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1. Genomic instability analysis in DNA from Papanicolaou test provides proof-of-principle early diagnosis of high-grade serous ovarian cancer

Author

Paracchini, L, Mannarino, L, Romualdi, C, Zadro, R, Beltrame, L, Nerini, I, Zola, P, Laudani, M, Pagano, E, Giordano, L, Fruscio, R, Landoni, F, Franceschi, S, Dalessandro, M, Canzonieri, V, Bocciolone, L, Lorusso, D, Bosetti, C, Raspagliesi, F, Garassino, I, D'Incalci, M, Marchini, S, Grassi, T, Bianchi, T, Cursano, G, Mangili, G, Scambia, G, Marchetti, C, Boldorini, R, De Rosa, G, Ferrero, A, Feyles, E, Goia, M, Manini, C, Orlassino, R, Surico, D, Volante, M, Greggi, S, Jaconi, M, Bella, C, Vitobello, D, di Loreto, C, Pizzolitto, S, Zanconati, F, Ciccone, G, Armaroli, P, Larato, C, Rizzolo, R, Paracchini L., Mannarino L., Romualdi C., Zadro R., Beltrame L., Nerini I. F., Zola P., Laudani M. E., Pagano E., Giordano L., Fruscio R., Landoni F., Franceschi S., Dalessandro M. L., Canzonieri V., Bocciolone L., Lorusso D., Bosetti C., Raspagliesi F., Garassino I. M. G., D'Incalci M., Marchini S., Grassi T., Bianchi T., Cursano G., Mangili G., Scambia G., Marchetti C., Boldorini R., De Rosa G., Ferrero A., Feyles E., Goia M., Manini C., Orlassino R., Surico D., Volante M., Greggi S., Jaconi M., Bella C. D., Vitobello D., di Loreto C., Pizzolitto S., Zanconati F., Ciccone G., Armaroli P., Larato C., Rizzolo R., Paracchini, L, Mannarino, L, Romualdi, C, Zadro, R, Beltrame, L, Nerini, I, Zola, P, Laudani, M, Pagano, E, Giordano, L, Fruscio, R, Landoni, F, Franceschi, S, Dalessandro, M, Canzonieri, V, Bocciolone, L, Lorusso, D, Bosetti, C, Raspagliesi, F, Garassino, I, D'Incalci, M, Marchini, S, Grassi, T, Bianchi, T, Cursano, G, Mangili, G, Scambia, G, Marchetti, C, Boldorini, R, De Rosa, G, Ferrero, A, Feyles, E, Goia, M, Manini, C, Orlassino, R, Surico, D, Volante, M, Greggi, S, Jaconi, M, Bella, C, Vitobello, D, di Loreto, C, Pizzolitto, S, Zanconati, F, Ciccone, G, Armaroli, P, Larato, C, Rizzolo, R, Paracchini L., Mannarino L., Romualdi C., Zadro R., Beltrame L., Nerini I. F., Zola P., Laudani M. E., Pagano E., Giordano L., Fruscio R., Landoni F., Franceschi S., Dalessandro M. L., Canzonieri V., Bocciolone L., Lorusso D., Bosetti C., Raspagliesi F., Garassino I. M. G., D'Incalci M., Marchini S., Grassi T., Bianchi T., Cursano G., Mangili G., Scambia G., Marchetti C., Boldorini R., De Rosa G., Ferrero A., Feyles E., Goia M., Manini C., Orlassino R., Surico D., Volante M., Greggi S., Jaconi M., Bella C. D., Vitobello D., di Loreto C., Pizzolitto S., Zanconati F., Ciccone G., Armaroli P., Larato C., and Rizzolo R.

Abstract

Late diagnosis and the lack of screening methods for early detection define high-grade serous ovarian cancer (HGSOC) as the gynecological malignancy with the highest mortality rate. In the work presented here, we investigated a retrospective and multicentric cohort of 250 archival Papanicolaou (Pap) test smears collected during routine gynecological screening. Samples were taken at different time points (from 1 month to 13.5 years before diagnosis) from 113 presymptomatic women who were subsequently diagnosed with HGSOC (pre-HGSOC) and from 77 healthy women. Genome instability was detected through low-pass whole-genome sequencing of DNA derived from Pap test samples in terms of copy number profile abnormality (CPA). CPA values of DNA extracted from Pap test samples from pre-HGSOC women were substantially higher than those in samples from healthy women. Consistently with the longitudinal analysis of clonal pathogenic TP53 mutations, this assay could detect HGSOC presence up to 9 years before diagnosis. This finding confirms the continual shedding of tumor cells from fimbriae toward the endocervical canal, suggesting a new path for the early diagnosis of HGSOC. We integrated the CPA score into the EVA (early ovarian cancer) test, the sensitivity of which was 75% (95% CI, 64.97 to 85.79), the specificity 96% (95% CI, 88.35 to 100.00), and the accuracy 81%. This proof-of-principle study indicates that the early diagnosis of HGSOC is feasible through the analysis of genomic alterations in DNA from endocervical smears.

Published
2023

2. Effectiveness of Intensive Versus Minimalist Follow-Up Regimen on Survival in Patients with Endometrial Cancer (TOTEM Study): A Randomized, Pragmatic, Parallel Group, Multicenter Trial

Author

Zola, P, Ciccone, G, Piovano, E, Fuso, L, Di Cuonzo, D, Castiglione, A, Pagano, E, Peirano, E, Landoni, F, Sartori, E, Narducci, F, Bertetto, O, Ferrero, A, Zola, Paolo, Ciccone, Giovannino, Piovano, Elisa, Fuso, Luca, Di Cuonzo, Daniela, Castiglione, Anna, Pagano, Eva, Peirano, Elena, Landoni, Fabio, Sartori, Enrico, Narducci, Fabrice, Bertetto, Oscar, Ferrero, Annamaria, Zola, P, Ciccone, G, Piovano, E, Fuso, L, Di Cuonzo, D, Castiglione, A, Pagano, E, Peirano, E, Landoni, F, Sartori, E, Narducci, F, Bertetto, O, Ferrero, A, Zola, Paolo, Ciccone, Giovannino, Piovano, Elisa, Fuso, Luca, Di Cuonzo, Daniela, Castiglione, Anna, Pagano, Eva, Peirano, Elena, Landoni, Fabio, Sartori, Enrico, Narducci, Fabrice, Bertetto, Oscar, and Ferrero, Annamaria

Abstract

PURPOSEIn the absence of clear evidence from randomized trials, the intensity of follow-up regimens after surgical treatment of endometrial cancer is highly variable in clinical practice. To reduce this uncertainty, we conducted a randomized trial to test whether an intensive (INT) versus a minimalist (MIN) follow-up regimen improves overall survival (OS) in patients undergoing operation for endometrial cancer.METHODSThe TOTEM study was a large, pragmatic randomized trial, conducted in 42 hospitals (in Italy and France) including patients surgically treated for endometrial cancer, in complete clinical remission, International Federation of Gynecology and Obstetrics stage I-IV. After stratification by center and risk of relapse (low or high), patients were randomly assigned (1:1) to INT or MIN hospital-based follow-up regimens. The study was powered to demonstrate an absolute improvement of 5% of the 5-year OS with the INT regimen.RESULTSIn total, 1,871 patients were randomly assigned between November 2008 and July 2018, and 1,847 patients (98.7%) were available for the final analysis (60% low risk). After a median follow-up of 69 months, the 5-year OS was 90.6% in the INT and 91.9% in the MIN arms (hazard ratio, 1.13, 95% CI, 0.86 to 1.50, P =.380). No differences in OS were found in subgroup analyses considering age, cancer treatment, risk of relapse, and degree of adherence of the center to the scheduled follow-up. The probability of detecting a relapse was slightly higher in the INT arm (hazard ratio, 1.17; 95% CI, 0.92 to 1.48; P =.194).CONCLUSIONAn INT follow-up in endometrial cancer-treated patients does not improve OS, even in high-risk patients. According to available evidence, there is no need to routinely add vaginal cytology, laboratory, or imaging investigations to the MIN regimens used in this trial.

Published
2022

3. Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials.

Author

Axfors C., Janiaud P., Schmitt A.M., van't Hooft J., Smith E.R., Haber N.A., Abayomi A., Abduljalil M., Abdulrahman A., Acosta-Ampudia Y., Aguilar-Guisado M., Al-Beidh F., Alejandria M.M., Alfonso R.N., Ali M., AlQahtani M., AlZamrooni A., Anaya J.-M., Ang M.A.C., Aomar I.F., Argumanis L.E., Averyanov A., Baklaushev V.P., Balionis O., Benfield T., Berry S., Birocco N., Bonifacio L.B., Bowen A.C., Bown A., Cabello-Gutierrez C., Camacho B., Camacho-Ortiz A., Campbell-Lee S., Cao D.H., Cardesa A., Carnate J.M., Castillo G.J.J., Cavallo R., Chowdhury F.R., Chowdhury F.U.H., Ciccone G., Cingolani A., Climacosa F.M.M., Compernolle V., Cortez C.F.N., Costa Neto A., D'Antico S., Daly J., Danielle F., Davis J.S., De Rosa F.G., Denholm J.T., Denkinger C.M., Desmecht D., Diaz-Coronado J.C., Diaz Ponce-Medrano J.A., Donneau A.-F., Dumagay T.E., Dunachie S., Dungog C.C., Erinoso O., Escasa I.M.S., Estcourt L.J., Evans A., Evasan A.L.M., Fareli C.J., Fernandez-Sanchez V., Galassi C., Gallo J.E., Garcia P.J., Garcia P.L., Garcia J.A., Garigliany M., Garza-Gonzalez E., Gauiran D.T.V., Gaviria Garcia P.A., Giron-Gonzalez J.-A., Gomez-Almaguer D., Gordon A.C., Gothot A., Grass Guaqueta J.S., Green C., Grimaldi D., Hammond N.E., Harvala H., Heralde F.M., Herrick J., Higgins A.M., Hills T.E., Hines J., Holm K., Hoque A., Hoste E., Ignacio J.M., Ivanov A.V., Janssen M., Jennings J.H., Jha V., King R.A.N., Kjeldsen-Kragh J., Klenerman P., Kotecha A., Krapp F., Labanca L., Laing E., Landin-Olsson M., Laterre P.-F., Lim L.-L., Lim J., Ljungquist O., Llaca-Diaz J.M., Lopez-Robles C., Lopez-Cardenas S., Lopez-Plaza I., Lucero J.A.C., Lundgren M., Macias J., Maganito S.C., Malundo A.F.G., Manrique R.D., Manzini P.M., Marcos M., Marquez I., Martinez-Marcos F.J., Mata A.M., McArthur C.J., McQuilten Z.K., McVerry B.J., Menon D.K., Meyfroidt G., Mirasol M.A.L., Misset B., Molton J.S., Mondragon A.V., Monsalve D.M., Moradi Choghakabodi P., Morpeth S.C., Mouncey P.R., Moutschen M., Muller-Tidow C., Murphy E., Najdovski T., Nichol A.D., Nielsen H., Novak R.M., O'Sullivan M.V.N., Olalla J., Osibogun A., Osikomaiya B., Oyonarte S., Pardo-Oviedo J.M., Patel M.C., Paterson D.L., Pena-Perez C.A., Perez-Calatayud A.A., Perez-Alba E., Perkina A., Perry N., Pouladzadeh M., Poyato I., Price D.J., Quero A.K.H., Rahman M.M., Rahman M.S., Ramesh M., Ramirez-Santana C., Rasmussen M., Rees M.A., Rego E., Roberts J.A., Roberts D.J., Rodriguez Y., Rodriguez-Bano J., Rogers B.A., Rojas M., Romero A., Rowan K.M., Saccona F., Safdarian M., Santos M.C.M., Sasadeusz J., Scozzari G., Shankar-Hari M., Sharma G., Snelling T., Soto A., Tagayuna P.Y., Tang A., Tatem G., Teofili L., Tong S.Y.C., Turgeon A.F., Veloso J.D., Venkatesh B., Ventura-Enriquez Y., Webb S.A., Wiese L., Wiken C., Wood E.M., Yusubalieva G.M., Zacharowski K., Zarychanski R., Khanna N., Moher D., Goodman S.N., Ioannidis J.P.A., Hemkens L.G., Axfors C., Janiaud P., Schmitt A.M., van't Hooft J., Smith E.R., Haber N.A., Abayomi A., Abduljalil M., Abdulrahman A., Acosta-Ampudia Y., Aguilar-Guisado M., Al-Beidh F., Alejandria M.M., Alfonso R.N., Ali M., AlQahtani M., AlZamrooni A., Anaya J.-M., Ang M.A.C., Aomar I.F., Argumanis L.E., Averyanov A., Baklaushev V.P., Balionis O., Benfield T., Berry S., Birocco N., Bonifacio L.B., Bowen A.C., Bown A., Cabello-Gutierrez C., Camacho B., Camacho-Ortiz A., Campbell-Lee S., Cao D.H., Cardesa A., Carnate J.M., Castillo G.J.J., Cavallo R., Chowdhury F.R., Chowdhury F.U.H., Ciccone G., Cingolani A., Climacosa F.M.M., Compernolle V., Cortez C.F.N., Costa Neto A., D'Antico S., Daly J., Danielle F., Davis J.S., De Rosa F.G., Denholm J.T., Denkinger C.M., Desmecht D., Diaz-Coronado J.C., Diaz Ponce-Medrano J.A., Donneau A.-F., Dumagay T.E., Dunachie S., Dungog C.C., Erinoso O., Escasa I.M.S., Estcourt L.J., Evans A., Evasan A.L.M., Fareli C.J., Fernandez-Sanchez V., Galassi C., Gallo J.E., Garcia P.J., Garcia P.L., Garcia J.A., Garigliany M., Garza-Gonzalez E., Gauiran D.T.V., Gaviria Garcia P.A., Giron-Gonzalez J.-A., Gomez-Almaguer D., Gordon A.C., Gothot A., Grass Guaqueta J.S., Green C., Grimaldi D., Hammond N.E., Harvala H., Heralde F.M., Herrick J., Higgins A.M., Hills T.E., Hines J., Holm K., Hoque A., Hoste E., Ignacio J.M., Ivanov A.V., Janssen M., Jennings J.H., Jha V., King R.A.N., Kjeldsen-Kragh J., Klenerman P., Kotecha A., Krapp F., Labanca L., Laing E., Landin-Olsson M., Laterre P.-F., Lim L.-L., Lim J., Ljungquist O., Llaca-Diaz J.M., Lopez-Robles C., Lopez-Cardenas S., Lopez-Plaza I., Lucero J.A.C., Lundgren M., Macias J., Maganito S.C., Malundo A.F.G., Manrique R.D., Manzini P.M., Marcos M., Marquez I., Martinez-Marcos F.J., Mata A.M., McArthur C.J., McQuilten Z.K., McVerry B.J., Menon D.K., Meyfroidt G., Mirasol M.A.L., Misset B., Molton J.S., Mondragon A.V., Monsalve D.M., Moradi Choghakabodi P., Morpeth S.C., Mouncey P.R., Moutschen M., Muller-Tidow C., Murphy E., Najdovski T., Nichol A.D., Nielsen H., Novak R.M., O'Sullivan M.V.N., Olalla J., Osibogun A., Osikomaiya B., Oyonarte S., Pardo-Oviedo J.M., Patel M.C., Paterson D.L., Pena-Perez C.A., Perez-Calatayud A.A., Perez-Alba E., Perkina A., Perry N., Pouladzadeh M., Poyato I., Price D.J., Quero A.K.H., Rahman M.M., Rahman M.S., Ramesh M., Ramirez-Santana C., Rasmussen M., Rees M.A., Rego E., Roberts J.A., Roberts D.J., Rodriguez Y., Rodriguez-Bano J., Rogers B.A., Rojas M., Romero A., Rowan K.M., Saccona F., Safdarian M., Santos M.C.M., Sasadeusz J., Scozzari G., Shankar-Hari M., Sharma G., Snelling T., Soto A., Tagayuna P.Y., Tang A., Tatem G., Teofili L., Tong S.Y.C., Turgeon A.F., Veloso J.D., Venkatesh B., Ventura-Enriquez Y., Webb S.A., Wiese L., Wiken C., Wood E.M., Yusubalieva G.M., Zacharowski K., Zarychanski R., Khanna N., Moher D., Goodman S.N., Ioannidis J.P.A., and Hemkens L.G.

Abstract

Background: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX). Method(s): In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. Result(s): A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3

Published
2021

4. Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials.

Author

Axfors C., Janiaud P., Schmitt A.M., van't Hooft J., Smith E.R., Haber N.A., Abayomi A., Abduljalil M., Abdulrahman A., Acosta-Ampudia Y., Aguilar-Guisado M., Al-Beidh F., Alejandria M.M., Alfonso R.N., Ali M., AlQahtani M., AlZamrooni A., Anaya J.-M., Ang M.A.C., Aomar I.F., Argumanis L.E., Averyanov A., Baklaushev V.P., Balionis O., Benfield T., Berry S., Birocco N., Bonifacio L.B., Bowen A.C., Bown A., Cabello-Gutierrez C., Camacho B., Camacho-Ortiz A., Campbell-Lee S., Cao D.H., Cardesa A., Carnate J.M., Castillo G.J.J., Cavallo R., Chowdhury F.R., Chowdhury F.U.H., Ciccone G., Cingolani A., Climacosa F.M.M., Compernolle V., Cortez C.F.N., Costa Neto A., D'Antico S., Daly J., Danielle F., Davis J.S., De Rosa F.G., Denholm J.T., Denkinger C.M., Desmecht D., Diaz-Coronado J.C., Diaz Ponce-Medrano J.A., Donneau A.-F., Dumagay T.E., Dunachie S., Dungog C.C., Erinoso O., Escasa I.M.S., Estcourt L.J., Evans A., Evasan A.L.M., Fareli C.J., Fernandez-Sanchez V., Galassi C., Gallo J.E., Garcia P.J., Garcia P.L., Garcia J.A., Garigliany M., Garza-Gonzalez E., Gauiran D.T.V., Gaviria Garcia P.A., Giron-Gonzalez J.-A., Gomez-Almaguer D., Gordon A.C., Gothot A., Grass Guaqueta J.S., Green C., Grimaldi D., Hammond N.E., Harvala H., Heralde F.M., Herrick J., Higgins A.M., Hills T.E., Hines J., Holm K., Hoque A., Hoste E., Ignacio J.M., Ivanov A.V., Janssen M., Jennings J.H., Jha V., King R.A.N., Kjeldsen-Kragh J., Klenerman P., Kotecha A., Krapp F., Labanca L., Laing E., Landin-Olsson M., Laterre P.-F., Lim L.-L., Lim J., Ljungquist O., Llaca-Diaz J.M., Lopez-Robles C., Lopez-Cardenas S., Lopez-Plaza I., Lucero J.A.C., Lundgren M., Macias J., Maganito S.C., Malundo A.F.G., Manrique R.D., Manzini P.M., Marcos M., Marquez I., Martinez-Marcos F.J., Mata A.M., McArthur C.J., McQuilten Z.K., McVerry B.J., Menon D.K., Meyfroidt G., Mirasol M.A.L., Misset B., Molton J.S., Mondragon A.V., Monsalve D.M., Moradi Choghakabodi P., Morpeth S.C., Mouncey P.R., Moutschen M., Muller-Tidow C., Murphy E., Najdovski T., Nichol A.D., Nielsen H., Novak R.M., O'Sullivan M.V.N., Olalla J., Osibogun A., Osikomaiya B., Oyonarte S., Pardo-Oviedo J.M., Patel M.C., Paterson D.L., Pena-Perez C.A., Perez-Calatayud A.A., Perez-Alba E., Perkina A., Perry N., Pouladzadeh M., Poyato I., Price D.J., Quero A.K.H., Rahman M.M., Rahman M.S., Ramesh M., Ramirez-Santana C., Rasmussen M., Rees M.A., Rego E., Roberts J.A., Roberts D.J., Rodriguez Y., Rodriguez-Bano J., Rogers B.A., Rojas M., Romero A., Rowan K.M., Saccona F., Safdarian M., Santos M.C.M., Sasadeusz J., Scozzari G., Shankar-Hari M., Sharma G., Snelling T., Soto A., Tagayuna P.Y., Tang A., Tatem G., Teofili L., Tong S.Y.C., Turgeon A.F., Veloso J.D., Venkatesh B., Ventura-Enriquez Y., Webb S.A., Wiese L., Wiken C., Wood E.M., Yusubalieva G.M., Zacharowski K., Zarychanski R., Khanna N., Moher D., Goodman S.N., Ioannidis J.P.A., Hemkens L.G., Axfors C., Janiaud P., Schmitt A.M., van't Hooft J., Smith E.R., Haber N.A., Abayomi A., Abduljalil M., Abdulrahman A., Acosta-Ampudia Y., Aguilar-Guisado M., Al-Beidh F., Alejandria M.M., Alfonso R.N., Ali M., AlQahtani M., AlZamrooni A., Anaya J.-M., Ang M.A.C., Aomar I.F., Argumanis L.E., Averyanov A., Baklaushev V.P., Balionis O., Benfield T., Berry S., Birocco N., Bonifacio L.B., Bowen A.C., Bown A., Cabello-Gutierrez C., Camacho B., Camacho-Ortiz A., Campbell-Lee S., Cao D.H., Cardesa A., Carnate J.M., Castillo G.J.J., Cavallo R., Chowdhury F.R., Chowdhury F.U.H., Ciccone G., Cingolani A., Climacosa F.M.M., Compernolle V., Cortez C.F.N., Costa Neto A., D'Antico S., Daly J., Danielle F., Davis J.S., De Rosa F.G., Denholm J.T., Denkinger C.M., Desmecht D., Diaz-Coronado J.C., Diaz Ponce-Medrano J.A., Donneau A.-F., Dumagay T.E., Dunachie S., Dungog C.C., Erinoso O., Escasa I.M.S., Estcourt L.J., Evans A., Evasan A.L.M., Fareli C.J., Fernandez-Sanchez V., Galassi C., Gallo J.E., Garcia P.J., Garcia P.L., Garcia J.A., Garigliany M., Garza-Gonzalez E., Gauiran D.T.V., Gaviria Garcia P.A., Giron-Gonzalez J.-A., Gomez-Almaguer D., Gordon A.C., Gothot A., Grass Guaqueta J.S., Green C., Grimaldi D., Hammond N.E., Harvala H., Heralde F.M., Herrick J., Higgins A.M., Hills T.E., Hines J., Holm K., Hoque A., Hoste E., Ignacio J.M., Ivanov A.V., Janssen M., Jennings J.H., Jha V., King R.A.N., Kjeldsen-Kragh J., Klenerman P., Kotecha A., Krapp F., Labanca L., Laing E., Landin-Olsson M., Laterre P.-F., Lim L.-L., Lim J., Ljungquist O., Llaca-Diaz J.M., Lopez-Robles C., Lopez-Cardenas S., Lopez-Plaza I., Lucero J.A.C., Lundgren M., Macias J., Maganito S.C., Malundo A.F.G., Manrique R.D., Manzini P.M., Marcos M., Marquez I., Martinez-Marcos F.J., Mata A.M., McArthur C.J., McQuilten Z.K., McVerry B.J., Menon D.K., Meyfroidt G., Mirasol M.A.L., Misset B., Molton J.S., Mondragon A.V., Monsalve D.M., Moradi Choghakabodi P., Morpeth S.C., Mouncey P.R., Moutschen M., Muller-Tidow C., Murphy E., Najdovski T., Nichol A.D., Nielsen H., Novak R.M., O'Sullivan M.V.N., Olalla J., Osibogun A., Osikomaiya B., Oyonarte S., Pardo-Oviedo J.M., Patel M.C., Paterson D.L., Pena-Perez C.A., Perez-Calatayud A.A., Perez-Alba E., Perkina A., Perry N., Pouladzadeh M., Poyato I., Price D.J., Quero A.K.H., Rahman M.M., Rahman M.S., Ramesh M., Ramirez-Santana C., Rasmussen M., Rees M.A., Rego E., Roberts J.A., Roberts D.J., Rodriguez Y., Rodriguez-Bano J., Rogers B.A., Rojas M., Romero A., Rowan K.M., Saccona F., Safdarian M., Santos M.C.M., Sasadeusz J., Scozzari G., Shankar-Hari M., Sharma G., Snelling T., Soto A., Tagayuna P.Y., Tang A., Tatem G., Teofili L., Tong S.Y.C., Turgeon A.F., Veloso J.D., Venkatesh B., Ventura-Enriquez Y., Webb S.A., Wiese L., Wiken C., Wood E.M., Yusubalieva G.M., Zacharowski K., Zarychanski R., Khanna N., Moher D., Goodman S.N., Ioannidis J.P.A., and Hemkens L.G.

Abstract

Background: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX). Method(s): In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. Result(s): A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3

Published
2021

5. Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials

Author

Axfors, C, Janiaud, P, Schmitt, AM, Van't Hooft, J, Smith, ER, Haber, NA, Abayomi, A, Abduljalil, M, Abdulrahman, A, Acosta-Ampudia, Y, Aguilar-Guisado, M, Al-Beidh, F, Alejandria, MM, Alfonso, RN, Ali, M, AlQahtani, M, AlZamrooni, A, Anaya, J-M, Ang, MAC, Aomar, IF, Argumanis, LE, Averyanov, A, Baklaushev, VP, Balionis, O, Benfield, T, Berry, S, Birocco, N, Bonifacio, LB, Bowen, AC, Bown, A, Cabello-Gutierrez, C, Camacho, B, Camacho-Ortiz, A, Campbell-Lee, S, Cao, DH, Cardesa, A, Carnate, JM, Castillo, GJJ, Cavallo, R, Chowdhury, FR, Chowdhury, FUH, Ciccone, G, Cingolani, A, Climacosa, FMM, Compernolle, V, Cortez, CFN, Neto, AC, D'Antico, S, Daly, J, Danielle, F, Davis, JS, De Rosa, FG, Denholm, JT, Denkinger, CM, Desmecht, D, Diaz-Coronado, JC, Diaz Ponce-Medrano, JA, Donneau, A-F, Dumagay, TE, Dunachie, S, Dungog, CC, Erinoso, O, Escasa, IMS, Estcourt, LJ, Evans, A, Evasan, ALM, Fareli, CJ, Fernandez-Sanchez, V, Galassi, C, Gallo, JE, Garcia, PJ, Garcia, PL, Garcia, JA, Garigliany, M, Garza-Gonzalez, E, Gauiran, DT, Gaviria Garcia, PA, Giron-Gonzalez, J-A, Gomez-Almaguer, D, Gordon, AC, Gothot, A, Grass Guaqueta, JS, Green, C, Grimaldi, D, Hammond, NE, Harvala, H, Heralde, FM, Herrick, J, Higgins, AM, Hills, TE, Hines, J, Holm, K, Hoque, A, Hoste, E, Ignacio, JM, Ivanov, A, Janssen, M, Jennings, JH, Jha, V, King, RAN, Kjeldsen-Kragh, J, Klenerman, P, Kotecha, A, Krapp, F, Labanca, L, Laing, E, Landin-Olsson, M, Laterre, P-F, Lim, L-L, Lim, J, Ljungquist, O, Llaca-Diaz, JM, Lopez-Robles, C, Lopez-Cardenas, S, Lopez-Plaza, I, Lucero, JAC, Lundgren, M, Macias, J, Maganito, SC, Malundo, AFG, Manrique, RD, Manzini, PM, Marcos, M, Marquez, I, Javier Martinez-Marcos, F, Mata, AM, McArthur, CJ, McQuilten, ZK, McVerry, BJ, Menon, DK, Meyfroidt, G, Mirasol, MAL, Misset, B, Molton, JS, Mondragon, A, Monsalve, DM, Choghakabodi, PM, Morpeth, SC, Mouncey, PR, Moutschen, M, Muller-Tidow, C, Murphy, E, Najdovski, T, Nichol, AD, Nielsen, H, Novak, RM, O'Sullivan, MVN, Olalla, J, Osibogun, A, Osikomaiya, B, Oyonarte, S, Pardo-Oviedo, JM, Patel, MC, Paterson, DL, Pena-Perez, CA, Perez-Calatayud, AA, Perez-Alba, E, Perkina, A, Perry, N, Pouladzadeh, M, Poyato, I, Price, DJ, Quero, AKH, Rahman, MM, Rahman, MS, Ramesh, M, Ramirez-Santana, C, Rasmussen, M, Rees, MA, Rego, E, Roberts, JA, Roberts, DJ, Rodriguez, Y, Rodriguez-Bano, J, Rogers, BA, Rojas, M, Romero, A, Rowan, KM, Saccona, F, Safdarian, M, Santos, MCM, Sasadeusz, J, Scozzari, G, Shankar-Hari, M, Sharma, G, Snelling, T, Soto, A, Tagayuna, PY, Tang, A, Tatem, G, Teofili, L, Tong, SYC, Turgeon, AF, Veloso, JD, Venkatesh, B, Ventura-Enriquez, Y, Webb, SA, Wiese, L, Wiken, C, Wood, EM, Yusubalieva, GM, Zacharowski, K, Zarychanski, R, Khanna, N, Moher, D, Goodman, SN, Ioannidis, JPA, Hemkens, LG, Axfors, C, Janiaud, P, Schmitt, AM, Van't Hooft, J, Smith, ER, Haber, NA, Abayomi, A, Abduljalil, M, Abdulrahman, A, Acosta-Ampudia, Y, Aguilar-Guisado, M, Al-Beidh, F, Alejandria, MM, Alfonso, RN, Ali, M, AlQahtani, M, AlZamrooni, A, Anaya, J-M, Ang, MAC, Aomar, IF, Argumanis, LE, Averyanov, A, Baklaushev, VP, Balionis, O, Benfield, T, Berry, S, Birocco, N, Bonifacio, LB, Bowen, AC, Bown, A, Cabello-Gutierrez, C, Camacho, B, Camacho-Ortiz, A, Campbell-Lee, S, Cao, DH, Cardesa, A, Carnate, JM, Castillo, GJJ, Cavallo, R, Chowdhury, FR, Chowdhury, FUH, Ciccone, G, Cingolani, A, Climacosa, FMM, Compernolle, V, Cortez, CFN, Neto, AC, D'Antico, S, Daly, J, Danielle, F, Davis, JS, De Rosa, FG, Denholm, JT, Denkinger, CM, Desmecht, D, Diaz-Coronado, JC, Diaz Ponce-Medrano, JA, Donneau, A-F, Dumagay, TE, Dunachie, S, Dungog, CC, Erinoso, O, Escasa, IMS, Estcourt, LJ, Evans, A, Evasan, ALM, Fareli, CJ, Fernandez-Sanchez, V, Galassi, C, Gallo, JE, Garcia, PJ, Garcia, PL, Garcia, JA, Garigliany, M, Garza-Gonzalez, E, Gauiran, DT, Gaviria Garcia, PA, Giron-Gonzalez, J-A, Gomez-Almaguer, D, Gordon, AC, Gothot, A, Grass Guaqueta, JS, Green, C, Grimaldi, D, Hammond, NE, Harvala, H, Heralde, FM, Herrick, J, Higgins, AM, Hills, TE, Hines, J, Holm, K, Hoque, A, Hoste, E, Ignacio, JM, Ivanov, A, Janssen, M, Jennings, JH, Jha, V, King, RAN, Kjeldsen-Kragh, J, Klenerman, P, Kotecha, A, Krapp, F, Labanca, L, Laing, E, Landin-Olsson, M, Laterre, P-F, Lim, L-L, Lim, J, Ljungquist, O, Llaca-Diaz, JM, Lopez-Robles, C, Lopez-Cardenas, S, Lopez-Plaza, I, Lucero, JAC, Lundgren, M, Macias, J, Maganito, SC, Malundo, AFG, Manrique, RD, Manzini, PM, Marcos, M, Marquez, I, Javier Martinez-Marcos, F, Mata, AM, McArthur, CJ, McQuilten, ZK, McVerry, BJ, Menon, DK, Meyfroidt, G, Mirasol, MAL, Misset, B, Molton, JS, Mondragon, A, Monsalve, DM, Choghakabodi, PM, Morpeth, SC, Mouncey, PR, Moutschen, M, Muller-Tidow, C, Murphy, E, Najdovski, T, Nichol, AD, Nielsen, H, Novak, RM, O'Sullivan, MVN, Olalla, J, Osibogun, A, Osikomaiya, B, Oyonarte, S, Pardo-Oviedo, JM, Patel, MC, Paterson, DL, Pena-Perez, CA, Perez-Calatayud, AA, Perez-Alba, E, Perkina, A, Perry, N, Pouladzadeh, M, Poyato, I, Price, DJ, Quero, AKH, Rahman, MM, Rahman, MS, Ramesh, M, Ramirez-Santana, C, Rasmussen, M, Rees, MA, Rego, E, Roberts, JA, Roberts, DJ, Rodriguez, Y, Rodriguez-Bano, J, Rogers, BA, Rojas, M, Romero, A, Rowan, KM, Saccona, F, Safdarian, M, Santos, MCM, Sasadeusz, J, Scozzari, G, Shankar-Hari, M, Sharma, G, Snelling, T, Soto, A, Tagayuna, PY, Tang, A, Tatem, G, Teofili, L, Tong, SYC, Turgeon, AF, Veloso, JD, Venkatesh, B, Ventura-Enriquez, Y, Webb, SA, Wiese, L, Wiken, C, Wood, EM, Yusubalieva, GM, Zacharowski, K, Zarychanski, R, Khanna, N, Moher, D, Goodman, SN, Ioannidis, JPA, and Hemkens, LG

Abstract

BACKGROUND: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX ). METHODS: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. RESULTS: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% o

Published
2021

6. Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials

Author

Axfors, C., Janiaud, P., Schmitt, A. M., van't Hooft, J., Smith, E. R., Haber, N. A., Abayomi, A., Abduljalil, M., Abdulrahman, A., Acosta-Ampudia, Y., Aguilar-Guisado, M., Al-Beidh, F., Alejandria, M. M., Alfonso, R. N., Ali, M., Alqahtani, M., Alzamrooni, A., Anaya, J. -M., Ang, M. A. C., Aomar, I. F., Argumanis, L. E., Averyanov, A., Baklaushev, V. P., Balionis, O., Benfield, T., Berry, S., Birocco, N., Bonifacio, L. B., Bowen, A. C., Bown, A., Cabello-Gutierrez, C., Camacho, B., Camacho-Ortiz, A., Campbell-Lee, S., Cao, D. H., Cardesa, A., Carnate, J. M., Castillo, G. J. J., Cavallo, R., Chowdhury, F. R., Chowdhury, F. U. H., Ciccone, G., Cingolani, Antonella, Climacosa, F. M. M., Compernolle, V., Cortez, C. F. N., Costa Neto, A., D'Antico, S., Daly, J., Danielle, F., Davis, J. S., De Rosa, F. G., Denholm, J. T., Denkinger, C. M., Desmecht, D., Diaz-Coronado, J. C., Diaz Ponce-Medrano, J. A., Donneau, A. -F., Dumagay, T. E., Dunachie, S., Dungog, C. C., Erinoso, O., Escasa, I. M. S., Estcourt, L. J., Evans, A., Evasan, A. L. M., Fareli, C. J., Fernandez-Sanchez, V., Galassi, C., Gallo, J. E., Garcia, P. J., Garcia, P. L., Garcia, J. A., Garigliany, M., Garza-Gonzalez, E., Gauiran, D. T. V., Gaviria Garcia, P. A., Giron-Gonzalez, J. -A., Gomez-Almaguer, D., Gordon, A. C., Gothot, A., Grass Guaqueta, J. S., Green, C., Grimaldi, D., Hammond, N. E., Harvala, H., Heralde, F. M., Herrick, J., Higgins, A. M., Hills, T. E., Hines, J., Holm, K., Hoque, A., Hoste, E., Ignacio, J. M., Ivanov, A. V., Janssen, M., Jennings, J. H., Jha, V., King, R. A. N., Kjeldsen-Kragh, J., Klenerman, P., Kotecha, A., Krapp, F., Labanca, L., Laing, E., Landin-Olsson, M., Laterre, P. -F., Lim, L. -L., Lim, J., Ljungquist, O., Llaca-Diaz, J. M., Lopez-Robles, C., Lopez-Cardenas, S., Lopez-Plaza, I., Lucero, J. A. C., Lundgren, M., Macias, J., Maganito, S. C., Malundo, A. F. G., Manrique, R. D., Manzini, P. M., Marcos, M., Marquez, I., Martinez-Marcos, F. J., Mata, A. M., Mcarthur, C. J., Mcquilten, Z. K., Mcverry, B. J., Menon, D. K., Meyfroidt, G., Mirasol, M. A. L., Misset, B., Molton, J. S., Mondragon, A. V., Monsalve, D. M., Moradi Choghakabodi, P., Morpeth, S. C., Mouncey, P. R., Moutschen, M., Muller-Tidow, C., Murphy, E., Najdovski, T., Nichol, A. D., Nielsen, H., Novak, R. M., O'Sullivan, M. V. N., Olalla, J., Osibogun, A., Osikomaiya, B., Oyonarte, S., Pardo-Oviedo, J. M., Patel, M. C., Paterson, D. L., Pena-Perez, C. A., Perez-Calatayud, A. A., Perez-Alba, E., Perkina, A., Perry, N., Pouladzadeh, M., Poyato, I., Price, D. J., Quero, A. K. H., Rahman, M. M., Rahman, M. S., Ramesh, M., Ramirez-Santana, C., Rasmussen, M., Rees, M. A., Rego, E., Roberts, J. A., Roberts, D. J., Rodriguez, Y., Rodriguez-Bano, J., Rogers, B. A., Rojas, M., Romero, A., Rowan, K. M., Saccona, F., Safdarian, M., Santos, M. C. M., Sasadeusz, J., Scozzari, G., Shankar-Hari, M., Sharma, G., Snelling, T., Soto, A., Tagayuna, P. Y., Tang, A., Tatem, G., Teofili, Luciana, Tong, S. Y. C., Turgeon, A. F., Veloso, J. D., Venkatesh, B., Ventura-Enriquez, Y., Webb, S. A., Wiese, L., Wiken, C., Wood, E. M., Yusubalieva, G. M., Zacharowski, K., Zarychanski, R., Khanna, N., Moher, D., Goodman, S. N., Ioannidis, J. P. A., Hemkens, L. G., Cingolani A. (ORCID:0000-0002-3793-2755), Teofili L. (ORCID:0000-0002-7214-1561), Axfors, C., Janiaud, P., Schmitt, A. M., van't Hooft, J., Smith, E. R., Haber, N. A., Abayomi, A., Abduljalil, M., Abdulrahman, A., Acosta-Ampudia, Y., Aguilar-Guisado, M., Al-Beidh, F., Alejandria, M. M., Alfonso, R. N., Ali, M., Alqahtani, M., Alzamrooni, A., Anaya, J. -M., Ang, M. A. C., Aomar, I. F., Argumanis, L. E., Averyanov, A., Baklaushev, V. P., Balionis, O., Benfield, T., Berry, S., Birocco, N., Bonifacio, L. B., Bowen, A. C., Bown, A., Cabello-Gutierrez, C., Camacho, B., Camacho-Ortiz, A., Campbell-Lee, S., Cao, D. H., Cardesa, A., Carnate, J. M., Castillo, G. J. J., Cavallo, R., Chowdhury, F. R., Chowdhury, F. U. H., Ciccone, G., Cingolani, Antonella, Climacosa, F. M. M., Compernolle, V., Cortez, C. F. N., Costa Neto, A., D'Antico, S., Daly, J., Danielle, F., Davis, J. S., De Rosa, F. G., Denholm, J. T., Denkinger, C. M., Desmecht, D., Diaz-Coronado, J. C., Diaz Ponce-Medrano, J. A., Donneau, A. -F., Dumagay, T. E., Dunachie, S., Dungog, C. C., Erinoso, O., Escasa, I. M. S., Estcourt, L. J., Evans, A., Evasan, A. L. M., Fareli, C. J., Fernandez-Sanchez, V., Galassi, C., Gallo, J. E., Garcia, P. J., Garcia, P. L., Garcia, J. A., Garigliany, M., Garza-Gonzalez, E., Gauiran, D. T. V., Gaviria Garcia, P. A., Giron-Gonzalez, J. -A., Gomez-Almaguer, D., Gordon, A. C., Gothot, A., Grass Guaqueta, J. S., Green, C., Grimaldi, D., Hammond, N. E., Harvala, H., Heralde, F. M., Herrick, J., Higgins, A. M., Hills, T. E., Hines, J., Holm, K., Hoque, A., Hoste, E., Ignacio, J. M., Ivanov, A. V., Janssen, M., Jennings, J. H., Jha, V., King, R. A. N., Kjeldsen-Kragh, J., Klenerman, P., Kotecha, A., Krapp, F., Labanca, L., Laing, E., Landin-Olsson, M., Laterre, P. -F., Lim, L. -L., Lim, J., Ljungquist, O., Llaca-Diaz, J. M., Lopez-Robles, C., Lopez-Cardenas, S., Lopez-Plaza, I., Lucero, J. A. C., Lundgren, M., Macias, J., Maganito, S. C., Malundo, A. F. G., Manrique, R. D., Manzini, P. M., Marcos, M., Marquez, I., Martinez-Marcos, F. J., Mata, A. M., Mcarthur, C. J., Mcquilten, Z. K., Mcverry, B. J., Menon, D. K., Meyfroidt, G., Mirasol, M. A. L., Misset, B., Molton, J. S., Mondragon, A. V., Monsalve, D. M., Moradi Choghakabodi, P., Morpeth, S. C., Mouncey, P. R., Moutschen, M., Muller-Tidow, C., Murphy, E., Najdovski, T., Nichol, A. D., Nielsen, H., Novak, R. M., O'Sullivan, M. V. N., Olalla, J., Osibogun, A., Osikomaiya, B., Oyonarte, S., Pardo-Oviedo, J. M., Patel, M. C., Paterson, D. L., Pena-Perez, C. A., Perez-Calatayud, A. A., Perez-Alba, E., Perkina, A., Perry, N., Pouladzadeh, M., Poyato, I., Price, D. J., Quero, A. K. H., Rahman, M. M., Rahman, M. S., Ramesh, M., Ramirez-Santana, C., Rasmussen, M., Rees, M. A., Rego, E., Roberts, J. A., Roberts, D. J., Rodriguez, Y., Rodriguez-Bano, J., Rogers, B. A., Rojas, M., Romero, A., Rowan, K. M., Saccona, F., Safdarian, M., Santos, M. C. M., Sasadeusz, J., Scozzari, G., Shankar-Hari, M., Sharma, G., Snelling, T., Soto, A., Tagayuna, P. Y., Tang, A., Tatem, G., Teofili, Luciana, Tong, S. Y. C., Turgeon, A. F., Veloso, J. D., Venkatesh, B., Ventura-Enriquez, Y., Webb, S. A., Wiese, L., Wiken, C., Wood, E. M., Yusubalieva, G. M., Zacharowski, K., Zarychanski, R., Khanna, N., Moher, D., Goodman, S. N., Ioannidis, J. P. A., Hemkens, L. G., Cingolani A. (ORCID:0000-0002-3793-2755), and Teofili L. (ORCID:0000-0002-7214-1561)

Abstract

Background: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX). Methods: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung–Knapp–Sidik–Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. Results: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of

Published
2021

7. Age and organ damage correlate with poor survival in myeloma patients: Meta-analysis of 1435 individual patient data from 4 randomized trials

Author

Bringhen, S. (Sara), Mateos, M.V., Zweegman, S. (Sonja), Larocca, A. (Alessandra), Falcone, A.P. (Antonietta Pia), Oriol, A. (Albert), Rossi, D. (Davide), Cavalli, S. (Silvia), Wijermans, P.W. (Pierre), Ria, R. (Roberto), Offidani, M. (Massimo), Lahuerta, J.J., Liberati, A.M., Mina, R. (Roberto), Callea, V. (Vincenzo), Schaafsma, M.R. (Martijn), Cerrato, C. (Chiara), Marasca, R. (Roberto), Franceschini, L. (Luca), Evangelista, A. (Arturo), Teruel, A.-I. (Ana-Isabel), Holt, B. (Bronno) van der, Montefusco, V. (Vittorio), Ciccone, G. (Giovannino), Boccadoro, M. (Mario), San Miguel, J.F. (Jesús Fernando), Sonneveld, P. (Pieter), Palumbo, A. (Antonio), Bringhen, S. (Sara), Mateos, M.V., Zweegman, S. (Sonja), Larocca, A. (Alessandra), Falcone, A.P. (Antonietta Pia), Oriol, A. (Albert), Rossi, D. (Davide), Cavalli, S. (Silvia), Wijermans, P.W. (Pierre), Ria, R. (Roberto), Offidani, M. (Massimo), Lahuerta, J.J., Liberati, A.M., Mina, R. (Roberto), Callea, V. (Vincenzo), Schaafsma, M.R. (Martijn), Cerrato, C. (Chiara), Marasca, R. (Roberto), Franceschini, L. (Luca), Evangelista, A. (Arturo), Teruel, A.-I. (Ana-Isabel), Holt, B. (Bronno) van der, Montefusco, V. (Vittorio), Ciccone, G. (Giovannino), Boccadoro, M. (Mario), San Miguel, J.F. (Jesús Fernando), Sonneveld, P. (Pieter), and Palumbo, A. (Antonio)

Abstract

Thalidomide and bortezomib are extensively used to treat elderly myeloma patients. In these patients, treatmentrelated side effects are frequent and full drug doses difficult to tolerate. We retrospectively analyzed data from 1435 elderly patients enrolled in 4 European phase III trials including thalidomide and/or bortezomib. After a median follow up of 33 months (95%CI: 10-56 months), 513 of 1435 patients (36%) died; median overall survival was 50 months (95%CI: 46-60 months). The risk of death was increased in patients aged 75 years or over (HR 1.44, 95%CI: 1.20-1.72; P<0.001), in patients with renal failure (HR 2.02, 95%C

Published
2013
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8. Safety of thalidomide in newly diagnosed elderly myeloma patients: A meta-analysis of data from individual patients in six randomized trials

Author

Palumbo, A. (Antonio), Waage, A. (Anders), Hulin, C., Beksaç, M. (Meral), Zweegman, S. (Sonja), Gay, F. (Francesca), Gimsing, P. (Peter), Leleu, X., Wijermans, P.W. (Pierre), Sucak, G. (Gülsan), Pezzatti, S. (Sara), Juliusson, G. (Gunnar), Pégourié, B. (Brigitte), Schaafsma, M.R. (Martijn), Galli, M. (Matilde), Turesson, I., Kolb, B. (Brigitte), Holt, B. (Bronno) van der, Baldi, I. (Ileana), Rolke, J. (Jürgen), Ciccone, G. (Giovannino), Wetterwald, M. (Marc), Lokhorst, H.M. (Henk), Boccadoro, M. (Mario), Rodon, J. (Jordi), Sonneveld, P. (Pieter), Palumbo, A. (Antonio), Waage, A. (Anders), Hulin, C., Beksaç, M. (Meral), Zweegman, S. (Sonja), Gay, F. (Francesca), Gimsing, P. (Peter), Leleu, X., Wijermans, P.W. (Pierre), Sucak, G. (Gülsan), Pezzatti, S. (Sara), Juliusson, G. (Gunnar), Pégourié, B. (Brigitte), Schaafsma, M.R. (Martijn), Galli, M. (Matilde), Turesson, I., Kolb, B. (Brigitte), Holt, B. (Bronno) van der, Baldi, I. (Ileana), Rolke, J. (Jürgen), Ciccone, G. (Giovannino), Wetterwald, M. (Marc), Lokhorst, H.M. (Henk), Boccadoro, M. (Mario), Rodon, J. (Jordi), and Sonneveld, P. (Pieter)

Abstract

Treatment with melphalan-prednisone-thalidomide improves the outcome of patients with multiple myeloma and is now considered a standard of care for patients not eligible for transplantation. However, this treatment is a major source of morbidity. A meta-analysis of data from individual patients (n=1680) in six randomized trials was performed, comparing the effects of melphalan-prednisone-thalidomide versus melphalan-prednisone. The main objective was to estimate the risk of serious adverse events and their impact on outcome. The primary endpoints were the 2-year cumulative incidence of grade 3-4 hematologic and non-hematologic toxicities. At least 75% of the grade 3-4 toxicities occurred during the first 6 months of treatment in both treatment groups. The cumulative incidence of grade 3-4 hematologic toxicities was higher in the melphalan-prednisone-thalidomide group than in the melphalan-prednisone group (28% versus 22%; HR 1.32, 95% CI 1.05-1.66) as was the cumulative incidence of non-hematologic toxicities (39% versus 17%, HR 2.78, 95% CI 2.21-3.50). Grade 3-4 non-hematologic toxicities were significantly increased in patients with poor Performance Status. Occurrence of grade 3-4 non-hematologic toxicities had a negative impact on both progression-free survival (HR 1.24, 95% CI 1.07-1.45) and overall survival, (HR 1.23, 95% CI 1.03-1.47). Besides toxicities, progression-free and overall survival were also negatively affected by advanced International Staging System stage, high creatinine levels and poor Performance Status. Age had a negative impact on survival as well. Although melphalan-prednisone-thalidomide improved outcome, it increased toxicities, especially non-hematologic ones. Serious non-hematologic toxicities, older age, poor Performance Status, and high creatinine levels negatively affected survival.

Published
2013
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9. Safety of thalidomide in newly diagnosed elderly myeloma patients: a meta-analysis of data from individual patients in six randomized trials

Author

Palumbo, A, Waage, A, Hulin, C, Beksac, M, Zweegman, S, Gay, F, Gimsing, P, Leleu, X, Wijermans, P, Sucak, G, Pezzatti, S, Juliusson, G, Pegourie, B, Schaafsma, M, Galli, M, Turesson, I, Kolb, B, van der Holt, Ronnie, Baldi, I, Rolke, J, Ciccone, G, Wetterwald, M, Lokhorst, H, Boccadoro, M, Rodon, P, Sonneveld, Pieter, Palumbo, A, Waage, A, Hulin, C, Beksac, M, Zweegman, S, Gay, F, Gimsing, P, Leleu, X, Wijermans, P, Sucak, G, Pezzatti, S, Juliusson, G, Pegourie, B, Schaafsma, M, Galli, M, Turesson, I, Kolb, B, van der Holt, Ronnie, Baldi, I, Rolke, J, Ciccone, G, Wetterwald, M, Lokhorst, H, Boccadoro, M, Rodon, P, and Sonneveld, Pieter

Published
2013

10. Blood stream infections after allogeneic stem cell transplantation: a single-center experience with the use of levofloxacin prophylaxis

Author

Busca, A, Cavecchia, I, Locatelli, Franco, D'Ardia, S, De Rosa, F G, Marmont, F, Ciccone, G, Baldi, I, Serra, R, Gaido, E, Falda, M, Locatelli, F (ORCID:0000-0002-7976-3654), Busca, A, Cavecchia, I, Locatelli, Franco, D'Ardia, S, De Rosa, F G, Marmont, F, Ciccone, G, Baldi, I, Serra, R, Gaido, E, Falda, M, and Locatelli, F (ORCID:0000-0002-7976-3654)

Abstract

Blood stream infections (BSIs) remain one of the major causes of morbidity and mortality for patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). In the present study, we evaluated the incidence and characteristics of BSIwithin 1year after allogeneic HSCT in 269 consecutive adult patients who received antibacterial prophylaxis with levofloxacin. Cumulative incidence of BSI was 12%(95% confidence interval, 8 16%). Bacteria were responsible for 30 out of the 32 BSIs, while fungi were responsible for 2 episodes of BSI. The median onset of BSI was day 8 (range 1 328 days) post transplant, and 66% of BS occurred before neutrophil recovery. Gram-positive organisms accounted for 60%(n = 518) of bacteremia, and gram-negative isolates for 40%(n = 512) of the cases. Coagulasenegative staphylococci were the most commonly isolated gram-positive pathogens (53% of the cases), while Escherichia coli was the most commonly isolated gram-negative bacteria (58% of the cases). Candida albicans and Candida guillermondii were isolated from patients with candidemia. Resistance to uoroquinolones (FQ) was common with 13% of gram-positive isolates being susceptible to FQ, while 50% of the gram-negative rods were susceptible to FQ. Crude mortality and mortality attributable to BSI were both 3%(1 of 32). In conclusion, our data suggest that despite the emergence of antibiotic resistance, FQ prophylaxis may be considered an appealing approach in allogeneic HSCT recipients and is also worth evaluating in randomized studies.

Published
2012

11. Early vs late tracheotomy for prevention of pneumonia in mechanically ventilated adult ICU patients: a randomized controlled trial

Author

Terragni, P, Antonelli, M, Fumagalli, R, Faggiano, C, Berardino, M, Pallavicini, F, Miletto, A, Mangione, S, Sinardi, A, Pastorelli, M, Vivaldi, N, Pasetto, A, Della Rocca, G, Urbino, R, Filippini, C, Pagano, E, Evangelista, A, Ciccone, G, Mascia, L, Ranieri, V, Terragni, PP, Pallavicini, FB, Sinardi, AU, Ranieri, VM, FUMAGALLI, ROBERTO, Terragni, P, Antonelli, M, Fumagalli, R, Faggiano, C, Berardino, M, Pallavicini, F, Miletto, A, Mangione, S, Sinardi, A, Pastorelli, M, Vivaldi, N, Pasetto, A, Della Rocca, G, Urbino, R, Filippini, C, Pagano, E, Evangelista, A, Ciccone, G, Mascia, L, Ranieri, V, Terragni, PP, Pallavicini, FB, Sinardi, AU, Ranieri, VM, and FUMAGALLI, ROBERTO

Abstract

Context: Tracheotomy is used to replace endotracheal intubation in patients requiring prolonged ventilation; however, there is considerable variability in the time considered optimal for performing tracheotomy. This is of clinical importance because timing is a key criterion for performing a tracheotomy and patients who receive one require a large amount of health care resources. Objective: To determine the effectiveness of early tracheotomy (after 6-8 days of laryngeal intubation) compared with late tracheotomy (after 13-15 days of laryngeal intubation) in reducing the incidence of pneumonia and increasing the number of ventilator-free and intensive care unit (ICU)-free days. Design, Setting, and Patients: Randomized controlled trial performed in 12 Italian ICUs from June 2004 to June 2008 of 600 adult patients enrolled without lung infection, who had been ventilated for 24 hours, had a Simplified Acute Physiology Score II between 35 and 65, and had a sequential organ failure assessment score of 5 or greater. Intervention: Patients who had worsening of respiratory conditions, unchanged or worse sequential organ failure assessment score, and no pneumonia 48 hours after inclusion were randomized to early tracheotomy (n=209; 145 received tracheotomy) or late tracheotomy (n=210; 119 received tracheotomy). Main Outcome Measures: The primary endpoint was incidence of ventilator-associated pneumonia; secondary endpoints during the 28 days immediately following randomization were number of ventilator-free days, number of ICU-free days, and number of patients in each group who were still alive. Results: Ventilator-associated pneumonia was observed in 30 patients in the early tracheotomy group (14%; 95% confidence interval [CI], 10%-19%) and in 44 patients in the late tracheotomy group (21%; 95% CI, 15%-26%) (P=.07). During the 28 days immediately following randomization, the hazard ratio of developing ventilator-associated pneumonia was 0.66 (95% CI, 0.42-1.04), remaining c

Published
2010

12. Dose-dense and high-dose chemotherapy plus rituximab with autologous stem cell transplantation for primary treatment of diffuse large B-cell lymphoma with a poor prognosis: A phase II multicenter study

Author

Vitolo, U, Chiappella, A, Angelucci, E, Rossi, G, Liberati, A, Cabras, M, Botto, B, Ciccone, G, Gaidano, G, Falchi, L, Freilone, R, Novero, D, Orsucci, L, Pavone, V, Pogliani, E, Rota Scalabrini, D, Salvi, F, Tonso, A, Tucci, A, Levis, A, Liberati, AM, Cabras, MG, Levis, A., POGLIANI, ENRICO MARIA, Vitolo, U, Chiappella, A, Angelucci, E, Rossi, G, Liberati, A, Cabras, M, Botto, B, Ciccone, G, Gaidano, G, Falchi, L, Freilone, R, Novero, D, Orsucci, L, Pavone, V, Pogliani, E, Rota Scalabrini, D, Salvi, F, Tonso, A, Tucci, A, Levis, A, Liberati, AM, Cabras, MG, Levis, A., and POGLIANI, ENRICO MARIA

Abstract

We investigated the addition of rituximab to dose-dense and high-dose chemotherapy with autologous stem cell transplantation in patients with untreated poor-prognosis diffuse large B-cell lymphoma.

Published
2009

13. Respiratory symptoms in children living near busy roads and their relationship to vehicular traffic: results of an Italian multicenter study (SIDRIA 2)

Author

Migliore, E, Berti, Giovanna, Galassi, C, Pearce, N, Forastiere, F, Calabrese, R, Armenio, L, Biggeri, A, Bisanti, L, Bugiani, M, Cadum, E, Chellini, E, Dell'Orco, V, Giannella, G, Sestini, P, Corbo, Giuseppe Maria, Pistelli, R, Viegi, G, Ciccone, G, Corbo, Giuseppe Maria (ORCID:0000-0002-8104-4659), Pistelli, R (ORCID:0000-0003-3776-2482), Migliore, E, Berti, Giovanna, Galassi, C, Pearce, N, Forastiere, F, Calabrese, R, Armenio, L, Biggeri, A, Bisanti, L, Bugiani, M, Cadum, E, Chellini, E, Dell'Orco, V, Giannella, G, Sestini, P, Corbo, Giuseppe Maria, Pistelli, R, Viegi, G, Ciccone, G, Corbo, Giuseppe Maria (ORCID:0000-0002-8104-4659), and Pistelli, R (ORCID:0000-0003-3776-2482)

Abstract

Epidemiological studies have provided evidence that exposure to vehicular traffic increases the prevalence of respiratory symptoms and may exacerbate pre-existing asthma in children. Self-reported exposure to road traffic has been questioned as a reliable measurement of exposure to air pollutants. The aim of this study was to investigate whether there were specific effects of cars and trucks traffic on current asthma symptoms (i.e. wheezing) and cough or phlegm, and to examine the validity of self-reported traffic exposure.

Published
2009

14. Intermediate-dose melphalan improves survival of myeloma patients aged 50 to 70: results of a randomized controlled trial

Author

Palumbo, A, Bringhen, S, Petrucci, M, Musto, P, Rossini, F, Nunzi, M, Lauta, V, Bergonzi, C, Barbui, A, Caravita, T, Capaldi, A, Pregno, P, Guglielmelli, T, Grasso, M, Callea, V, Bertola, A, Cavallo, F, Falco, P, Rus, C, Massaia, M, Mandelli, F, Carella, A, Pogliani, E, Liberati, A, Dammacco, F, Ciccone, G, Boccadoro, M, Petrucci, MT, Lauta, VM, Carella, AM, Liberati, AM, Boccadoro, M., POGLIANI, ENRICO MARIA, Palumbo, A, Bringhen, S, Petrucci, M, Musto, P, Rossini, F, Nunzi, M, Lauta, V, Bergonzi, C, Barbui, A, Caravita, T, Capaldi, A, Pregno, P, Guglielmelli, T, Grasso, M, Callea, V, Bertola, A, Cavallo, F, Falco, P, Rus, C, Massaia, M, Mandelli, F, Carella, A, Pogliani, E, Liberati, A, Dammacco, F, Ciccone, G, Boccadoro, M, Petrucci, MT, Lauta, VM, Carella, AM, Liberati, AM, Boccadoro, M., and POGLIANI, ENRICO MARIA

Abstract

High-dose therapy is an effective standard treatment for multiple myeloma patients. Evidence that intermediate-dose therapy improves survival is limited. At diagnosis, about 70% of patients are older than 65. Intermediate-dose regimen is very well tolerated in older patients. In a multicenter study, 194 patients were randomized to receive at diagnosis either conventional chemotherapy (6 courses of oral melphalan and prednisone [MP]) or intermediate-dose therapy (2 courses of melphalan at 100 mg/m(2) [MEL100]) with stem cell support. Response rate was higher after MEL100. Near-complete remission (nCR) was 6% after MP and 25% after MEL100 (P = .0002). At 3 years, MEL100 increased event-free survival (EFS) from 16% to 37% and overall survival (OS) from 62% to 77% (P < .001). Similar results were observed in patients aged 65 to 70: nCR was 8% after MP and 25% after MEL100 (P = .05); at 3 years, MEL100 improved EFS from 18% to 31% (P = .01) and OS from 58% to 73% (P = .01). Patients aged 65 to 70 had a median OS of 37.2 months (MP) versus 58 months (MEL100). Intermediate-dose melphalan improves response rate, EFS, and OS in myeloma patients, specifically in those aged 65 to 70. It constitutes a more effective first-line regimen than standard treatment for elderly patients.

Published
2004

15. A comparison of cytotoxic T lymphocyte precursor frequencies in responder/stimulator pairs with increasing degrees of mismatch

Author

Affaticati, P., Locatelli, Franco, Falda, M., Busca, A., Sizzano, F., Roggero, S., Dall'Omo, A. M., Menardi, G., Mele, Luca, Magistroni, P., Loera, B., Ciccone, G., Curtoni, E. S., Locatelli F. (ORCID:0000-0002-7976-3654), Mele L., Affaticati, P., Locatelli, Franco, Falda, M., Busca, A., Sizzano, F., Roggero, S., Dall'Omo, A. M., Menardi, G., Mele, Luca, Magistroni, P., Loera, B., Ciccone, G., Curtoni, E. S., Locatelli F. (ORCID:0000-0002-7976-3654), and Mele L.

Abstract

Limiting dilution assays of helper or cytotoxic T cell precursor (HTL-p and CTL-p) frequencies have been developed to measure, with high sensitivity and specificity, donor/recipient alloreactivity before bone marrow transplantation (BMT). Most studies demonstrated a significant correlation between the frequency of donor host-specific CTL-p before transplant and the incidence of severe (≥ grade II) acute graft-versus-host disease (aGvHD) in unrelated donor BMT. Recently we demonstrated that the CTL-p assay was sensitive enough to provide similar predictive information also in HLA-identical sibling BMT. In the present study, the CTL-p frequencies were compared in four groups of responder/stimulator pairs with different degree of mismatch: (1) monozygotic twins (MZ) (n=7), (2) HLA-identical sibling pairs (SIB) (n=67), (3) HLA-matched unrelated pairs (HLA-A, B serologically and HLA-DRBI allele-matched) (MUP) (n=59), (4) 2-4 antigen HLA-mismatched pairs (MM) (n=27). Logistic regression analysis showed that as mismatch increased, the probability of a high (>1:100.000) CTL-p frequency (HF) significantly increased. Then, MUP group was divided in two subgroups: (3a) well-matched pairs (WM) (n=20): matched for HLA-DRB3, B4, B5 alleles and, by DNA heteroduplex analysis, for HLA-A, B genes; (3b) matched pairs (M) (n=39): with either a single HLA-A, B mismatch as revealed by DNA heteroduplex analysis, or a single mismatch in HLA-DRB3, B4, B5 alleles. The CTL-p frequencies were analysed again in the five groups, re-using a logistic regression model. The probability of a HF response was significantly higher in the M than in SIB group. Otherwise, WM and SIB groups had the same probability of a HF response. The probability of a HF response in the M group was significantly higher than in WM group, and lower, though not significantly, than in MM group. The results confirmed not only the power of CTL-p assay in the identification of functionally significant polymorphisms, but also i

Published
2001

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