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4. Molecular profiling of blastic plasmacytoid dendritic cell neoplasm reveals a unique pattern and suggests selective sensitivity to NF-kB pathway inhibition

Author

Sapienza, M R, Fuligni, F, Agostinelli, C, Tripodo, C, Righi, S, Laginestra, M A, Pileri, Jr, A, Mancini, M, Rossi, M, Ricci, F, Gazzola, A, Melle, F, Mannu, C, Ulbar, F, Arpinati, M, Paulli, M, Maeda, T, Gibellini, D, Pagano, L, Pimpinelli, N, Santucci, M, Cerroni, L, Croce, C M, Facchetti, F, Piccaluga, P P, and Pileri, S A

Published
2014
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5. Effect of hydrolyzed infant formula vs conventional formula on risk of type 1 diabetes the TRIGR randomized clinical trial

Author

Knip M., Akerblom H. K., Altaji E., Becker D., Bruining J., Castano L., Danne T., De Beaufort C., Dosch H. -M., Dupre J., Fraser W. D., Howard N., Ilonen J., Konrad D., Kordonouri O., Krischer J. P., Lawson M. L., Ludvigsson J., Madacsy L., Mahon J. L., Ormisson A., Palmer J. P., Pozzilli P., Savilahti E., Serrano-Rios M., Songini M., Taback S., Vaarala O., White N. H., Virtanen S. M., Wasikowa R., Mandrup-Poulsen T., Arjas E., Lernmark A., Laara E., Schmidt B., Hyytinen M., Koski K., Koski M., Merentie K., Pajakkala E., Reunanen A., Salonen M., Terhonen T., Virkkunen S., Cuthbertson D., Gainer B., Hadley D., Malloy J., Nallamshetty L., Shanker L., Bradley B., Lough G., Fraser W., Sermer M., Taback S. P., Franciscus M., Nucci A., Palmer J., Alahuhta K., Barlund S., Korhonen T., Kovanen L., Lehtonen E., Niinisto S., Pekkala M., Sorkio S., Toivanen L., Vahatalo L., Uusitalo U., Ohman T., Bongiorno R., Catteau J., Fraser G., Lloyd M., Crock P., Giles M., Siech K., See D. W., Brown C., Craig M., Johnston A., Bere L. J., Clarson C. L., Jenner M., McManus R., Renato N., Lovell M., Higo D., Kent N., Kwan J., Marshall C., Metzger D., Chanoine J. -P., Stewart L., Thompson D., Edwards A., Lange I., Mercer J., Pacaud D., Josephine H., Schwarz W., Stephure D. K., Boer J., Chatur T., Chick C., Couch B., Demianczuk N., Girgis R., Marks S., Ryan E., Thompson M., Dean H. J., Grant L., Hamelin K., LaForte J., Murphy L., Catte D., Schneider C., Sellers E. A. C., Woo V., Boland A., Clark H. D., Cooper T., Gruslin A., Karovitch A., Keely E., Malcolm J. C., Sauro V., Tawagi G. F., Andrighetti S., Arnold G., Barrett J., Blumer I., Daneman D., Donat D., Ehrlich R., Feig D., Gottesman I., Gysler M., Karkanis S., Kenshole A., Knight B., Lackie E., Lewis V., Martin M. J., Maxwell C., Oliver G., Panchum P., Shilletto N., Simone A., Skidmore M., Turrini T., Wong S., Allen C., Belanger L., Bouchard I., Ferland S., Frenette L., Garrido-Russo M., Leblanc M., Imbeault J., Morin V., Olivier G., Weisnagell J., Costain G., Dornan J., Heath K., MacSween M. -C., McGibbon A., Ramsay C., Sanderson F., Sanderson S., Benabdesselam L., Gonthier M., Huot C., Thibeault M., Laforte D., Legault L., Perron P., Armson A., Canning P., Cummings E. A., Ivanko V., McLeod L., Mokashi A., Scott K., Bridger T., Crane J., Crummell C., Curtis J. C., Dawson C., Joyce C., Newhook L. A., Newman S., Druken E., Begum-Hasan J., Breen A., Houlden R., Woods M., Carrson G., Kelly S., Martel M. J., Penner M., Sankaran K., Hardy-Brown K., King N., White R. A., Park M., Popkin J., Robson L., Coles K., Al Taji E., Cerna M., Cerny M., Francova H., Hainerova I., Kothankova H., Koukalova R., Krakorova V., Mendlova P., Sitova R., Stechova K., Vavrinec J., Vosahlo J., Zlatohlavkova B., Brazdova L., Faksova P., Gregorova D., Kantor L., Malkova K., Venhacova J., Venhacova P., Cipra A., Skvor J., Budejovice C., Tomsikova Z., Botkova-Krauseova H., Mockova A., Paterova P., Gogelova P., Kandrnalova J., Einberg U., Jakovlev U., Posiadlo S., Rannaste E., Raukas R., Riikjarv M. -A., Valla K., Astover V., Kirss A., Retpap J., Taht E., Tillmann V., Vahtra S., Heikkila M., Hirvasniemi M., Luopajarvi K., Johansson S., Kleemola P., Laukkanen E., Parkkola A., Pigg H. -M., Puttonen H., Renlund M., Salonen K., Suomalainen H., Tenkula T., Teramo K., Jarvenpaa A. -L., Hamalainen A. -M., Jussila R., Kiiveri S., Haavisto H., Holopainen S., Kupiainen H., Leeve T., Lumme K., Nironen T., Tenhola S., Tiilikainen T., Keinonen H., Lautala P., Salonen P., Vesanto M., Aspholm A. S., Asunta P., Ikavalko H., Jason E., Jaminki S., Kekki P., Koskinen M., Lehtimaki S., Lahde J., Makela M., Peltoniemi S., Poutiainen L., Ranta K., Salonsaari T., Sarviharju-Tujula S. -L., Selvenius J., Siljander H., Haanpaa P. -L., Holm C., Juutilainen A., Jarvelainen V., Kangaskolkka-Keskilohko A. -M., Laino E., Marjamaki L., Suominen E., Ylitalo S., Hokkanen M., Lounamaa R., Matikainen M., Nuuja A., Paalanen I., Puupponen A. R., Salo-Edwards H., Alanne S., Kultti T., Linjama H., Muhonen K., Vaaraniemi M., Talvitie T., Backman M., Hanhijarvi R., Koivula P., Lindstrom K., Martikainen A., Nurmi P., Bjork A., Huopio H., Komulainen J., Lehtomaki S., Muikku E., Pesola J., Sankilampi U., Arkkola T., Hekkala A., Jurvakainen S., Koivikko M. -L., Kahonen M., Leinonen E., Mykkanen T., Pohjola H., Riikonen K., Niittyvuopio A., Stenius A., Tapanainen P., Veijola R., Alar A., Jovio S., Korpela P., Makinen E., Hietanen L., Kivisto J., Kaar M. -L., Lehtimaki P., Mustila T., Popov E., Saatela S., Taittonen L., Ahtiainen K., Laaksonen N., Luoto M., Viitala J., Virransalo R., Nykanen P., Paajanen S., Parkkinen S., Pyrhonen H., Sarkka T., Aschemeier B., Bektas S., Biester T., Datz N., Deiss D., Fath M., Lupke K., Muller B., Nestoris C., Rothes S., Sadeghian E., Semler K., Arato A., Krikovszky D., Nobilis A., Szenasi J., Benevento D., Anguissola G. B., Biagioni M., Bizzarri C., Cherubini V., Ferrito L., Giordano C., Giorgetti C., Khazrai Y. M., Kyanvash S., Maddaloni E., Napoli A., Piergiovanni F., Pitocco D., Suraci T., Tabacco G., Valente L., Visalli N., Carboni M. B., Cavallo R., Cau V., Isola C., Ledda A., Loddo M., Mannu C., Pettinau M., Pisano S., Porceddu M., Putzu C., Rita A., Peters D., Schierloh U., Bisschoff M., Blonk L., Lappenschaar T., Manai B., Seesink M., Sperling-Conrad M., Verhagen M., Zoethout J. A., Basiak A., Chalas M., Chesiak M., Gramza A., Iwankiewicz J., Sieradzan E., Wikiera B., Ciechanowska M., Dziatkowiak H., Futona B., Gorska A., Glowacka-Wony M., Kaim I., Klich B., Starzyk J., Wolanin M., Tokarska L., Chucherco D., Deja G., Firek-Pedras M., Jarosz-Chobot P., Kalina M., Kutrowska-Adamusiak K., Minkina-Pedras M., Muchaka-Bianga M., Bodalski J., Mlynarski W., Szadkowska A., Cieslak A., Cypryk K., Dziatosz K., Jastzebowska J., Krysiak A., Szymanska U., Wilcznski J., Zawodniak-Szalapska M., Aguay A., Bilbao J. R., Chueca M., Cortazar A., Echarte G., Frutos T. G., Jimenez P., Martul P., Moreno A., Oyarzabal M., Rica I., Salgado Y., Martinez-Larrad M. T., Hawkins F. G., Hernandez R., Herranz L., Pallardo L. F., Deibarra L. S., Fernandez B. H., Luis J. L., Ortiz-Quintana L., Recarte P. P., Arnau D. R., Aronsson L., Boden S., Fredriksson J., Isacsson E., Johansson I., Karlsson E., Lock C., Sandstrom A. -M., Konefal M. S., Andreasson C., Dahlstrom U., Hanas R., Lundqvist K., Windell L., Jansson I., Karlsson A. -K., Lindbladh B., Odenman I., Pettersson C., Sundberg F., Sundqvist M., Aronsson S., Bellman I., Bengtsson A. -B., Lyden G. -B., Nilsson N. -O., Soderblom M., Unt C., Augustsson M., Bengtsson M., Fors H., Helmrich A., Johansson T. O., Andersson A. -C., Boiard-Stomlid A., Hellgren G., Kallsholm H., Lindqvist J., Nilsson M., Nordwall M., Stromstedt C., Ahsberg C., Lindh A., Lindhe C., Samuelsson C., Wiik A., Edenwall H., Ljumgcrantz M., Persson I. -B., Strigard E., Svensson B. -L., Aman J., Breivik G. -E., Detlofsson I. -L., Kroon M., Sarnblad S., Johansson C., Ilvered R., Lundberg A., Akesson K., Beccarelli A., Gadient M., Rappold-Amrein C., Schoenle E., Daftary A., Damagro-Elias M. E., Gilmour C., Klein M. B., Lain C., Salerno D., Smith M. E., Vats K., Pfaff D. J., Malone P., Mansfield P., Munns M., Nickel K., Pompilio K., Siemion W., Taculad R., Van Horn K., Zdanadewic M., Chambliss C., Jones J., Sadler M., Tanner-Blasiar M., Bell C., Camper N., Devaskar S., Devaskar U., Horowitz H., Rogers L., Shannahan R., Silk K., Bermudez Z., Colon R., Frazer T., Martinez-Nieves B., Torres J., Vega J., Chan M., Cook S., Goland R., Greenberg E., Jules N., Montes J., Nelson M., Parra-Valencia Z., Schachner H., Softness B., Kiviniemi M., Suomenin R., Alexander A., Hyrckowian E., Nichol L., Trucco M., Karjalainen E., Louhio T., Sarnesto A., Valtonen E., Davydova B., Helander S., Hamalainen J., Harkonen T., Joutsjoki L., Kararic M., Latva-Koivisto M., Lonn E., Nurmi T., Ollila I., Rinkinen J., Ronkainen M., Tukiainen H., Cederlof A., Kiikeri M., Tsupari S., Cheng R., Bryant K., Chan Y., Maezawa Y., Paltser G., Rasavi R., Tsui H., Winer S., Wu P., Yantha J., Pediatrics, Knip M., Akerblom H.K., Altaji E., Becker D., Bruining J., Castano L., Danne T., De Beaufort C., Dosch H.-M., Dupre J., Fraser W.D., Howard N., Ilonen J., Konrad D., Kordonouri O., Krischer J.P., Lawson M.L., Ludvigsson J., Madacsy L., Mahon J.L., Ormisson A., Palmer J.P., Pozzilli P., Savilahti E., Serrano-Rios M., Songini M., Taback S., Vaarala O., White N.H., Virtanen S.M., Wasikowa R., Mandrup-Poulsen T., Arjas E., Lernmark A., Laara E., Schmidt B., Hyytinen M., Koski K., Koski M., Merentie K., Pajakkala E., Reunanen A., Salonen M., Terhonen T., Virkkunen S., Cuthbertson D., Gainer B., Hadley D., Malloy J., Nallamshetty L., Shanker L., Bradley B., Lough G., Fraser W., Sermer M., Taback S.P., Franciscus M., Nucci A., Palmer J., Alahuhta K., Barlund S., Korhonen T., Kovanen L., Lehtonen E., Niinisto S., Pekkala M., Sorkio S., Toivanen L., Vahatalo L., Uusitalo U., Ohman T., Bongiorno R., Catteau J., Fraser G., Lloyd M., Crock P., Giles M., Siech K., See D.W., Brown C., Craig M., Johnston A., Bere L.J., Clarson C.L., Jenner M., McManus R., Renato N., Lovell M., Higo D., Kent N., Kwan J., Marshall C., Metzger D., Chanoine J.-P., Stewart L., Thompson D., Edwards A., Lange I., Mercer J., Pacaud D., Josephine H., Schwarz W., Stephure D.K., Boer J., Chatur T., Chick C., Couch B., Demianczuk N., Girgis R., Marks S., Ryan E., Thompson M., Dean H.J., Grant L., Hamelin K., LaForte J., Murphy L., Catte D., Schneider C., Sellers E.A.C., Woo V., Boland A., Clark H.D., Cooper T., Gruslin A., Karovitch A., Keely E., Malcolm J.C., Sauro V., Tawagi G.F., Andrighetti S., Arnold G., Barrett J., Blumer I., Daneman D., Donat D., Ehrlich R., Feig D., Gottesman I., Gysler M., Karkanis S., Kenshole A., Knight B., Lackie E., Lewis V., Martin M.J., Maxwell C., Oliver G., Panchum P., Shilletto N., Simone A., Skidmore M., Turrini T., Wong S., Allen C., Belanger L., Bouchard I., Ferland S., Frenette L., Garrido-Russo M., Leblanc M., Imbeault J., Morin V., Olivier G., Weisnagell J., Costain G., Dornan J., Heath K., MacSween M.-C., McGibbon A., Ramsay C., Sanderson F., Sanderson S., Benabdesselam L., Gonthier M., Huot C., Thibeault M., Laforte D., Legault L., Perron P., Armson A., Canning P., Cummings E.A., Ivanko V., McLeod L., Mokashi A., Scott K., Bridger T., Crane J., Crummell C., Curtis J.C., Dawson C., Joyce C., Newhook L.A., Newman S., Druken E., Begum-Hasan J., Breen A., Houlden R., Woods M., Carrson G., Kelly S., Martel M.J., Penner M., Sankaran K., Hardy-Brown K., King N., White R.A., Park M., Popkin J., Robson L., Coles K., Al Taji E., Cerna M., Cerny M., Francova H., Hainerova I., Kothankova H., Koukalova R., Krakorova V., Mendlova P., Sitova R., Stechova K., Vavrinec J., Vosahlo J., Zlatohlavkova B., Brazdova L., Faksova P., Gregorova D., Kantor L., Malkova K., Venhacova J., Venhacova P., Cipra A., Skvor J., Budejovice C., Tomsikova Z., Botkova-Krauseova H., Mockova A., Paterova P., Gogelova P., Kandrnalova J., Einberg U., Jakovlev U., Posiadlo S., Rannaste E., Raukas R., Riikjarv M.-A., Valla K., Astover V., Kirss A., Retpap J., Taht E., Tillmann V., Vahtra S., Heikkila M., Hirvasniemi M., Luopajarvi K., Johansson S., Kleemola P., Laukkanen E., Parkkola A., Pigg H.-M., Puttonen H., Renlund M., Salonen K., Suomalainen H., Tenkula T., Teramo K., Jarvenpaa A.-L., Hamalainen A.-M., Jussila R., Kiiveri S., Haavisto H., Holopainen S., Kupiainen H., Leeve T., Lumme K., Nironen T., Tenhola S., Tiilikainen T., Keinonen H., Lautala P., Salonen P., Vesanto M., Aspholm A.S., Asunta P., Ikavalko H., Jason E., Jaminki S., Kekki P., Koskinen M., Lehtimaki S., Lahde J., Makela M., Peltoniemi S., Poutiainen L., Ranta K., Salonsaari T., Sarviharju-Tujula S.-L., Selvenius J., Siljander H., Haanpaa P.-L., Holm C., Juutilainen A., Jarvelainen V., Kangaskolkka-Keskilohko A.-M., Laino E., Marjamaki L., Suominen E., Ylitalo S., Hokkanen M., Lounamaa R., Matikainen M., Nuuja A., Paalanen I., Puupponen A.R., Salo-Edwards H., Alanne S., Kultti T., Linjama H., Muhonen K., Vaaraniemi M., Talvitie T., Backman M., Hanhijarvi R., Koivula P., Lindstrom K., Martikainen A., Nurmi P., Bjork A., Huopio H., Komulainen J., Lehtomaki S., Muikku E., Pesola J., Sankilampi U., Arkkola T., Hekkala A., Jurvakainen S., Koivikko M.-L., Kahonen M., Leinonen E., Mykkanen T., Pohjola H., Riikonen K., Niittyvuopio A., Stenius A., Tapanainen P., Veijola R., Alar A., Jovio S., Korpela P., Makinen E., Hietanen L., Kivisto J., Kaar M.-L., Lehtimaki P., Mustila T., Popov E., Saatela S., Taittonen L., Ahtiainen K., Laaksonen N., Luoto M., Viitala J., Virransalo R., Nykanen P., Paajanen S., Parkkinen S., Pyrhonen H., Sarkka T., Aschemeier B., Bektas S., Biester T., Datz N., Deiss D., Fath M., Lupke K., Muller B., Nestoris C., Rothes S., Sadeghian E., Semler K., Arato A., Krikovszky D., Nobilis A., Szenasi J., Benevento D., Anguissola G.B., Biagioni M., Bizzarri C., Cherubini V., Ferrito L., Giordano C., Giorgetti C., Khazrai Y.M., Kyanvash S., Maddaloni E., Napoli A., Piergiovanni F., Pitocco D., Suraci T., Tabacco G., Valente L., Visalli N., Carboni M.B., Cavallo R., Cau V., Isola C., Ledda A., Loddo M., Mannu C., Pettinau M., Pisano S., Porceddu M., Putzu C., Rita A., Peters D., Schierloh U., Bisschoff M., Blonk L., Lappenschaar T., Manai B., Seesink M., Sperling-Conrad M., Verhagen M., Zoethout J.A., Basiak A., Chalas M., Chesiak M., Gramza A., Iwankiewicz J., Sieradzan E., Wikiera B., Ciechanowska M., Dziatkowiak H., Futona B., Gorska A., Glowacka-Wony M., Kaim I., Klich B., Starzyk J., Wolanin M., Tokarska L., Chucherco D., Deja G., Firek-Pedras M., Jarosz-Chobot P., Kalina M., Kutrowska-Adamusiak K., Minkina-Pedras M., Muchaka-Bianga M., Bodalski J., Mlynarski W., Szadkowska A., Cieslak A., Cypryk K., Dziatosz K., Jastzebowska J., Krysiak A., Szymanska U., Wilcznski J., Zawodniak-Szalapska M., Aguay A., Bilbao J.R., Chueca M., Cortazar A., Echarte G., Frutos T.G., Jimenez P., Martul P., Moreno A., Oyarzabal M., Rica I., Salgado Y., Martinez-Larrad M.T., Hawkins F.G., Hernandez R., Herranz L., Pallardo L.F., Deibarra L.S., Fernandez B.H., Luis J.L., Ortiz-Quintana L., Recarte P.P., Arnau D.R., Aronsson L., Boden S., Fredriksson J., Isacsson E., Johansson I., Karlsson E., Lock C., Sandstrom A.-M., Konefal M.S., Andreasson C., Dahlstrom U., Hanas R., Lundqvist K., Windell L., Jansson I., Karlsson A.-K., Lindbladh B., Odenman I., Pettersson C., Sundberg F., Sundqvist M., Aronsson S., Bellman I., Bengtsson A.-B., Lyden G.-B., Nilsson N.-O., Soderblom M., Unt C., Augustsson M., Bengtsson M., Fors H., Helmrich A., Johansson T.O., Andersson A.-C., Boiard-Stomlid A., Hellgren G., Kallsholm H., Lindqvist J., Nilsson M., Nordwall M., Stromstedt C., Ahsberg C., Lindh A., Lindhe C., Samuelsson C., Wiik A., Edenwall H., Ljumgcrantz M., Persson I.-B., Strigard E., Svensson B.-L., Aman J., Breivik G.-E., Detlofsson I.-L., Kroon M., Sarnblad S., Johansson C., Ilvered R., Lundberg A., Akesson K., Beccarelli A., Gadient M., Rappold-Amrein C., Schoenle E., Daftary A., Damagro-Elias M.E., Gilmour C., Klein M.B., Lain C., Salerno D., Smith M.E., Vats K., Pfaff D.J., Malone P., Mansfield P., Munns M., Nickel K., Pompilio K., Siemion W., Taculad R., Van Horn K., Zdanadewic M., Chambliss C., Jones J., Sadler M., Tanner-Blasiar M., Bell C., Camper N., Devaskar S., Devaskar U., Horowitz H., Rogers L., Shannahan R., Silk K., Bermudez Z., Colon R., Frazer T., Martinez-Nieves B., Torres J., Vega J., Chan M., Cook S., Goland R., Greenberg E., Jules N., Montes J., Nelson M., Parra-Valencia Z., Schachner H., Softness B., Kiviniemi M., Suomenin R., Alexander A., Hyrckowian E., Nichol L., Trucco M., Karjalainen E., Louhio T., Sarnesto A., Valtonen E., Davydova B., Helander S., Hamalainen J., Harkonen T., Joutsjoki L., Kararic M., Latva-Koivisto M., Lonn E., Nurmi T., Ollila I., Rinkinen J., Ronkainen M., Tukiainen H., Cederlof A., Kiikeri M., Tsupari S., Cheng R., Bryant K., Chan Y., Maezawa Y., Paltser G., Rasavi R., Tsui H., Winer S., Wu P., Yantha J., University of Zurich, and Knip, Mikael

Subjects
Male, Risk, medicine.medical_specialty, Casein, Breastfeeding, 030209 endocrinology & metabolism, 610 Medicine & health, 2700 General Medicine, Endocrinology and Diabetes, Disease-Free Survival, law.invention, Follow-Up Studie, Nutrition Policy, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Double-Blind Method, SDG 3 - Good Health and Well-being, law, Internal medicine, Diabetes mellitus, medicine, Humans, Cumulative incidence, 030212 general & internal medicine, Child, Infant Nutritional Physiological Phenomena, Original Investigation, 2. Zero hunger, Type 1 diabetes, business.industry, Hazard ratio, Absolute risk reduction, Infant, Newborn, Caseins, General Medicine, ta3121, medicine.disease, Infant Formula, 3. Good health, Diabetes Mellitus, Type 1, Infant formula, 10036 Medical Clinic, Endokrinologi och diabetes, Female, business, Human, Follow-Up Studies
Abstract

IMPORTANCE Early exposure to complex dietary proteins may increase the risk of type 1 diabetes in children with genetic disease susceptibility. There are no intact proteins in extensively hydrolyzed formulas. OBJECTIVE To test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of type 1 diabetes in young children. DESIGN, SETTING, AND PARTICIPANTS An international double-blind randomized clinical trial of 2159 infants with human leukocyte antigen-conferred disease susceptibility and a first-degree relative with type 1 diabetes recruited from May 2002 to January 2007 in 78 study centers in 15 countries; 1081 were randomized to be weaned to the extensively hydrolyzed casein formula and 1078 to a conventional formula. The follow-up of the participants ended on February 28, 2017. INTERVENTIONS The participants received either a casein hydrolysate or a conventional adapted cows milk formula supplemented with 20% of the casein hydrolysate. The minimum duration of study formula exposure was 60 days by 6 to 8 months of age. MAIN OUTCOMES AND MEASURES Primary outcome was type 1 diabetes diagnosed according to World Health Organization criteria. Secondary outcomes included age at diabetes diagnosis and safety (adverse events). RESULTS Among 2159 newborn infants (1021 female [47.3%]) who were randomized, 1744 (80.8%) completed the trial. The participants were observed for a median of 11.5 years (quartile [Q] 1-Q3, 10.2-12.8). The absolute risk of type 1 diabetes was 8.4% among those randomized to the casein hydrolysate (n = 91) vs 7.6% among those randomized to the conventional formula (n = 82) (difference, 0.8%[95% CI, -1.6% to 3.2%]). The hazard ratio for type 1 diabetes adjusted for human leukocyte antigen risk group, duration of breastfeeding, duration of study formula consumption, sex, and region while treating study center as a random effect was 1.1 (95% CI, 0.8 to 1.5; P = .46). The median age at diagnosis of type 1 diabetes was similar in the 2 groups (6.0 years [Q1-Q3, 3.1-8.9] vs 5.8 years [Q1-Q3, 2.6-9.1]; difference, 0.2 years [95% CI, -0.9 to 1.2]). Upper respiratory infections were the most common adverse event reported (frequency, 0.48 events/year in the hydrolysate group and 0.50 events/year in the control group). CONCLUSIONS AND RELEVANCE Among infants at risk for type 1 diabetes, weaning to a hydrolyzed formula compared with a conventional formula did not reduce the cumulative incidence of type 1 diabetes after median follow-up for 11.5 years. These findings do not support a need to revise the dietary recommendations for infants at risk for type 1 diabetes. Funding Agencies|Eunice Kennedy Shriver National Institute of Child Health and Development (NICHD); National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health [HD040364, HD042444, HD051997]; Canadian Institutes of Health Research; Commission of the European Communities [QLK1-2002-00372]; European Foundation for the Study of Diabates/JDRF/Novo Nordisk; Academy of Finland (Centre of Excellence in Molecular Systems Immunology and Physiology Research) [250114]; Dutch Diabetes Research Foundation; Finnish Diabetes Research Foundation; JDRF

Published
2018

6. MINIMAL RESIDUAL DISEASE (MRD) EVALUATION IN LYMPHOMAS WITHIN THE FIL (FONDAZIONE ITALIANA LINFOMI) MRD NETWORK: INTER-LABORATORY REPRODUCIBILITY ON BORDERLINE SAMPLES

Author

Della Starza, I, Cavalli, M, De Novi, LA, Genuardi, E, Mantoan, B, Drandi, D, Monitillo, L, Ciabatti, E, Grassi, S, Gazzola, A, Mannu, C, Agostinelli, C, Piccaluga, PP, Galimberti, S, Guarini, A, Foa, R, Ladetto, M, Ferrero, S, Del Giudice, I, Della Starza, I, Cavalli, M, De Novi, LA, Genuardi, E, Mantoan, B, Drandi, D, Monitillo, L, Ciabatti, E, Grassi, S, Gazzola, A, Mannu, C, Agostinelli, C, Piccaluga, PP, Galimberti, S, Guarini, A, Foa, R, Ladetto, M, Ferrero, S, and Del Giudice, I

Subjects
MINIMAL RESIDUAL DISEASE (MRD), LYMPHOMAS
Published
2017

7. Regional differences in milk and complementary feeding patterns in infants participating in an international nutritional type 1 diabetes prevention trial

Author

Nucci, A. M., Virtanen, S. M., Sorkio, S., Barlund, S., Cuthbertson, D., Uusitalo, U., Lawson, M. L., Salonen, M., Berseth, C. L., Ormisson, A., Lehtonen, E., Savilahti, E., Becker, D. J., Dupre, J., Krischer, J. P., Knip, M., Akerblom, H. K., Mandrup-Poulsen, T., Arjas, E., Laara, E., Lernmark, A., Schmidt, B., Hyytinen, M., Koski, K., Koski, M., Pajakkala, E., Shanker, L., Bradley, B., Dosch, H. -M., Fraser, W., Lawson, M., Mahon, J. L., Sermer, M., Taback, S. P., Becker, D., Franciscus, M., Nucci, A., Palmer, J., Pekkala, M., Catteau, J., Howard, N., Crock, P., Craig, M., Clarson, C. L., Bere, L., Thompson, D., Metzger, D., Kwan, J., Stephure, D. K., Pacaud, D., Ho, J., Schwarz, W., Girgis, R., Thompson, M., Catte, D., Daneman, D., Martin, M. -J., Morin, V., Frenette, L., Ferland, S., Sanderson, S., Heath, K., Huot, C., Gonthier, M., Thibeault, M., Legault, L., Laforte, D., Cummings, E. A., Scott, K., Bridger, T., Crummell, C., Newman, S., Houlden, R., Breen, A., Carson, G., Kelly, S., Sankaran, K., Penner, M., White, R. A., Hardy Brown, K., King, N., Popkin, J., Robson, L., Coles, K., Al Taji, E., Aldhoon, I., Mendlova, P., Vavrinec, J., Vosahlo, J., Brazdova, L., Venhacova, J., Venhacova, P., Cipra, A., Tomsikova, Z., Paterova, P., Gogelova, P., Einberg, U., Riikjarv, M. -A., Tillmann, V., Hirvasniemi, M., Kleemola, P., Parkkola, A., Suomalainen, H., Jarvenpaa, A. -L., Hamalainen, A. -M., Haavisto, H., Tenhola, S., Lautala, P., Salonen, P., Aspholm, S., Siljander, H., Holm, C., Ylitalo, S., Lounamaa, R., Nuuja, A., Talvitie, T., Lindstrom, K., Huopio, H., Pesola, J., Veijola, R., Tapanainen, P., Alar, A., Korpela, P., Kaar, M. -L., Mustila, T., Virransalo, R., Nykanen, P., Aschemeier, B., Danne, T., Kordonouri, O., Krikovszky, D., Madacsy, L., Khazrai, Y. M., Maddaloni, E., Pozzilli, P., Mannu, C., Songini, M., de Beaufort, C., Schierloh, U., Bruining, J., Basiak, A., Wasikowa, R., Ciechanowska, M., Deja, G., Jarosz-Chobot, P., Szadkowska, A., Cypryk, K., Zawodniak-Szalapska, M., Castano, L., Gonzalez Frutos, T., Oyarzabal, M., Serrano-Rios, M., Martinez-Larrad, M. T., Hawkins, F. G., Rodriguez Arnau, D., Ludvigsson, J., Smolinska Konefal, M., Hanas, R., Lindblad, B., Nilsson, N. -O., Fors, H., Nordwall, M., Lindh, A., Edenwall, H., Aman, J., Johansson, C., Gadient, M., Schoenle, E., Daftary, A., Klein, M. B., Gilmour, C., Malone, P., Tanner-Blasiar, M., White, N., Devaskar, U., Horowitz, H., Rogers, L., Colon, R., Frazer, T., Torres, J., Goland, R., Greenberg, E., Nelson, M., Schachner, H., Softness, B., Ilonen, J., Trucco, M., Nichol, L., Harkonen, T., Vaarala, O., and Luopajarvi, K.

Subjects
Canada, endocrine system diseases, infant feeding, breastfeeding, type 1 diabetes, breastfeeding duration, complementary feeding, infant formula, Infant, Article, United States, Diet, Nutrition Policy, Europe, Diabetes Mellitus, Type 1, Milk, Nutrition Assessment, Double-Blind Method, Surveys and Questionnaires, Animals, Humans, Infant Food, Prospective Studies, Infant Nutritional Physiological Phenomena
Abstract

Differences in breastfeeding, other milk feeding and complementary feeding patterns were evaluated in infants at increased genetic risk with and without maternal type 1 diabetes (T1D). The Trial to Reduce IDDM in the Genetically at Risk is an international nutritional primary prevention double-blinded randomized trial to test whether weaning to extensively hydrolyzed vs. intact cow's milk protein formula will decrease the development of T1D-associated autoantibodies and T1D. Infant diet was prospectively assessed at two visits and seven telephone interviews between birth and 8 months. Countries were grouped into seven regions: Australia, Canada, Northern Europe, Southern Europe, Central Europe I, Central Europe II and the United States. Newborn infants with a first-degree relative with T1D and increased human leukocyte antigen-conferred susceptibility to T1D were recruited. A lower proportion of infants born to mothers with than without T1D were breastfed until 6 months of age in all regions (range, 51% to 60% vs. 70% to 80%). Complementary feeding patterns differed more by region than by maternal T1D. In Northern Europe, a higher proportion of infants consumed vegetables and fruits daily compared with other regions. Consumption of meat was more frequent in all European regions, whereas cereal consumption was most frequent in Southern Europe, Canada and the United States. Maternal T1D status was associated with breastfeeding and other milk feeding patterns similarly across regions but was unrelated to the introduction of complementary foods. Infant feeding patterns differed significantly among regions and were largely inconsistent with current recommended guidelines.

Published
2017

8. Comparison of different DNA extraction methods from peripheral blood cells: advices from the Fondazione Italiana Linfomi - MRD Network

Author

Mannu C, Gazzola A, Ciabatti E, Fuligni F, Cavalli M, Della Starza I, Genuardi E, Mantoan B, Monitillo L, Del Giudice I, Ladetto M, Gaidano G, Sabattini E, Pileri SA, Galimberti S, PICCALUGA P., on behalf of Fondazione Italiana Linfomi MrdNetwork, Mannu C, Gazzola A, Ciabatti E, Fuligni F, Cavalli M, Della Starza I, Genuardi E, Mantoan B, Monitillo L, Del Giudice I, Ladetto M, Gaidano G, Sabattini E, Pileri SA, Galimberti S, PICCALUGA P., and on behalf of Fondazione Italiana Linfomi - MrdNetwork.

Subjects
Minimal Residual Disease, DNA extraction
Abstract

Genomic DNA extraction is a primary component of genomic research and diagnostic routine analysis. Recently, the importance of this process has been highlighted by the necessity to standardize the diagnostic procedure. In this regard, the Minimal Residual Disease (MRD) Network of the Fondazione Italiana Linfomi (FIL MRD Network) has performed a comparative study of four different commercially available kits for DNA extraction, applying them on a panel of cellular pellets, with the aim of defining possible technical recommendations in order to harmonize and standardize diagnostic procedures in the clinical setting. Overall, all four kits usually allowed the recovery of a significant quantity of high-quality DNA (in most conditions), although specific indications could be addressed for cellular pellets of different sizes.

Published
2014

10. Use of IGK gene rearrangement analysis for clonality assesment of lymphoid malignancies. A single center experience

Author

Mannu C., Artioli P., Chili L., Da Pozzo G., Piccioli M., Sandri F., SAGRAMOSO SACCHETTI, CARLO ALBERTO, GAZZOLA, ANNA, ROSSI, MAURA, SAPIENZA, MARIA ROSARIA, LAGINESTRA, MARIA ANTONELLA, BACCI, FRANCESCO, SABATTINI, ELENA, AGOSTINELLI, CLAUDIO, RIGHI, SIMONA, PILERI, STEFANO, PICCALUGA, PIER PAOLO, Mannu C., Sagramoso C., Gazzola A., Rossi M., Sapienza M.R., La ginestra A., Bacci F., Sabattini E., Agostinelli C., Artioli P., Chili L., Da Pozzo G., Piccioli M., Righi S., Sandri F., Pileri S.A., and Piccaluga P.P.

Subjects
IGK gene rearrangement, lymphoid malignancie
Published
2010

11. BCL10 expression in peripheral T-cell lymphoma not otherwise specified

Author

ROSSI, MAURA, AGOSTINELLI, CLAUDIO, GAZZOLA, ANNA, SAPIENZA, MARIA ROSARIA, LAGINESTRA, MARIA ANTONELLA, SAGRAMOSO SACCHETTI, CARLO ALBERTO, SABATTINI, ELENA, BACCI, FRANCESCO, Mannu C., Artioli P., Rossi M., Agostinelli C., Gazzola A., Mannu C., Sapienza M.R., Laginestra M.A., Sagramoso C., Sabattini E., Bacci F., and Artioli P.

Subjects
T-cell lymphoma, BCL10
Published
2010

12. Variable activation of canonical and alternative NF-Kappa B pathway in peripheral T-Cell Lymphoma not otherwise specified

Author

PICCALUGA, PIER PAOLO, AGOSTINELLI, CLAUDIO, GAZZOLA, ANNA, SISTA, MARIA TERESA, RIGHI, SIMONA, BACCI, FRANCESCO, SABATTINI, ELENA, ROSSI, MAURA, ZINZANI, PIER LUIGI, PILERI, STEFANO, Mannu C., Went P., Piccaluga P.P., Agostinelli C., Gazzola A., Sista M.T., Righi S., Bacci F., Sabattini E., Rossi M., Mannu C., Went P., Zinzani P.L., and Pileri S.A.

Subjects
T-cell lymhpoma, NF-KB
Published
2010

15. Ficoll‐hypaque separation vs whole blood lysis: Comparison of efficiency and impact on minimal residual disease analysis.

Author

Genuardi, E., Barbero, D., Dogliotti, I., Mantoan, B., Drandi, D., Gambella, M., Zaccaria, G. M., Monitillo, L., Della Starza, I., Cavalli, M., De Novi, L. A., Ciabatti, E., Grassi, S., Gazzola, A., Mannu, C., Del Giudice, I., Galimberti, S., Agostinelli, C., Piccaluga, P. P., and Ladetto, M.

Subjects
CARCINOGENESIS, ERYTHROCYTES, CENTRIFUGATION, STATISTICAL correlation, LEUCOCYTES, LYMPHOMAS, MULTIPLE myeloma, MONONUCLEAR leukocytes
Abstract

Abstract: Introduction: The high‐throughput era remarkably changed molecular laboratory practice. Actually, the increasing number of processed samples requires to reduce the risk of operator biases, by automating or simplifying as much as possible both the analytical and the pre‐analytical phases. Minimal residual disease (MRD) studies in hematology often require a simultaneous processing of many bone marrow and peripheral blood samples from patients enrolled in prospective, multicenter, clinical trials, monitored at several planned time points. Methods: In this study, we demonstrate that red blood cell lysis (RBL) pre‐analytical procedure can replace the time‐consuming Ficoll stratification as cell recovering step. Here, we show a MRD comparison study using both total white blood cells and mononuclear cells recovered by the 2 procedures from 46 follicular lymphoma (FL), 15 multiple myeloma (MM), and 11 mantle cell lymphoma (MCL) patients enrolled in prospective clinical trials. Results: The experiments were performed in the 4 laboratories of the Fondazione Italiana Linfomi (FIL) MRD Network and showed superimposable results, in terms of good correlation (R = 0.87) of the MRD data obtained by recovering blood cells by the 2 approaches. Conclusion: Based on these results, the FIL MRD Network suggests to optimize the pre‐analytical phases introducing RBL approach for cell recovery in the clinical trials including MRD analysis. [ABSTRACT FROM AUTHOR]

Published
2018
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16. Molecular profiling of blastic plasmacytoid dendritic cell neoplasm reveals a unique pattern and suggests selective sensitivity to NF-kB pathway inhibition

Author

Sapienza, Mr, Fuligni, F, Agostinelli, C, Tripodo, C, Righi, S, Laginestra, Ma, Pileri, A, Mancini, M, Rossi, M, Ricci, F, Gazzola, A, Melle, F, Mannu, C, Ulbar, F, Arpinati, M, Paulli, M, Maeda, T, Gibellini, D, Pagano, Livio, Pimpinelli, N, Santucci, M, Cerroni, L, Croce, Cm, Facchetti, F, Piccaluga, Pp, Pileri, Sa, Pagano, Livio (ORCID:0000-0001-8287-928X), Sapienza, Mr, Fuligni, F, Agostinelli, C, Tripodo, C, Righi, S, Laginestra, Ma, Pileri, A, Mancini, M, Rossi, M, Ricci, F, Gazzola, A, Melle, F, Mannu, C, Ulbar, F, Arpinati, M, Paulli, M, Maeda, T, Gibellini, D, Pagano, Livio, Pimpinelli, N, Santucci, M, Cerroni, L, Croce, Cm, Facchetti, F, Piccaluga, Pp, Pileri, Sa, and Pagano, Livio (ORCID:0000-0001-8287-928X)

Abstract

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare disease of controversial origin recently recognized as a neoplasm deriving from plasmacytoid dendritic cells (pDCs). Nevertheless, it remains an orphan tumor with obscure biology and dismal prognosis. To better understand the pathobiology of BPDCN and discover new targets for effective therapies, the gene expression profile (GEP) of 25 BPDCN samples was analyzed and compared with that of pDCs, their postulated normal counterpart. Validation was performed by immunohistochemistry (IHC), whereas functional experiments were carried out ex vivo. For the first time at the molecular level, we definitely recognized the cellular derivation of BPDCN that proved to originate from the myeloid lineage and in particular, from resting pDCs. Furthermore, thanks to an integrated bioinformatic approach we discovered aberrant activation of the NF-kB pathway and suggested it as a novel therapeutic target. We tested the efficacy of anti-NF-kB-treatment on the BPDCN cell line CAL-1, and successfully demonstrated by GEP and IHC the molecular shutoff of the NF-kB pathway. In conclusion, we identified a molecular signature representative of the transcriptional abnormalities of BPDCN and developed a cellular model proposing a novel therapeutic approach in the setting of this otherwise incurable disease.

Published
2014

17. Pathogenetic and diagnostic significance of microRNA deregulation in peripheral T-cell lymphoma not otherwise specified

Author

Laginestra, M A, primary, Piccaluga, P P, additional, Fuligni, F, additional, Rossi, M, additional, Agostinelli, C, additional, Righi, S, additional, Sapienza, M R, additional, Motta, G, additional, Gazzola, A, additional, Mannu, C, additional, Sabattini, E, additional, Bacci, F, additional, Tabanelli, V, additional, Sacchetti, C A S, additional, Barrese, T Z, additional, Etebari, M, additional, Melle, F, additional, Clò, A, additional, Gibellini, D, additional, Tripodo, C, additional, Inghirami, G, additional, Croce, C M, additional, and Pileri, S A, additional

Published
2014
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19. CDKN1B/p27 expression in peripheral T cell lymphoma not otherwise specified

Author

Gazzola, A., primary, Sista, M. T., additional, Agostinelli, C., additional, Righi, S., additional, Sapienza, M. R., additional, Mannu, C., additional, Rossi, M., additional, Bacci, F., additional, Sabattini, E., additional, Went, P., additional, Zinzani, P. L., additional, Pileri, S. A., additional, and Piccaluga, P. P., additional

Published
2010
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20. Safety of cryopreserved ovarian tissue autotransplantation in leukaemia patients

Author

Fabbri, R., Macciocca, M., Vicenti, R., Piccaluga, P. P., Elena Sabattini, Gazzola, A., Mannu, C., Paradisi, R., Rossi, S., Fabbri, R, Macciocca, M, Vicenti, R, Piccaluga, PP, Sabattini, E, Gazzola, A, Mannu, C, Paradisi, R, and Rossi, S

Subjects
autotransplantation, ovarian tissue cryopreservation, leukaemia, Real-Time PCR

21. Partial nodal involvement by marginal zone lymphoma. Use of IGK gene rearrangement analysis in diagnostic work-up

Author

anna gazzola, Sabattini, E., Mannu, C., Bacci, F., Sacchetti, C. A. S., Artioli, P., Chilli, L., Da Pozzo, G., Piccioli, M., Falini, B., Pileri, S. A., Piccaluga, P. P., GAZZOLA A, SABATTINI E, MANNU C, BACCI F, SAGRAMOSO SACCHETTI CA, ARTIOLI P, CHILLI L, DA POZZO G, PICCIOLI M, FALINI B, PILERI SA, and PICCALUGA P.

Subjects
Hyperplasia, Biopsy, Immunoglobulins, Inguinal Canal, Lymphoma, B-Cell, Marginal Zone, MOLECULAR DIAGNOSIS, marginal zone lymphoma, Diagnosis, Differential, Bone Marrow, Humans, Female, IGK gene rearrangement, Lymph Nodes, Gene Rearrangement, B-Lymphocyte, Aged
Abstract

Nodal marginal zone lymphoma (NMZL) is an indolent B-cell lymphoma that originates from the marginal zone of B-cell follicles. The tumour is rather uncommon, and shares some morphologic and immunophenotypic similarities with the extranodal form of marginal zone lymphomas. However, diagnosis of NMZL implies the exclusion of lymphoplasmacytic lymphoma, follicular lymphoma, and lymph node involvement by extra nodal or splenic marginal zone B-cell lymphoma In addition, its distinction from reactive conditions, including T-zone hyperplasia, are sometimes problematic based on morphologic grounds. We describe a patient who presented with cervical and inguinal lymphadenopathies and high inflammation indexes. Bone marrow and lymph node biopsies were performed for definitive diagnosis. Bone marrow histological and immunophenotypic examinations were normal and excluded haematological disease. In contrast, lymph node evaluation showed some features compatible with a possible lymphoproliferative disorder, even though no definite diagnosis could be made based on morphologic and immunohistochemical investigation. In particular, the problem of a differential diagnosis between NMZL and a florid hyperplasia of monocytoid B-elements was posed. Thus, in order to assess the nature (neoplastic vs. reactive) of the lesion, molecular analysis of the immunoglobulin genes was performed by PCR. Notably, although no clonal rearrangements were revealed by IGHV@ analysis, further evaluation of the immunoglobulin light chain (IGKV@) confirmed the presence of a clonal B-cell population. Accordingly, a final diagnosis of NMZL was made. In conclusion, this case is a good example of the crucial role of complete molecular analysis in the diagnostic work up of lymphoproliferative disorders.

25. Systemic Epstein-Barr-virus-positive T cell lymphoproliferative childhood disease in a 22-year-old Caucasian man: A case report and review of the literature

Author

Meloni Giovanna, Sista Maria, Righi Simona, Mannu Claudia, Capria Saveria, Bacci Francesco, Gazzola Anna, Sabattini Elena, Agostinelli Claudio, Tabanelli Valentina, Pileri Stefano A, and Piccaluga Pier

Subjects
Medicine
Abstract

Abstract Introduction Systemic Epstein-Barr-virus-positive T cell lymphoproliferative disease of childhood is an extremely rare disorder, characterized by clonal proliferation of Epstein-Barr-virus-infected T cells with an activated cytotoxic phenotype. The disease is more frequent in Asia and South America, with only few cases reported in Western countries. A prompt diagnosis, though often difficult, is a necessity due to the very aggressive clinical course of the disease. Case presentation We report the clinicopathological features of fulminant T cell lymphoproliferative disease that arose in the setting of acute primary Epstein-Barr virus infection. Our patient, a 23-year-old man, presented to our facility with persisting fever, hepatosplenomegaly and severe pancytopenia. On bone marrow biopsy, an abundant lymphoid infiltrate was observed. Immunophenotypic and molecular studies revealed that the atypical lymphoid cells displayed a CD8+, Epstein-Barr-encoded-RNA-positive T cell phenotype with clonal rearrangement of the T cell receptor genes, the final diagnosis being systemic Epstein-Barr-virus-positive T cell lymphoproliferative disease. On reviewing the literature we found only 14 similar cases, all presenting with very aggressive clinical courses and requiring extensive phenotyping and molecular techniques for final diagnosis. Conclusion Though extremely rare, this disease can occur in Europe, and a comprehensive diagnostic approach is thus recommended in all case of Epstein-Barr-virus-positive lymphoproliferative disorders. Unfortunately, at present no specific treatment is available; however, prompt administration of anti- Epstein-Barr virus treatment and rapid attempts to control the hemophagocytic syndrome are indicated.

Published
2011
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26. CDKN1B/p27 expression in peripheral T cell lymphoma not otherwise specified

Author

Pier Paolo Piccaluga, Claudia Mannu, Maria Teresa Sista, Maura Rossi, Francesco Bacci, Claudio Agostinelli, Anna Gazzola, Maria Rosaria Sapienza, Elena Sabattini, Pier Luigi Zinzani, Simona Righi, Stefano Pileri, Philip Went, Gazzola A, Sista MT, Agostinelli C, Righi S, Sapienza MR, Mannu C, Rossi M, Bacci F, Sabattini E, Went P, Zinzani PL, Pileri SA, Piccaluga PP., Gazzola A., Sista M.T., Agostinelli C., Righi S., Sapienza M.R., Mannu C., Rossi M., Bacci F., SAbattini E., Went P., Zinzani P.L., Pileri S.A., and Piccaluga P.P.

Subjects
Pathology, medicine.medical_specialty, Tumor suppressor gene, T cell, Gene Expression, Peripheral T-cell lymphoma not otherwise specified, Biology, Polymorphism, Single Nucleotide, Pathology and Forensic Medicine, CDKN1B/P27, T-Lymphocyte Subsets, Gene expression, medicine, Humans, RNA, Messenger, RNA, Neoplasm, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, PTCL NOS, Intracellular Signaling Peptides and Proteins, Lymphoma, T-Cell, Peripheral, General Medicine, Cell cycle, Prognosis, medicine.disease, Survival Analysis, Molecular biology, Peripheral T-cell lymphoma, Neoplasm Proteins, Genes, cdc, medicine.anatomical_structure, Regulatory sequence, CDKN1B, peripheral T-cell lymphomas, Cyclin-Dependent Kinase Inhibitor p27
Abstract

Aims Peripheral T cell lymphoma not otherwise specified (PTCL/NOS) is the commonest PTCL subtype. Recently, proliferation pathways have been found to be commonly altered in PTCL/NOS. CDKN1B/p27, a critical regulator of cell cycle and proliferation, has been suggested to be involved in T cell lymphomagenesis. This study aimed to evaluate the possible occurrence of CDKN1B/p27 aberrations in PTCL/NOS. Methods CDKN1B/p27 expression at RNA and protein level by DNA and tissue microarrays, in 28 and 98 cases, respectively, was studied. Additionally, direct sequencing of CDKN1B in 81 PTCL/NOS was performed. Results CDKN1B mRNA was similarly expressed in PTCL/NOS and normal T lymphocytes. In addition, structural abnormalities were not found; these included mutations and deletions in any exons, exon–intron junctions or regulatory regions. Furthermore, physiological expression of p27 in neoplastic cells was demonstrated by immunohistochemistry; this was mutually exclusive with Ki-67, as expected when the system is intact. Consistently, the expression of other molecules that are functionally related to CDKN1B/p27 in controlling cell cycle (including CCNE1) did not appear to be affected at either the mRNA or protein level. Finally, it was found that p27 expression was not significantly related with overall survival. Conclusion CDKN1B/p27 aberrations seem to be uncommon in PTCL/NOS pathogenesis.

Published
2010
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27. Pathobiology of Hodgkin Lymphoma

Author

Simona Righi, Anna Gazzola, Maria Antonella Laginestra, Elena Sabattini, Francesco Bacci, Carlo A. Sagramoso-Sacchetti, Claudio Agostinelli, Claudia Mannu, Pier Paolo Piccaluga, Maria Rosaria Sapienza, Maria Teresa Sista, Claudio Tripodo, Stefano Pileri, Maura Rossi, Piccaluga P.P., Agostinelli C., Gazzola A., Tripodo C., Bacci F., Sabattini E., Sista M.T., Mannu C., Sapienza M.R., Rossi M., Laginestra M.A., Sagramoso-Sacchetti C.A., Righi S., Pileri S.A., Piccaluga, PP, Agostinelli, C, Gazzola, A, Tripodo, C, Bacci, F, Sabattini, E, Sista, MT, Mannu, C, Sapienza, MR, Rossi, M, Laginestra, MA, Sagramoso-Sacchetti, CA, Righi, S, and Pileri, SA

Subjects
Pathology, medicine.medical_specialty, business.industry, Mixed cellularity, Lymphocyte, Hematology, Review Article, Histogenesis, medicine.disease, Phenotype, Virus, Lymphoma, Pathobiology, medicine.anatomical_structure, hemic and lymphatic diseases, medicine, Hodgkin lymphoma, Diseases of the blood and blood-forming organs, RC633-647.5, business, Who classification, microenvironment
Abstract

Despite its well-known histological and clinical features, Hodgkin's lymphoma (HL) has recently been the object of intense research activity, leading to a better understanding of its phenotype, molecular characteristics, histogenesis, and possible mechanisms of lymphomagenesis. There is complete consensus on the B-cell derivation of the tumor in most cases, and on the relevance of Epstein-Barr virus infection and defective cytokinesis in at least a proportion of patients. The REAL/WHO classification recognizes a basic distinction between lymphocyte predominance HL (LP-HL) and classic HL (cHL), reflecting the differences in clinical presentation and behavior, morphology, phenotype, and molecular features. cHL has been classified into four subtypes: lymphocyte rich, nodular sclerosing, with mixed cellularity, and lymphocyte depleted. The borders between cHL and anaplastic large-cell lymphoma have become sharper, whereas those between LP-HL and T-cell-rich B-cell lymphoma remain ill defined. Treatments adjusted to the pathobiological characteristics of the tumor in at-risk patients have been proposed and are on the way to being applied.

Published
2010

28. Quality Assessment for PCR-based Minimal Residual Disease in Lymphoma: 10 Years of Cross-laboratory Standardization Process Within the Fondazione Italiana Linfomi MRD Network

Author

Barbara Mantoan, Elisa Genuardi, Martina Ferrante, Irene Della Starza, Elena Ciabatti, Susanna Grassi, Lucia Anna De Novi, Marzia Cavalli, Claudia Mannu, Anna Gazzola, Riccardo Bomben, Massimo Degan, Beatrice Alessandria, Christiane Pott, Marie-Hélène Delfau-Larue, Ramon García-Sanz, Claudio Agostinelli, Valter Gattei, Sara Galimberti, Ilaria Del Giudice, Gianluca Gaidano, Marco Ladetto, Simone Ferrero, Daniela Drandi, on behalf of the Fondazione Italiana Linfomi (FIL) MRD Network, Mantoan B., Genuardi E., Ferrante M., Starza I.D., Ciabatti E., Grassi S., de Novi L.A., Cavalli M., Mannu C., Gazzola A., Bomben R., Degan M., Alessandria B., Pott C., Delfau-Larue M.-H., Garcia-Sanz R., Agostinelli C., Gattei V., Galimberti S., Del Giudice I., Gaidano G., Ladetto M., Ferrero S., and Drandi D.

Subjects
Oncology, medicine.medical_specialty, Letter, Standardization, Quality assessment, business.industry, Hematology, medicine.disease, Minimal residual disease, Lymphoma, MRD, lymphoma, Internal medicine, Medicine, Diseases of the blood and blood-forming organs, RC633-647.5, business
Abstract

No abstract available

Published
2021
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29. Minimal residual disease (MRD) in non-Hodgkin lymphomas: Interlaboratory reproducibility on marrow samples with very low levels of disease within the FIL (Fondazione Italiana Linfomi) MRD Network

Author

Claudio Agostinelli, Claudia Mannu, Irene Della Starza, Ilaria Del Giudice, Daniela Barbero, Simone Ferrero, Marco Ladetto, Lucia Anna De Novi, Sara Galimberti, Elena Ciabatti, Valter Gattei, Robin Foà, S Grassi, Elisa Genuardi, Daniela Drandi, Anna Guarini, Massimo Degan, Riccardo Bomben, Barbara Mantoan, Pier Paolo Piccaluga, Marzia Cavalli, Anna Gazzola, Della Starza I., Cavalli M., De Novi L.A., Genuardi E., Mantoan B., Drandi D., Barbero D., Ciabatti E., Grassi S., Gazzola A., Mannu C., Agostinelli C., Piccaluga P.P., Bomben R., Degan M., Gattei V., Guarini A., Foa R., Galimberti S., Ladetto M., Ferrero S., and Del Giudice I.

Subjects
Oncology, Cancer Research, Laboratory Proficiency Testing, Neoplasm, Residual, Interlaboratory reproducibility, Oncogene Proteins, Fusion, Quality Assurance, Health Care, Lymphoma, bcl-2, Follicular lymphoma, Gene Rearrangement, B-Lymphocyte, Heavy Chain, Immunoglobulin Variable Region, Polymerase Chain Reaction, Translocation, Genetic, 0302 clinical medicine, Bone Marrow, Digital polymerase chain reaction, FIL, MRD, PCR, PNQ samples, non-Hodgkin lymphoma, Gene Rearrangement, Oncogene Proteins, medicine.diagnostic_test, Genes, Immunoglobulin, Lymphoma, Non-Hodgkin, B-Lymphocyte, High-Throughput Nucleotide Sequencing, Bone Marrow Examination, Hematology, General Medicine, Italy, Proto-Oncogene Proteins c-bcl-2, 030220 oncology & carcinogenesis, Residual, PNQ sample, IGHV@, Immunoglobulin Heavy Chains, Human, medicine.medical_specialty, Immunoglobulin Heavy Chain, Reproducibility of Result, Non-Hodgkin, Translocation, 03 medical and health sciences, Clone Cell, Genetic, Internal medicine, medicine, Immunoglobulin, Humans, Fusion, business.industry, Reproducibility of Results, medicine.disease, Minimal residual disease, Genes, bcl-2, Clone Cells, Bone marrow examination, Health Care, Genes, Heavy Chain, Neoplasm, Mantle cell lymphoma, business, Quality Assurance, 030215 immunology
Abstract

In 2009, the four laboratories of the Fondazione Italiana Linfomi (FIL) minimal residual disease (MRD) Network started a collaborative effort to harmonize and standardize their methodologies at the national level, performing quality control (QC) rounds for follicular lymphoma (FL) and mantle cell lymphoma (MCL) MRD assessment. In 16 QC rounds between 2010 and 2017, the four laboratories received 208 bone marrow (BM) samples (126 FL; 82 MCL); 187 were analyzed, according to the EuroMRD Consortium guidelines, by both nested (NEST) polymerase chain reaction (PCR) and real-time quantitative (RQ) PCR for BCL2/IGH MBR or IGHV rearrangements. Here, we aimed at analyzing the samples that challenged the interlaboratory reproducibility and data interpretation. Overall, 156/187 BM samples (83%) were concordantly classified as NEST+/RQ+ or NEST-/RQ- by all the four laboratories. The remaining 31 samples (17%) resulted alternatively positive and negative in the interlaboratory evaluations, independently of the method and the type of rearrangement, and were defined "borderline" (brd) samples: 12 proved NEST brd/RQ brd, 7 NEST-/RQ brd, 10 NEST brd/RQ positive not quantifiable (PNQ), and 2 NEST brd/RQ-. Results did not change even increasing the number of replicates/sample. In 6/31 brd samples, droplet digital PCR (ddPCR) was tested and showed no interlaboratory discordance. Despite the high interlaboratory reproducibility in the MRD analysis obtained and maintained by the QC round strategy, samples with the lowest MRD levels can still represent a challenge: 17% (31/187) of our samples showed discordant results in interlaboratory assessments, with 6.4% (12/187) remained brd even applying the two methods. Thus, although representing a minority, brd samples are still problematic, especially when a clinically oriented interpretation of MRD results is required. Alternative, novel methods such as ddPCR and next-generation sequencing have the potential to overcome the current limitations.

Published
2019

30. Ficoll-hypaque separation vs whole blood lysis: Comparison of efficiency and impact on minimal residual disease analysis

Author

Irene Dogliotti, Manuela Gambella, Marzia Cavalli, Claudio Agostinelli, Elena Ciabatti, I. Del Giudice, Claudia Mannu, I. Della Starza, Pier Paolo Piccaluga, Elisa Genuardi, Daniela Barbero, Simone Ferrero, Anna Gazzola, S Grassi, Luigia Monitillo, Gian Maria Zaccaria, L.A. De Novi, Marco Ladetto, Daniela Drandi, Barbara Mantoan, S Galimberti, Genuardi, E., Barbero, D., Dogliotti, I., Mantoan, B., Drandi, D., Gambella, M., Zaccaria, G.M., Monitillo, L., Della Starza, I., Cavalli, M., De Novi, L.A., Ciabatti, E., Grassi, S., Gazzola, A., Mannu, C., Del Giudice, I., Galimberti, S., Agostinelli, C., Piccaluga, P.P., Ladetto, M., and Ferrero, S.

Subjects
medicine.medical_specialty, Neoplasm, Residual, cell recovering, Mononuclear, Clinical Biochemistry, Follicular lymphoma, Ficoll, Urology, Diatrizoate, Peripheral blood mononuclear cell, Hemolysis, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Internal medicine, medicine, red blood cell lysis, Leukocytes, Methods, Humans, Whole blood, Clinical Trials as Topic, Hematology, business.industry, Biochemistry (medical), General Medicine, medicine.disease, Minimal residual disease, medicine.anatomical_structure, minimal residual disease, Residual, 030220 oncology & carcinogenesis, Leukocytes, Mononuclear, Neoplasm, Mantle cell lymphoma, Bone marrow, business, red blood cell lysi, 030215 immunology
Abstract

Introduction The high-throughput era remarkably changed molecular laboratory practice. Actually, the increasing number of processed samples requires to reduce the risk of operator biases, by automating or simplifying as much as possible both the analytical and the pre-analytical phases. Minimal residual disease (MRD) studies in hematology often require a simultaneous processing of many bone marrow and peripheral blood samples from patients enrolled in prospective, multicenter, clinical trials, monitored at several planned time points. Methods In this study, we demonstrate that red blood cell lysis (RBL) pre-analytical procedure can replace the time-consuming Ficoll stratification as cell recovering step. Here, we show a MRD comparison study using both total white blood cells and mononuclear cells recovered by the 2 procedures from 46 follicular lymphoma (FL), 15 multiple myeloma (MM), and 11 mantle cell lymphoma (MCL) patients enrolled in prospective clinical trials. Results The experiments were performed in the 4 laboratories of the Fondazione Italiana Linfomi (FIL) MRD Network and showed superimposable results, in terms of good correlation (R = 0.87) of the MRD data obtained by recovering blood cells by the 2 approaches. Conclusion Based on these results, the FIL MRD Network suggests to optimize the pre-analytical phases introducing RBL approach for cell recovery in the clinical trials including MRD analysis.

Published
2017

31. Comparison of two real-time quantitative polymerase chain reaction strategies for minimal residual disease evaluation in lymphoproliferative disorders: correlation between immunoglobulin gene mutation load and real-time quantitative polymerase chain react

Author

Robin Foà, Claudia Mannu, Irene Della Starza, Ilaria Del Giudice, Elisa Genuardi, Gianluca Gaidano, Anna Gazzola, Marzia Cavalli, Daniela Barbero, Sara Galimberti, Luigia Monitillo, Marco Ladetto, Elena Ciabatti, Pier Paolo Piccaluga, Anna Guarini, Barbara Mantoan, Marina Urbano, Della Starza I, Cavalli M, Del Giudice I, Barbero D, Mantoan B, Genuardi E, Urbano M, Mannu C, Gazzola A, Ciabatti E, Guarini A, Foà R, Galimberti S, PICCALUGA P., Gaidano G, Ladetto M, and Monitillo L

Subjects
Lymphoproliferative disorders, Immunoglobulin gene, Cancer Research, Neoplasm, Residual, MRD, RQ-PCR, lymphoproliferative disorders, immunoglobulin genes, mutations, MINIMAL RESIDUAL DISEASE, Biology, Real-Time Polymerase Chain Reaction, medicine.disease_cause, Immunoglobulin genes, Mutations, Gene Frequency, Gene Rearrangement, Humans, Immunoglobulin Heavy Chains, Lymphoproliferative Disorders, Genes, Immunoglobulin, Mutation, Oncology, Hematology, LYMPHOMA, Immunoglobulin, medicine, Genetics, General Medicine, Gene rearrangement, medicine.disease, Minimal residual disease, Molecular biology, Real-Time PCR (qPCR), Real-time polymerase chain reaction, Genes, Residual, Neoplasm, Immunoglobulin heavy chain, Primer (molecular biology)
Abstract

We compared two strategies for minimal residual disease evaluation of B-cell lymphoproliferative disorders characterized by a variable immunoglobulin heavy chain (IGH) genes mutation load. Twenty-five samples from chronic lymphocytic leukaemia (n = 18) or mantle cell lymphoma (n = 7) patients were analyzed. Based on IGH variable region genes, 22/25 samples carried >2% mutations, 20/25 > 5%. In the IGH joining region genes, 23/25 samples carried >2% mutations, 18/25 > 5%. Real-time quantitative polymerase chain reaction was performed on IGH genes using two strategies: method A utilizes two patient-specific primers, whereas method B employs one patient-specific and one germline primer, with different positions on the variable, diversity and joining regions. Twenty-three samples (92%) resulted evaluable using method A, only six (24%) by method B. Method B poor performance was specifically evident among mutated IGH variable/joining region cases, although no specific mutation load above, which the real-time quantitative polymerase chain reaction failed was found. The molecular strategies for minimal residual disease evaluation should be adapted to the B-cell receptor features of the disease investigated. Copyright © 2013 John Wiley & Sons, Ltd.

Published
2013
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32. Hsa-miR-15a and Hsa-miR-16-1 Expression Is Not Related to Proliferation Centers Abundance and Other Prognostic Factors in Chronic Lymphocytic Leukemia

Author

Claudia Mannu, Anna Gazzola, Maria Antonella Laginestra, Gian Matteo Rigolin, Antonio Cuneo, Simona Righi, Stefano Pileri, Marco Luciani, Fabio Fuligni, Pier Paolo Piccaluga, Maria Ciccone, Maura Rossi, Maria Rosaria Sapienza, Claudio Agostinelli, Rossi M, Fuligni F, Ciccone M, Agostinelli C, Righi S, Luciani M, Laginestra MA, Rigolin GM, Sapienza MR, Gazzola A, Mannu C, Cuneo A, Pileri S, and Piccaluga PP

Subjects
Male, Article Subject, Chronic lymphocytic leukemia, lcsh:Medicine, Chromosome Disorders, CD38, Biology, General Biochemistry, Genetics and Molecular Biology, Downregulation and upregulation, leukimia, microRNA, medicine, Humans, Lymph node, Aged, Cell Proliferation, Aged, 80 and over, Regulation of gene expression, Paraffin Embedding, Chromosomes, Human, Pair 13, General Immunology and Microbiology, Gene Expression Regulation, Leukemic, ZAP70, lcsh:R, miR, General Medicine, Middle Aged, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, MicroRNAs, Leukemia, medicine.anatomical_structure, Immunology, Cancer research, Female, Lymph Nodes, Chromosome Deletion, Research Article
Abstract

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) is the commonest leukemia in adults. Here, we aimed to evaluate hsa-miR-15a/hsa-miR-16-1 expression in CLL tissues by qPCR and correlate it with the other clinicopathological features and clinical outcome. 40 formalin-fixed paraffin-embedded (FFPE) lymph node samples obtained from CLL/SLL patients were classified into two categories, “PCs rich” and “typical.” We found a significant common expression level of 4 miRNAs; however, we did not find any significant relationship between PCs presence and miRNAs expression. Moreover, neither the presence of 13q deletion nor the percentage of cells carrying the deletion strictly correlated with miRNAs expression levels, although a significant number of patients with 13q deletion presented hsa-miR-16-1-3p levels below the median value in normal samples (P<0.05). Finally, although no correlation was found between the expression of each miRNA and other clinicopathological features (Ki67, CD38, ZAP70, and IGVH@ hypermutations), the OS curves showed a positive trend in patients with miRNAs downregulation, though not statistically significant. In conclusion, we showed for the first time that all miRNAs can be successfully studied in FFPE CLL tissues and that del13q and PCs richness do not strictly correspond to miRNAs downregulation; therefore, a specific evaluation may be envisaged at least in patients enrolled in clinical trials.

Published
2013
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33. Prognostic Markers in Peripheral T-Cell Lymphoma

Author

Claudio Agostinelli, Elena Sabattini, Pier Paolo Piccaluga, Francesco Bacci, Claudia Mannu, Stefano Pileri, Anna Gazzola, Piccaluga PP, Agostinelli C, Gazzola A, Mannu C, Bacci F, Sabattini E, and Pileri SA.

Subjects
Oncology, PTCL, Cancer Research, Pathology, medicine.medical_specialty, Prognostication, Severity of Illness Index, Article, International Prognostic Index, Bone Marrow, Internal medicine, Humans, Medicine, Stage (cooking), Extranodal Involvement, Lactate Dehydrogenases, Hematology, Performance status, business.industry, Gene Expression Profiling, Not Otherwise Specified, Age Factors, Lymphoma, T-Cell, Peripheral, Peripheral T-cell lymphoma, Gene expression profile, Prognosis, medicine.disease, International prognostic index, Lymphoma, Bologna score, business
Abstract

Based on their own experience and knowledge of the literature, the authors review the pathobiological characteristics of peripheral T-cell lymphomas (PTCLs), focusing on the available prognostic indicators. The International Prognostic Index (IPI), which is based on age, performance status, lactate dehydrogenase [LDH], stage, and extranodal involvement, appears to be efficient as a prognostic index for PTCLs, at least in part and especially for certain PTCL subtypes. However, it is not so satisfactory for the two commonest PTCLs, PTCL not otherwise specified (PTCL/NOS) and angioimmunoblastic T-cell lymphoma (AITL), for which novel scores, possibly based on the biologic features of the tumors, have been explored. An Italian cooperative group proposed a revision of the IPI for PTCL unspecified (PTCL-U), the Prognostic Index for PTCL-U (PIT), which includes age, performance status, LDH, and bone marrow involvement. The PIT apparently offered some advantages, but they were not confirmed in subsequent studies. A clinical-biological score (the Bologna score) was then proposed, including tumor proliferation and clinical features (age, LDH, and performance status). This score appears promising and offers the intriguing advantage of integrating biological and clinical elements, but independent validation on a large series is still warranted. More recently, gene expression profiling has been used to identify novel molecular prognostic factors. In particular, inactivation of the NFκB pathway, high expression of proliferation-associated genes, and cytotoxic molecular phenotype seem to be associated with a worse outcome. So far, however, none of these indicators has been validated in an independent series. Finally, various reports have dealt specifically with the prognostication of NK-derived tumors, including nasal and nasal-type lymphomas. Both the IPI and dedicated models have turned out to be of prognostic relevance for these tumors. In conclusion, although the IPI is somewhat effective for PTCL prognostication, novel scores that are more refined and possibly disease-specific are warranted. The validation process for several models, including clinical-pathological and molecular models, is now ongoing.

Published
2010
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34. Minimal residual disease after conventional treatment significantly impacts on progression-free survival of patients with follicular lymphoma: The FIL FOLL05 trial

Author

Marzia Cavalli, Francesca Guerrini, Barbara Mantoan, Alessandra Dondi, Giuseppe A. Palumbo, Gianluca Gaidano, Luca Arcaini, Luigia Monitillo, Pier Paolo Piccaluga, Mario Petrini, Luigi Rigacci, Claudia Mannu, Irene Della Starza, Ilaria Del Giudice, Anna Gazzola, Alessandra Tucci, Stefano Luminari, Massimo Federico, Daniele Vallisa, Susanna Grassi, Sara Galimberti, Pellegrino Musto, Luigi Marcheselli, Elena Ciabatti, Umberto Vitolo, Carola Boccomini, Marco Ladetto, Giovanni Bertoldero, Alessandro Pulsoni, Galimberti S, Luminari S, Ciabatti E, Grassi S, Guerrini F, Dondi A, Marcheselli L, Ladetto M, PICCALUGA P., Gazzola A, Mannu C, Monitillo L, Mantoan B, Del Giudice I, Della Starza I, Cavalli M, Arcaini L, Tucci A, Palumbo GA, Rigacci L, Pulsoni A, Vitolo U, Boccomini C, Vallisa D, Bertoldero G, Gaidano G, Musto P, Petrini M, and Federico M.

Subjects
Male, Cancer Research, Neoplasm, Residual, Adolescent, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Clinical Trials, Phase III as Topic, Female, Gene Dosage, Gene Rearrangement, Genes, bcl-2, Humans, Immunoglobulin Heavy Chains, Lymphoma, Follicular, Middle Aged, Prognosis, ROC Curve, Real-Time Polymerase Chain Reaction, Treatment Outcome, Young Adult, Oncology, Lymphoma, bcl-2, Follicular lymphoma, Gastroenterology, hemic and lymphatic diseases, Phase III as Topic, medicine.anatomical_structure, Residual, medicine.medical_specialty, MRD, FOLL05, Chemoimmunotherapy, Internal medicine, medicine, Follicular lymphoma, MRD, Clinical Trials, Progression-free survival, business.industry, Follicular, Cancer, Gene rearrangement, medicine.disease, Minimal residual disease, Surgery, Genes, Neoplasm, Bone marrow, business
Abstract

Purpose: The role of the minimal residual disease (MRD) in follicular lymphoma is still debated. In this study, we assessed whether the BCL2/IGH rearrangement could have a prognostic role in patients receiving R-CHOP, R-FM, or R-CVP. Experimental Design: DNAs from 415 patients among the 504 cases enrolled in the FOLL05 trial (NCT00774826) were centralized and assessed for the BCL2/IGH at diagnosis, at the end of treatment, and after 12 and 24 months. Results: At diagnosis, the molecular marker was detected in 53% of cases. Patients without molecular marker or with a low molecular tumor burden ( Conclusions: In this study, standardized molecular techniques have been adopted and applied on bone marrow samples from a large cohort. Data reported show that the MRD detection is a powerful independent predictor of PFS in patients with follicular lymphoma receiving conventional chemoimmunotherapy. Clin Cancer Res; 20(24); 6398–405. ©2014 AACR.

Published
2014

35. Pathogenetic and diagnostic significance of microRNA deregulation in peripheral T-cell lymphoma not otherwise specified

Author

Claudio Agostinelli, Federica Melle, Giorgio Inghirami, Tabanelli, Anna Gazzola, Martina Rossi, G Motta, Alberto Clò, Simona Righi, Fabio Fuligni, Tomas Barrese, Pier Paolo Piccaluga, Claudio Tripodo, Carlo Alberto Sagramoso Sacchetti, Maria Antonella Laginestra, Davide Gibellini, Stefano Pileri, Claudia Mannu, Elena Sabattini, Francesco Bacci, Carlo M. Croce, Maryam Etebari, Maria Rosaria Sapienza, Laginestra, M., Piccaluga, P., Fuligni, F., Rossi, M., Agostinelli, C., Righi, S., Sapienza, M., Motta, G., Gazzola, A., Mannu, C., Sabattini, E., Bacci, E., Tabanelli, V., Sacchetti, C., Barrese, T., Etebari, M., Melle, F., Clò, A., Gibellini, D., Tripodo, C., Inghirami, G., Croce, C., Pileri, S., Laginestra, M.A, Piccaluga, P.P., Sapienza, M.R., Sagramoso Sacchetti, C.A., Barrese, T.Z., Croce, C.M., and Pileri, S.A.

Subjects
Female, Gene Expression Profiling, Humans, Lymphoma, T-Cell, Peripheral, Male, MicroRNAs, Oligonucleotide Array Sequence Analysis, RNA, Neoplasm, Gene Expression Regulation, Neoplastic, Oncology, Hematology, Medicine (all), medicine.medical_specialty, Pathology, Peripheral T-cell lymphoma not otherwise specified, Biology, hemic and lymphatic diseases, Internal medicine, microRNA, medicine, Regulation of gene expression, PTCLs/NOS, GEP, Oligonucleotide Array Sequence Analysi, Not Otherwise Specified, MicroRNA, medicine.disease, Lymphoma, Gene expression profiling, Original Article, CD8, Human
Abstract

Peripheral T-cell lymphomas not otherwise specified (PTCLs/NOS) are rare and aggressive tumours whose molecular pathogenesis and diagnosis are still challenging. The microRNA (miRNA) profile of 23 PTCLs/NOS was generated and compared with that of normal T-lymphocytes (CD4+, CD8+, naive, activated). The differentially expressed miRNA signature was compared with the gene expression profile (GEP) of the same neoplasms. The obtained gene patterns were tested in an independent cohort of PTCLs/NOS. The miRNA profile of PTCLs/NOS then was compared with that of 10 angioimmunoblastic T-cell lymphomas (AITLs), 6 anaplastic large-cell lymphomas (ALCLs)/ALK+ and 6 ALCLs/ALK - . Differentially expressed miRNAs were validated in an independent set of 20 PTCLs/NOS, 20 AITLs, 19 ALCLs/ALK - and 15 ALCLs/ALK+. Two hundred and thirty-six miRNAs were found to differentiate PTCLs/NOS from activated T-lymphocytes. To assess which miRNAs impacted on GEP, a multistep analysis was performed, which identified all miRNAs inversely correlated to different potential target genes. One of the most discriminant miRNAs was selected and its expression was found to affect the global GEP of the tumours. Moreover, two sets of miRNAs were identified distinguishing PTCL/NOS from AITL and ALCL/ALK - , respectively. The diagnostic accuracy of this tool was very high (83.54%) and its prognostic value validated.

Published
2014

36. Pathobiology of anaplastic large cell lymphoma

Author

Claudio Agostinelli, Giorgio Inghirami, Francesco Bacci, Pier Paolo Piccaluga, Anna Gazzola, Carlo Sagramoso, Elena Sabattini, Fernando Roncolato, Stefano Pileri, Roberto Piva, Claudia Mannu, Piccaluga PP, Gazzola A, Mannu C, Agostinelli C, Bacci F, Sabattini E, Sagramoso C, Piva R, Roncolato F, Inghirami G, and Pileri SA.

Subjects
Pathology, medicine.medical_specialty, Response to therapy, business.industry, Hematology, Review Article, medicine.disease, Phenotype, hemic and lymphatic diseases, Medicine, Diseases of the blood and blood-forming organs, RC633-647.5, business, Who classification, Anaplastic large-cell lymphoma
Abstract

The authors revise the concept of anaplastic large cell lymphoma (ALCL) in the light of the recently updated WHO classification of Tumors of Hematopoietic and Lymphoid Tissues both on biological and clinical grounds. The main histological findings are illustrated with special reference to the cytological spectrum that is indeed characteristic of the tumor. The phenotype is reported in detail: the expression of the ALK protein as well as the chromosomal abnormalities is discussed with their potential pathogenetic implications. The clinical features of ALCL are presented by underlining the difference in terms of response to therapy and survival between the ALK-positive and ALK-negative forms. Finally, the biological rationale for potential innovative targeted therapies is presented.

Published
2011

37. Use of IGK gene rearrangement analysis for clonality assessment of lymphoid malignancies: a single center experience

Author

Mannu, Claudia, Gazzola, Anna, Bacci, Francesco, Sabattini, Elena, Sagramoso, Carlo, Roncolato, Fernando, Rossi, Maura, Laginestra, Maria Antonella, Sapienza, Maria Rosaria, Agostinelli, Claudio, Leo, Antonio, MILENA PICCIOLI, Righi, Simona, Artioli, Patrizia, Chilli, Luigi, Da Pozzo, Gianpaolo, Biase, Giuseppe, Sandri, Federica, Pileri, Stefano A., Piccaluga, Pier Paolo, Mannu C., Gazzola A., Bacci F., Sabattini E., Sagramoso C., Roncolato F., Rossi M., Laginestra M.A., Sapienza M.R., Agostinelli C., De Leo A., Piccioli M., Righi S., Artioli P., Chilli L., Da Pozzo G., De Biase G., Sandri F., Pileri S.A., and Piccaluga P.P.

Subjects
IGK, PCR, BIOMED-2, immune system diseases, hemic and lymphatic diseases, Original Article, molecular diagnostic, non Hodgkin lymphoma
Abstract

Diagnosis of B-non Hodgkin lymphomas (NHLs) is based on clinical, morphological and immunohistochemi-cal features. However, in up to 10-15% of cases, analysis of immunoglobulin heavy (IGH) or light (IGK/IGL) chains genes is required to discriminate between malignant and reactive lymphoid proliferations. In this study, we evaluated the feasibility and efficiency of IGK analysis in the routine diagnostic of B-cell lymphoproliferative disorders (B-LD) when applied to formalin-fixed paraffin-embedded (FFPE) tissues. Clonality patterns were studied in 59 B-LD using the BIOMED-2 protocol for IGK assays, after failure of the IGH assay. PCR products were evaluated by both heterodu-plex and GeneScan analysis. IGK analysis was technically successful in all cases. Overall, it supported the histopa-thological suspicion in 52/59 cases (88%), the sensitivity and specificity being 83% and 80%, respectively. Further, positive and negative predictive values were 95% and 50%, respectively. Interestingly, among various lymphoma subtypes, marginal zone lymphoma and follicular lymphoma most frequently required IGK analysis. In conclusion, IGK study according to the BIOMED-2 protocol resulted feasible and extremely useful in supporting challenging diagnosis of B-LD even if applied on FFPE samples. Accordingly, when NHL is suspected, negative results at IGH analysis should not be considered as conclusive and further investigation of IGK is appropriate.

Published
2011

38. Systemic Epstein-Barr-virus-positive T cell lymphoproliferative childhood disease in a 22-year-old Caucasian man: A case report and review of the literature

Author

Claudio Agostinelli, Stefano Pileri, Valentina Tabanelli, Simona Righi, Claudia Mannu, Maria Teresa Sista, Saveria Capria, Anna Gazzola, Pier Paolo Piccaluga, Elena Sabattini, Giovanna Meloni, Francesco Bacci, Tabanelli V., Agostinelli C., Sabattini E., Gazzola A., Bacci F., Capria S., Mannu C., Righi S., Sista M.T., Meloni G., Pileri S.A., and Piccaluga P.P.

Subjects
Epstein-Barr-viru, Pathology, medicine.medical_specialty, PTCL, Fulminant, T cell, Hepatosplenomegaly, Lymphoproliferative disorders, lcsh:Medicine, Case Report, Disease, EBV, hemic and lymphatic diseases, medicine, Cytotoxic T cell, Medicine(all), business.industry, lcsh:R, Peripheral T-cell lymphoma, General Medicine, medicine.disease, Pancytopenia, medicine.anatomical_structure, medicine.symptom, business, CD8
Abstract

Introduction Systemic Epstein-Barr-virus-positive T cell lymphoproliferative disease of childhood is an extremely rare disorder, characterized by clonal proliferation of Epstein-Barr-virus-infected T cells with an activated cytotoxic phenotype. The disease is more frequent in Asia and South America, with only few cases reported in Western countries. A prompt diagnosis, though often difficult, is a necessity due to the very aggressive clinical course of the disease. Case presentation We report the clinicopathological features of fulminant T cell lymphoproliferative disease that arose in the setting of acute primary Epstein-Barr virus infection. Our patient, a 23-year-old man, presented to our facility with persisting fever, hepatosplenomegaly and severe pancytopenia. On bone marrow biopsy, an abundant lymphoid infiltrate was observed. Immunophenotypic and molecular studies revealed that the atypical lymphoid cells displayed a CD8+, Epstein-Barr-encoded-RNA-positive T cell phenotype with clonal rearrangement of the T cell receptor genes, the final diagnosis being systemic Epstein-Barr-virus-positive T cell lymphoproliferative disease. On reviewing the literature we found only 14 similar cases, all presenting with very aggressive clinical courses and requiring extensive phenotyping and molecular techniques for final diagnosis. Conclusion Though extremely rare, this disease can occur in Europe, and a comprehensive diagnostic approach is thus recommended in all case of Epstein-Barr-virus-positive lymphoproliferative disorders. Unfortunately, at present no specific treatment is available; however, prompt administration of anti- Epstein-Barr virus treatment and rapid attempts to control the hemophagocytic syndrome are indicated.

Published
2010

39. Identification of Novel Cryptic Chromosomal Abnormalities in Primary Myelofibrosis by Single-Nucleotide Polymorphism Oligonucleotide Microarray

Author

Alessandro Isidori, Stefania Paolini, Meris Donati, Elena Sabattini, Simona Righi, Claudia Mannu, Antonella Laginestra, Anna Gazzola, Nicola Vianelli, Claudio Agostinelli, Roberto Emiliani, Carlo Finelli, Michele De Nictolis, Massimo Valentini, Francesco Alesiani, Maura Rossi, Pier Paolo Piccaluga, Stefano Pileri, Stefano Ascani, Maria Rosaria Sapienza, Giovanni Martinelli, Giuseppe Visani, Ilaria Iacobucci, Visani G., Isidori A., Sapienza MR., Righi S., Laginestra A., Agostinelli C., Sabattini E., De Nictolis M., Valentini M., Donati M., Emiliani R., Gazzola A., Mannu C., Rossi M., Alesiani F., Martinelli G., Iacobucci I., Paolini S., Ascani S., Finelli C., Vianelli N., Pileri SA., and Piccaluga PP.

Subjects
Genetics, Immunology, Single-Nucleotide Polymorphism, Single-nucleotide polymorphism, Cell Biology, Hematology, Biology, medicine.disease, Biochemistry, Uniparental disomy, Loss of heterozygosity, Primary Myelofibrosi, Germline mutation, Chromosome abnormality, medicine, Copy-number variation, Genotyping, Oligonucleotide Microarray, SNP array
Abstract

Abstract 1890 Poster Board I-913 Background. Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm (MPN) characterised by a proliferation of predominantly megakaryocytes and granulocytes in bone marrow that in fully developed disease is replaced by fibrous tissue. At molecular level, no specific defect has been identified yet. Cytogenetic abnormalities occur in up to 30% of patients, the commonest including del(13)(q12-22), der(6)t(1;6)(q21-23;p21.3), del (20q), and partial trisomy 1q. In addition, approximately 50% of patients with PMF exhibit a single, recurrent, somatic mutation in the gene encoding the cytoplasmic tyrosine kinase Janus kinase 2 (JAK2). However, such mutation is not specific, also occurring in other MPN. Recently a couple of reports dealt with single-nucleotide polymorphism (SNP) array karyotyping of MPD, including some PMF. Importantly, such studies could identify previously uncovered genetic lesions, highlighting the importance of novel high resolution technologies for the detection of formerly unknown, cryptic aberrations. In this study we performed high resolution karyotyping by SNP oligonucleotide microarray by using the most updated Affymetrix array (Genome-Wide Human SNP Array 6.0) in 20 cases of myelofibrosis (MF) in order to identify novel cryptic genomic aberrations. Methods. DNA (500 ng) was extracted from peripheral blood cells (PBMNC) of 14 primary and 6 secondary MF patients. PBMNC were depleted from lymphocytes by magnetic beads. Briefly, CD3+ cells were labeled with anti-CD3 MoAb directly coupled to magnetic microbeads (Miltenyi Biotech), washed and subsequently purified using Mini-MACS technology. After selection, cell present in the positive (CD3) and negative (PBMNC) fractions were counted and submitted to flow cytometry analysis. DNA was processed and hybridized to the Affymetrix SNP arrays 6.0 as for manufacturer instruction. A whole-genome copy number variation (CNV), genotyping, loss of heterozygosity (LOH) and uniparental disomy (UPD) analyses were performed using the Partek Suite 6.0. Ten lab-specific as well as 90 HapMap samples relative to Caucasian healthy donor were used as control reference. Genomic abnormalities were defined as recurrent when occurring in at least 25% of cases. JAK2 mutational status was assessed as reported, by alle-specific PCR. Clinical information and complete follow up were retrieved for all cases. Direct sequencing, FISH, qPCR and immunohistochemistry (IHC) has been chosen for validation. Results. In all patients we could detect several CNV. The median number of CNV was 60 (range, 34-72), including 46 amplifications (A) and 14 deletions (D). All commonest previously described abnormalities were detected. In addition, several formerly uncovered recurrent lesions were identified, mainly involving 1p, 1q, 2p, 4p, 4q, 5q, 6p, 6q, 7q, 8p, 9q 10q, 11p 11q, 12p, 14q, 15q, 16p, 16q, 17q, 18q, 19q, 20p, 22q. The median size of such CNV was 424,582 Kbp (1,379 Kbp-71,277 Mbp). We then compared JAK2+ vs. JAK2− cases. Of note, we found numerous definite aberrations (A or D) distinguishing the two groups and specifically affecting 16q23.1, 1p36.13, 3q26, 14q13.2, 5q33.2, 6q14.1, 7q33, 8p23.1, and 9p11.2. Grippingly, several genes of potential interest for PMF pathogenesis were identified within the involved loci, including RET, SCAPER, WWOX and SIRPB1. Among others, the product of such genes has been selected for validation by IHC. Similarly, many miRNA were recognized, which may deserve further investigation. Conclusions. By using a newly developed highly sensitive array we identified novel cryptic lesions in patients affected by MF. Future studies on larger series, as well as functional analyses will definitely assess their role in the pathogenesis of the disease. Of note, consistent differences were recorded in JAK2+ vs. JAK2−, supporting the hypothesis of different genetic mechanisms occurring in the two sub-groups. Acknowledgments: this work was supported by AIL Pesaro Onlus, Centro Interdipartimentale per la Ricerca sul Cancro “G. Prodi”, BolognAIL, AIRC, FIRB, RFO, Fondazione Cassa di Risparmio in Bologna, Fondazione della Banca del Monte e Ravenna, Progetto Strategico di Ateneo 2006.*GV and MRS equally contributed to this work. Disclosures: No relevant conflicts of interest to declare.

Published
2009

40. Clonality and Phenotype in Spleens From Patients with Primary Immune Thrombocytopenia

Author

Claudia Mannu, Stefano Pizzolitto, Carla Di Loreto, Nicola Polverelli, Stefano Pileri, Anna Gazzola, Pier Paolo Piccaluga, Anna Candoni, Eleonora Toffoletti, Elena Sabattini, Carlo Sagramoso, Nicola Vianelli, Francesco Zaja, Sabattini, E, Piccaluga, Pp, Mannu, C, Candoni, A, Gazzola, A, Sagramoso, C, Toffoletti, Eleonora, Vianelli, N, Polverelli, N, Pileri, S, DI LORETO, Carla, Pizzolitto, S, and Zaja, Francesco

Subjects
White pulp, Pathology, medicine.medical_specialty, biology, CD3, Lymphocyte, T cell, Immunology, FOXP3, Cell Biology, Hematology, Marginal zone, Biochemistry, medicine.anatomical_structure, Red pulp, medicine, biology.protein, CD8
Abstract

Abstract 3291 Primary immune thrombocytopenia (PIT) results from both increased platelet destruction and insufficient platelet production. Although the development of autoantibodies against platelet glycoproteins remains central in the pathophysiology of PIT, several abnormalities in the immune modulation system have been identified (Blood 2008 Aug 15;112(4):1147; Hematol Oncol Clin North Am. 2009 Dec;23(6):1177; Hum Immunol. 2010 Jun;71(6):586); We analysed morphology, lymphocyte phenotype and heavy immunoglobulin (IgH) and TCR gamma (TCRg) gene rearrangements in spleens from 31 PIT patients to assess possible impact on diagnosis and course, in comparison with 19 spleens surgically removed for trauma. Age ranged from 15 to 68 (mean 41.61y) with M/F of 9/22 in PIT and 18 to 89 (mean: 66y) with M/F 11/8 in controls. All PIT patients experienced at least one line therapy before surgery and 4 underwent anti-CD20 immunotherapy. Immunohistochemistry for CD3, CD20, CD4, CD8, CD56, CD57, PD1, Tia1, Granzyme B, FoxP3, CD72 was made in all cases; both IgH and TCRg gene analysis were possible in 24/31 PIT and 17/19 controls, while 4/31 PIT and 2/19 controls were examined for either one (PIT: 2 TCR and 2 IgH, controls 1 TCR and 1 IgH) and 5 PIT and 1 control were excluded for unsatisfactory material. Ay histology all cases but 2 showed expanded white pulp (that was hypoplastic in the 2/4 cases that underwent Rituximab before surgery), moderate lymphocytic and modest granulocytic infiltrates in the red pulp; haemorragic lakes were present in control spleens. Immunohistochemistry showed similar stains in the 2 groups with normal distribution (white pulp: CD20+ B follicles, CD72-+ in the marginal zone, CD3+/CD4+ T cells, PD1/CD57+ T cells in the germinal centers; red pulp: regular CD20/CD3 and CD4/CD8 ratio, PD1/Tia1/Granzyme B expressed in roughly less than 20% CD3+ T cells; scattered CD57+/CD56- T cells. For molecular results see table 1 below. Monoclonality was defined if 1 or 2 peaks of amplified polymerase chain reaction products were obtained, oligoclonality with 3 to 5 peaks and polyclonality with a Gaussian peak distribution.Table 1IGHWDCtrlIGHWDCtrlPoly2015Poly-Oligo2116Oligo10Mono32Mono32TCRWDCtrlTCRWDCtrlPoly75Poly-Oligo128Oligo53Mono129Mono129 The results showed no statistically significant differences between PIT and controls as for morphology, phenotype and clonality. Since a decrease in regulatory T cells (T regs) is reported in PIT among other immune-impairments (Eur J Haematol. 2007 Oct;79(4):310; Zhonghua Nei Ke Za Zhi. 2010 Mar;49(3):213;Blood. 2009 Mar 12;113(11):256) we immunostained all cases with T reg-related nuclear molecule Foxp3: in control cases few cells in the white and red pulp were observed, while in PIT spleens fewer Foxp3 positive cells could only be seen in the red pulp: although results are slightly different, the low amount of positive cells in both groups decreases the reliable reproducibility of such observation. Moreover, the use of glucocorticoids by all patients before splenectomy, could have further reduced (Eur J Haematol. 2007 Oct;79(4):310) T regs levels. Overlapping molecular results were also obtained in the two groups in agreement with previous reports (Hematology. 2009 Aug;14(4):237; Platelets. 2009 Mar;20(2):135; Int J Hematol. 2003 Dec;78(5):461; Blood. 2002 Aug 15;100(4):1388). The attempt to translate the molecular findings into immunomorphologic differences between monoclonal and non monoclonal cases failed since neither amount/distribution of B and T cells nor T cell subtypes showed evident differences. On the whole, our results show that neither lymphoid phenotype nor IgH or TCRg clonality can be used as specific features of refractory PIT or guide treatment choice.Figure 1Figure 1. Disclosures: No relevant conflicts of interest to declare.

Published
2011
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41. Conventional PCR-based versus next-generation sequencing-based approach for T-cell receptor γ gene clonality assessment in mature T-cell lymphomas: A phase 3 diagnostic accuracy study.

Author

Donelli R, Gazzola A, Mannu C, Etebari M, Navari M, and Piccaluga PP

Abstract

Background: Clonality assessment is currently the major molecular analysis utilized to support the diagnosis of suspicious lymphoid malignancies. Clonal rearrangements of the V-J segments of T-cell receptor G chain locus (TCRγ or TRG) have been observed in almost all types of T neoplasms, such as T-cell-related non-Hodgkin lymphomas and leukemias. At present, the gold standard for clonality evaluation is multiplex polymerase chain reaction (PCR), plus subsequent capillary electrophoresis/heteroduplex analyses, and/or Sanger sequencing. This approach overcomes the problem with the conventional Southern blot hybridization and is more efficient, simple, fast, and reproducible. In the recent years, the new next-generation sequencing (NGS) technologies provided alternative techniques for the analysis of antigen receptors genes, which presented several advantages, such as increased efficiency, specificity (SP), sensitivity (ST), resolution, and objectivity of the results, leading to a better classification, stratification, and monitoring of lymphoid malignancies. Nonetheless, these technologies are still far from being the new gold standard since further studies are warranted to prove their utility. The present study aimed to assess the diagnostic accuracy of these two methods by comparing a commercial NGS-based assay for the evaluation of TRG locus with the gold standard PCR-based one, to fulfill the requirements of a phase 3 diagnostic accuracy study., Methods: We assessed the TRG gene rearrangements in 72 cases using the conventional and highly-validated PCR-based assay proposed by EuroClonality consortium, an alternative commercial PCR-based assay, namely, IdentiClone® TCR Gamma Gene Rearrangement Assay 2.0, and a commercial NGS-based assay, that is, Invivoscribe LymphoTrack® Dx MiSeq® (both by Invivoscribe Technologies Inc., San Diego, CA, USA), to determine the diagnostic accuracy of the latter, and compare them with reference diagnoses made based on observation of clinical manifestations, cytohistological, and immunohistochemical analyses. Statistical values were calculated using the Oxford CATmaker software package., Results: Using standardized criteria of interpretation, the obtained results showed a diagnostic accuracy of 90.3% (correspondence in 65 out of 72 cases) of the test under investigation, with a ST of 86%, a SP of 95%, a positive predicting value of 94%, and a negative predicting value of 88%, demonstrating that it had high efficiency and reliability in detecting clonal TRG gene rearrangements in T-cell non-Hodgkin lymphomas., Conclusions: This diagnostic accuracy study yielded comparable results using a validated PCR-based approach and a new NGS-based one. Subsequent studies and cost-effectiveness evaluation are needed to put the NGS-based clonality assessment into routine diagnostic practice., Competing Interests: The funding agency had no role in the design of the study, the collection, analyses or interpretation of data, the writing of the manuscript, or the decision to publish the results. The authors have no conflicts of interest to disclose., (© 2024 The Journal of Biological Methods, All rights reserved.)

Published
2024
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42. Single-Step IGHV Next-Generation Sequencing Detects Clonality and Somatic Hypermutation in Lymphoid Malignancies: A Phase III Diagnostic Accuracy Study.

Author

Gazzola A, Navari M, Mannu C, Donelli R, Etebari M, and Piccaluga PP

Abstract

Background: Multiplex PCR based on consensus primers followed by capillary electrophoresis and Sanger sequencing are considered as the gold standard method for the evaluation of clonality and somatic hypermutation in lymphoid malignancies. As an alternative, the next-generation sequencing (NGS) of immune receptor genes has recently been proposed as a solution, due to being highly effective and sensitive. Here, we designed a phase III diagnostic accuracy study intended to compare the current gold standard methods versus the first commercially available NGS approaches for testing immunoglobulin heavy chain gene rearrangements., Methods: We assessed IGH rearrangements in 68 samples by means of both the NGS approach (LymphoTrack ® IGH assay, and LymphoTrack ® IGH somatic hypermutation assay, run on Illumina MiSeq) and capillary electrophoresis/Sanger sequencing to assess clonality and somatic hypermutations (SHM)., Results: In comparison to the routine capillary-based analysis, the NGS clonality assay had an overall diagnostic accuracy of 96% (63/66 cases). Other studied criteria included sensitivity (95%), specificity (100%), positive predictive value (100%) and negative predictive value (75%). In discrepant cases, the NGS results were confirmed by a different set of primers that provided coverage of the IGH leader sequence. Furthermore, there was excellent agreement of the SHM determination with both the LymphoTrack ® FR1 and leader assays when compared to the Sanger sequencing analysis (84%), with NGS able to assess the SHM rate even in cases where the conventional approach failed., Conclusion: Overall, conventional Sanger sequencing and next-generation-sequencing-based clonality and somatic hypermutation analyses gave comparable results. For future use in a routine diagnostic workflow, NGS-based approaches should be evaluated prospectively and an analysis of cost-effectiveness should be performed.

Published
2023
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43. Primary pulmonary T-cell lymphoproliferative disorders with a limited-stage, low proliferative index, and unusual clinical behavior: two cases of a rare occurrence.

Author

Sabattini E, Bertuzzi C, Broccoli A, Agostinelli C, Gazzola A, Mannu C, Righi S, Ottaviani E, Terragna C, Motta G, Melle F, Ricci C, Ambrosi F, and Pileri SA

Subjects
Humans, T-Lymphocytes pathology, Mucous Membrane pathology, Lung pathology, Lymphoproliferative Disorders genetics, Lymphoma, T-Cell pathology
Abstract

Extranodal T-lymphoproliferative disorders or T-cell lymphomas (TLPD) are classified according to the WHO Classification (4th and upcoming 5th editions) (Swerdlow et al., IARC Press 1; Alaggio et al., Leukemia 36(7):1720-1748, 2) and to the International Consensus Classification Update (Campo et al., Blood 140(11):1229-1253, 3) upon several morphologic, phenotypic, and genetic features. None of those at present included has been characterized by primary pulmonary onset. We herein present two such cases which, to the best of our knowledge, have not been previously reported and that might represent another variant of T-cell proliferation at mucosal sites. The two cases share similar histological and phenotypic features, suggesting an origin from CD4 + effector memory T cells with the expression of a CD279/PD-1 antigen. They are both monoclonal, harbor few mutations, and show no disease progression outside the lung. They only differ concerning the local extension of the process and clinical setting. The two cases are examples of so far unreported primary pulmonary TLDP, with limited stage and low proliferative index. A possible relationship with a local yet unknown inflammatory trigger that might have favored the development of the T-cell clone cannot be ruled out., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Published
2023
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44. Myeloid nuclear differentiation antigen: an aid in differentiating lymphoplasmacytic lymphoma and splenic marginal zone lymphoma in bone marrow biopsies at presentation.

Author

Righi S, Novero D, Godio L, Bertuzzi C, Bacci F, Agostinelli C, Sagramoso C, Rossi M, Piccioli M, Gazzola A, Mannu C, Roncador G, and Sabattini E

Subjects
Antigens, Differentiation, Antigens, Nuclear genetics, Antigens, Nuclear metabolism, Biomarkers, Biopsy, Bone Marrow pathology, Humans, Mutation, Myeloid Differentiation Factor 88 genetics, Myeloid Differentiation Factor 88 metabolism, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Lymphoma, B-Cell, Marginal Zone diagnosis, Lymphoma, B-Cell, Marginal Zone genetics, Lymphoma, B-Cell, Marginal Zone pathology, Splenic Neoplasms diagnosis, Waldenstrom Macroglobulinemia diagnosis, Waldenstrom Macroglobulinemia genetics, Waldenstrom Macroglobulinemia pathology
Abstract

The differential diagnosis between lymphoplasmacytic lymphoma (LPL) and marginal zone B-cell lymphoma, particularly splenic type (SMZL), can be challenging on onset of bone marrow biopsy (BMB) since morphology and phenotype are not specific and clinical features can overlap or be mildly developed at diagnosis. The LPL-specific L265P mutation in the MYD88 gene is not available in all laboratories, and genetic aberrancies identified in SMZL (del7q, mutations of NOTCH2 and KLF2) are seldom searched in routine practice. The study aim is to investigate the potential role of myeloid nuclear differentiation antigen (MNDA) expression in this specific differential diagnosis. We report MNDA reactivity in 559 patients with small B-cell lymphoma including bone marrow biopsies from 90 LPL and 91 SMZL cases. MYD88 p.Leu265Pro mutation status was assessed and confirmed as positive in 24 of 90 LPL cases, which served as the test set. MNDA staining was negative in 23 of 24 LPL cases in the test set (96%). In the 157 remaining cases (66 LPL, 91 SMZL), which served as the validation set, the MYD88 p.Leu265Pro mutation was unavailable and MNDA was more frequently expressed in SMZL (p < 0.00001). In addition, immunohistochemical features more consistent with SMZL (i.e., presence of CD23+ follicular dendritic cell meshworks, polytypic plasma cells, DBA44 reactivity) were more often present in MNDA-positive cases (statistically significant for 2 such parameters). On the widest case series so far published focusing on LPL and SMZL immunohistochemical diagnosis at onset of BMB, we demonstrated that MNDA expression significantly support the diagnosis of SMZL. This observation may be of particular help in cases where the MYD88 p.Leu265Pro mutational status and/or SMZL-related genetic aberrations are unavailable., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Published
2022
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45. Quality Assessment for PCR-based Minimal Residual Disease in Lymphoma: 10 Years of Cross-laboratory Standardization Process Within the Fondazione Italiana Linfomi MRD Network.

Author

Mantoan B, Genuardi E, Ferrante M, Della Starza I, Ciabatti E, Grassi S, De Novi LA, Cavalli M, Mannu C, Gazzola A, Bomben R, Degan M, Alessandria B, Pott C, Delfau-Larue MH, García-Sanz R, Agostinelli C, Gattei V, Galimberti S, Del Giudice I, Gaidano G, Ladetto M, Ferrero S, and Drandi D

Published
2021
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46. Minimal residual disease (MRD) in non-Hodgkin lymphomas: Interlaboratory reproducibility on marrow samples with very low levels of disease within the FIL (Fondazione Italiana Linfomi) MRD Network.

Author

Della Starza I, Cavalli M, De Novi LA, Genuardi E, Mantoan B, Drandi D, Barbero D, Ciabatti E, Grassi S, Gazzola A, Mannu C, Agostinelli C, Piccaluga PP, Bomben R, Degan M, Gattei V, Guarini A, Foà R, Galimberti S, Ladetto M, Ferrero S, and Del Giudice I

Subjects
Clone Cells, Gene Rearrangement, B-Lymphocyte, Heavy Chain, Genes, Immunoglobulin, Genes, bcl-2, High-Throughput Nucleotide Sequencing, Humans, Immunoglobulin Heavy Chains genetics, Immunoglobulin Variable Region genetics, Italy epidemiology, Lymphoma, Non-Hodgkin genetics, Neoplasm, Residual, Oncogene Proteins, Fusion analysis, Proto-Oncogene Proteins c-bcl-2 genetics, Quality Assurance, Health Care, Reproducibility of Results, Translocation, Genetic, Bone Marrow pathology, Bone Marrow Examination standards, Laboratory Proficiency Testing, Lymphoma, Non-Hodgkin pathology, Polymerase Chain Reaction methods, Polymerase Chain Reaction standards
Abstract

In 2009, the four laboratories of the Fondazione Italiana Linfomi (FIL) minimal residual disease (MRD) Network started a collaborative effort to harmonize and standardize their methodologies at the national level, performing quality control (QC) rounds for follicular lymphoma (FL) and mantle cell lymphoma (MCL) MRD assessment. In 16 QC rounds between 2010 and 2017, the four laboratories received 208 bone marrow (BM) samples (126 FL; 82 MCL); 187 were analyzed, according to the EuroMRD Consortium guidelines, by both nested (NEST) polymerase chain reaction (PCR) and real-time quantitative (RQ) PCR for BCL2/IGH MBR or IGHV rearrangements. Here, we aimed at analyzing the samples that challenged the interlaboratory reproducibility and data interpretation. Overall, 156/187 BM samples (83%) were concordantly classified as NEST+/RQ+ or NEST-/RQ- by all the four laboratories. The remaining 31 samples (17%) resulted alternatively positive and negative in the interlaboratory evaluations, independently of the method and the type of rearrangement, and were defined "borderline" (brd) samples: 12 proved NEST brd/RQ brd, 7 NEST-/RQ brd, 10 NEST brd/RQ positive not quantifiable (PNQ), and 2 NEST brd/RQ-. Results did not change even increasing the number of replicates/sample. In 6/31 brd samples, droplet digital PCR (ddPCR) was tested and showed no interlaboratory discordance. Despite the high interlaboratory reproducibility in the MRD analysis obtained and maintained by the QC round strategy, samples with the lowest MRD levels can still represent a challenge: 17% (31/187) of our samples showed discordant results in interlaboratory assessments, with 6.4% (12/187) remained brd even applying the two methods. Thus, although representing a minority, brd samples are still problematic, especially when a clinically oriented interpretation of MRD results is required. Alternative, novel methods such as ddPCR and next-generation sequencing have the potential to overcome the current limitations., (© 2019 John Wiley & Sons, Ltd.)

Published
2019
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47. Aberrant expression of CD10 and BCL6 in mantle cell lymphoma.

Author

Pizzi M, Agostinelli C, Righi S, Gazzola A, Mannu C, Galuppini F, Fassan M, Visentin A, Piazza F, Semenzato GC, Rugge M, and Sabattini E

Subjects
Adult, Aged, Aged, 80 and over, Female, Humans, Immunoglobulin Heavy Chains genetics, Lymphoma, Mantle-Cell genetics, Lymphoma, Mantle-Cell metabolism, Male, Middle Aged, Young Adult, Biomarkers, Tumor analysis, Lymphoma, Mantle-Cell pathology, Neprilysin biosynthesis, Proto-Oncogene Proteins c-bcl-6 biosynthesis
Abstract

Aims: Mantle cell lymphoma (MCL) is characterized by distinctive histological and molecular features. Aberrant expression of BCL6 and CD10 has been reported occasionally, but the biological features of such cases are largely unknown. This study aimed to define the epidemiological, histological and cytogenetic characteristics of BCL6 and CD10-positive MCLs, also investigating possible biological features., Methods and Results: A total of 165 cases of cyclin D1 and t(11;14)(q13;q34)-positive MCLs were studied for CD10 and BCL6 immunohistochemical expression, which was documented in 26 of 165 (15.8%) cases (BCL6 17 of 165; CD10 11 of 165; BCL6 and CD10 co-expression two of 165). CD10-positivity was significantly more frequent in females (63.3%; P < 0.01). Either expression correlated significantly with higher mean proliferation index and higher prevalence of MUM1 positivity (P < 0.05). Fluorescence in-situ hybridization (FISH) for BCL6 (3q27) gene derangements was performed on the BCL6- and CD10-positive cases and 98 matched controls: amplifications were documented more frequently in BCL6-positive than -negative cases (50.0% versus 19.4% of cases) (P < 0.05). The mutational status of the variable immunoglobulin heavy chain genes (IGVH) was investigated by Sanger sequencing: five of the six successfully tested cases (83.3%) showed no somatic hypermutations., Conclusions: Aberrant CD10 and BCL6 expression defines a subset of MCLs with higher mean Ki-67 index and higher prevalence of MUM1 expression. BCL6 protein positivity correlates with cytogenetic aberrations involving the BCL6 gene. Although examined successfully in few cases, the high prevalence of unmutated IGVH genes also points at a pregerminal cell origin for these phenotypically aberrant cases., (© 2017 John Wiley & Sons Ltd.)

Published
2017
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48. Distinctive Histogenesis and Immunological Microenvironment Based on Transcriptional Profiles of Follicular Dendritic Cell Sarcomas.

Author

Laginestra MA, Tripodo C, Agostinelli C, Motta G, Hartmann S, Döring C, Rossi M, Melle F, Sapienza MR, Tabanelli V, Pileri A, Fuligni F, Gazzola A, Mannu C, Sagramoso CA, Lonardi S, Lorenzi L, Bacci F, Sabattini E, Borges A, Simonitsch-Klupp I, Cabecadas J, Campo E, Rosai J, Hansmann ML, Facchetti F, and Pileri SA

Subjects
Algorithms, B7-H1 Antigen genetics, Castleman Disease genetics, Castleman Disease immunology, Castleman Disease pathology, Chromatin genetics, Chromatin pathology, Cluster Analysis, Dendritic Cell Sarcoma, Follicular genetics, Gene Expression Regulation, Neoplastic, Humans, Programmed Cell Death 1 Ligand 2 Protein genetics, Programmed Cell Death 1 Receptor genetics, Signal Transduction, Up-Regulation, Dendritic Cell Sarcoma, Follicular immunology, Gene Expression Profiling methods, Gene Regulatory Networks, T-Lymphocytes, Helper-Inducer metabolism, T-Lymphocytes, Regulatory metabolism
Abstract

Follicular dendritic cell (FDC) sarcomas are rare mesenchymal tumors with variable clinical, morphologic, and phenotypic characteristics. Transcriptome analysis was performed on multiple FDC sarcomas and compared with other mesenchymal tumors, microdissected Castleman FDCs, and normal fibroblasts. Using unsupervised analysis, FDC sarcomas clustered with microdissected FDCs, distinct from other mesenchymal tumors and fibroblasts. The specific endowment of FDC-related gene expression programs in FDC sarcomas emerged by applying a gene signature of differentially expressed genes ( n = 1,289) between microdissected FDCs and fibroblasts. Supervised analysis comparing FDC sarcomas with microdissected FDCs and other mesenchymal tumors identified 370 and 2,927 differentially expressed transcripts, respectively, and on the basis of pathway enrichment analysis ascribed to signal transduction, chromatin organization, and extracellular matrix organization programs. As the transcriptome of FDC sarcomas retained similarity with FDCs, the immune landscape of FDC sarcoma was investigated by applying the CIBERSORT algorithm to FDC sarcomas and non-FDC mesenchymal tumors and demonstrated that FDC sarcomas were enriched in T follicular helper (T FH ) and T regulatory (T REG ) cell populations, as confirmed in situ by immunohistochemistry. The enrichment in specific T-cell subsets prompted investigating the mRNA expression of the inhibitory immune receptor PD-1 and its ligands PD-L1 and PD-L2, which were found to be significantly upregulated in FDC sarcomas as compared with other mesenchymal tumors, a finding also confirmed in situ Here, it is demonstrated for the first time the transcriptional relationship of FDC sarcomas with nonmalignant FDCs and their distinction from other mesenchymal tumors. Implications: The current study provides evidence of a peculiar immune microenvironment associated with FDC sarcomas that may have clinical utility. Mol Cancer Res; 15(5); 541-52. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Published
2017
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49. Atypical Afta Major Healing after Photodynamic Therapy.

Author

Casu C and Mannu C

Abstract

The aim of this study is to report a case of atypical Afta Major healing in a patient with recurrent aphthous stomatitis (SAR) with a type of photodynamic therapy. A female patient with SAR affected for about 2 years reported a history of hypothyroidism treated with Levothyroxine. The oral cavity clinical examination showed several major symptomatic ulcers, previously treated with topical and systemic therapies without any benefit. The largest of them is present for more than 40 days, in spite of topical cortisone applications, with significant pain symptoms reported by the patient. It was decided to perform a session of photodynamic therapy with a device that emits a LED light used in combination with a photosensitive reagent (Toluidine blue). The dye was applied on the entire surface of the lesion beyond the margins and even encroaching on healthy tissue. The light diode was turned on with a wavelength of 630 nm with cycles from 30 seconds, 10 consecutive times above it. After a few days, a curious phenomenon happened: healing of Afta Major starting from the center, which was almost completely healed towards the borders of the lesion. No previous literature reports this type of healing. Photodynamic therapy could be a successful treatment for SAR.

Published
2017
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50. Comparison of different DNA extraction methods from peripheral blood cells: advice from the Fondazione Italiana Linfomi Minimal Residual Disease Network.

Author

Mannu C, Gazzola A, Ciabatti E, Fuligni F, Cavalli M, Della Starza I, Genuardi E, Mantoan B, Monitillo L, Del Giudice I, Ladetto M, Gaidano G, Sabattini E, Pileri SA, Galimberti S, and Piccaluga PP

Abstract

Genomic DNA extraction is a primary component of genomic research and diagnostic routine analysis. Recently, the importance of this process has been highlighted by the necessity to standardize the diagnostic procedure. In this regard, the Minimal Residual Disease (MRD) Network of the Fondazione Italiana Linfomi (FIL MRD Network) has performed a comparative study of four different commercially available kits for DNA extraction, applying them on a panel of cellular pellets, with the aim of defining possible technical recommendations in order to harmonize and standardize diagnostic procedures in the clinical setting. Overall, all four kits usually allowed the recovery of a significant quantity of high-quality DNA (in most conditions), although specific indications could be addressed for cellular pellets of different sizes.

Published
2016
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