, Esseltine, Dixie-Lee, Cakana, Andrew, Liu, Kevin, Deraedt, William, van de Velde, Helgi, and San Miguel, Jesús F.

Published
2011
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48. Risk factors for, and reversibility of, peripheral neuropathy associated with bortezomib–melphalan–prednisone in newly diagnosed patients with multiple myeloma: subanalysis of the phase 3 VISTA study

Author

Dimopoulos, Meletios A., Mateos, Maria-Victoria, Richardson, Paul G., Schlag, Rudolf, Khuageva, Nuriet K., Shpilberg, Ofer, Kropff, Martin, Spicka, Ivan, Palumbo, Antonio, Wu, Ka Lung, Esseltine, Dixie-Lee, Liu, Kevin, Deraedt, William, Cakana, Andrew, Van De Velde, Helgi, and Miguel, Jesús F. San

Published
2011
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