Author's response to reviews

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1 Author's response to reviews Title: Characteristic mtor activity in Hodgkin-lymphomas offers a potential therapeutic target in high risk disease - a combined tissue microarray, in vitro and in vivo study Authors: Agnes Mark (markagi@korb1.sote.hu) Melinda Hajdu (melindahajdu@gmail.com) Zsofia Varadi (v.zsofka@fre .hu) Tamas B Sticz (tsticz@korb1.sote.hu) Noemi Nagy (n.noncsi@fre .hu) Judit Csomor (jmj.csomor@gmail.com) Lajos Berczi (berczi33@gmail.com) Viktoria Varga (vivarga@gmail.com) Monika Csoka (csokam@t-online.hu) Laszlo Kopper (kopper@korb1.sote.hu) Anna Sebestyen (anna@korb1.sote.hu) Version: 3 Date: 2 April 2013 Author's response to reviews: see over

2 Author's response to reviews Title: Characteristic mtor activity in Hodgkin-lymphomas offers a potential therapeutic target in high risk disease a combined tissue microarray, in vitro and in vivo study Authors: Ágnes Márk (markagi@korb1.sote.hu), Melinda Hajdu (melindahajdu@gmail.com), Zsófia Váradi (v.zsofka@fre .hu), Tamás Béla Sticz (tsticz@korb1.sote.hu), Noémi Nagy (n.noncsi@fre .hu), Judit Csomor (jmj.csomor@gmail.com), Lajos Berczi (berczi33@gmail.com), Viktória Varga (vivarga@gmail.com), Monika Csóka (csokam@tonline.hu), László Kopper (kopper@korb1.sote.hu), Anna Sebestyén (anna@korb1.sote.hu) Version: 3 Date: 25 March 2013 Author's response to reviews: see over

3 Answer for the revision of the manuscript MS: entitled Characteristic mtor activity in Hodgkin-lymphomas offers a potential therapeutic target in high risk disease a combined tissue microarray, in vitro and in vivo study sent to Journal of BMC Cancer Dear Editor and Reviewers, I would like to thank you for the review of our manuscript and for your comments. We carefully reviewed our manuscript according to the reviewer suggestions. All changes are highlighted in green. Statistical analysis did not identify any correlation beetween mtor activity and different clinical data of HL patients, such as survival. The prognosis of HL patients, as it known, is relatively good; therefore, the number of patients with poor prognosis based on 5 years survival data is low and we did not get significant differences in our analysis. However, we did find some tendencies, which could not be confirmed statistically. Of note, cases without mtor activity were low in number, but 100% of them had more than 5 year disease free survival. This tendency could not be confirmed statistically due to the high number of mtor-active cases with good and poor prognosis, but it may suggest that the lack of mtor activity in Hodgkin lymphoma may signify low risk of relapse and poor prognosis. We have thoroughly looked over the manuscript and changed all sentences which referred to a possible correlation between mtor activity and clinical data (pages 2, 12 and 14-17) and corrections were made for avoiding statements which may show any discrepancy. We attach the table with all clinical characteristics of HL patients which were investigated in correlation with mtor activity (Table 1) for the reviewer.

4 We would like to highlight that the presence of mtor activity probably indicates that the inclusion of mtor inhibition in the therapy of Hodgkin-lymphomas may be feasible and beneficial, especially in the subset of patients where standard protocols are ineffective. Moreover, our in vitro and in vivo data showed that the combination of mtor inhibitors with other agents will probably offer the highest efficiency for achieving the best clinical response, and may also allow dose reduction in order to decrease late treatment toxicity in these cases. We hope that the modifications in the article will help the clear understanding of our research in the field of lymphomas, and you will find our revised manuscript acceptable for publication in your Journal. Yours sincerely, Anna Sebestyén Corresponding author

5 Characteristics Total number of cases High mtor activity Low mtor activity p All HL cases 83 77/83 (93%) 6/83 (7%) Age, y (n=83) <18 27 (33%) 24/27 (89%) 3/ (49%) 39/41 (95%) 2/41 >45 15 (18%) 14/15 (93%) 1/ # Gender (n=83) Male 40 (48%) 36/40 (90%) 4/40 Female 43 (52%) 41/43 (95%) 2/ φ Ann Arbor stage (n=83) I-II 53 (64%) 49/53 (96%) 4/53 III-IV 30 (36%) 28/30 (97%) 2/30 1 φ B symptoms (n=83) Yes 25 (30%) 25/25 (100%) 0/25 No 58 (70%) 52/58 (95%) 6/ φ Histological type (n=83) NS 47 (57%) 44/47 (94%) 3/47 MC 18 (22%) 17/18 (94%) 1/18 LR 8 (10%) 8/8 (100%) 0/8 LD 3 (4%) 3/3 (100%) 0/3 NLPHL 7 (8%) 5/7 (71%) 2/ # All clinical data avalaible (n=72) Complete remission (disease free) 44/72 (61%) 40/44 (91%) 4/44 Relapsed patients (n=25) 25/72 (35%) 23/25 (92%) 2/25 CR after relapse 15/25 (60%) 13/15 (87%) 2/15 Stem cell transplanted 13/25 (52%) 12/13 (92%) 1*/13 Died 11/72 (15%) 11/11 (100%) 0/ # Table 1 The table includes the summary of all data with p values. *:This case with low mtor activity is in complete remission (more than 5 years) after transplantation. Statistical analysis was done with Fisher s exact test (φ) and with chi square test (#).