Title: Small cell carcinoma arising in Barrett's esophagus: a case report and review of the literature

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1 Author's response to reviews Title: Small cell carcinoma arising in Barrett's esophagus: a case report and review of the literature Authors: Haridimos Markogiannakis (markogiannakis@easy.com) Dimitrios Theodorou (Dtheodorou@hippocratio.gr) Konstantinos G Toutouzas (tousur@med.uoa.gr) Andreas Larentzakis (alarentz@med.uoa.gr) Michael Pattas (mpattas@yahoo.gr) Angeliki Bousiotou (poulira@otenet.gr) Pavlos Papacostas (oncologydepart@hippocratio.gr) Konstantinos Filis (kfilis@hotmail.com) Stilianos Katsaragakis (skatsar@mail.gr) Version: 2 Date: 22 November 2007 Author's response to reviews: see over

2 1 UNIVERSITY OF ATHENS ATHENS MEDICAL SCHOOL 1 st Department of Propaedeutic Surgery November 22, 2007 Editorial Office, Journal of Medical Case Reports Dear Sir/Madam, We are very pleased to be informed that you would be interested in evaluating a revised version of our paper entitled "Small cell carcinoma arising in Barrett s esophagus: a case report and review of the literature" (Manuscript ID: ) which we have submitted for consideration for publication in Journal of Medical Case Reports, that addresses the reviewers comments. Please find attached the revised manuscript of our paper with all revisions, made according to the reviewers comments. This is the Cover letter ("Response to Reviewers Letter") pointing out in detail how we have addressed each reviewers comment and all the changes that have been made. We appreciate the reviewers comments and we believe that they really helped us to improve our text. The paper has been improved according to the suggestions of the reviewers and all the comments of the reviewers were addressed in the manuscript (Please see below). 1

3 2 Answers to Reviewers comments: Reviewers comments: Reviewer #1: Comment #1: In the conclusion the authors write: "a better prognosis is possible with early diagnosis and treatment strategies..." This statement is hypothetic and can not be concluded from one case report, nor does the literature support this thesis. I would phrase this like a hypothesis.. Answer #1: We agree with the reviewer s comment. According to the reviewer s suggestion, this thesis has been phrased like a hypothesis in the revised version of our manuscript. In particular, in the Abstract section in the Conclusions, from the last sentence in page 2 to the 1 st sentence in page 3, the sentence: Prognosis is quite unfavorable; a better prognosis is, however, possible with early diagnosis and treatment strategies incorporating chemotherapy along with oncological radical surgery and/or radiotherapy as part of a multimodality approach. has been corrected to: Prognosis is quite unfavorable; a better prognosis might be possible with early diagnosis and treatment strategies incorporating chemotherapy along with oncological radical surgery and/or radiotherapy as part of a multimodality approach. in the revised paper. Moreover, in the Conclusions section of the initial text in page 8, the 3 rd sentence: Although prognosis is quite unfavorable and treatment protocols are not well established, a better prognosis is possible with early diagnosis and treatment strategies incorporating chemotherapy along with oncological radical surgery and/or radiotherapy as part of a multimodality approach. has been corrected as stated in the revised paper, in the Conclusions section, from the 3 rd sentence in page 8 to the 1 st sentence in page 9: Prognosis is quite unfavorable and treatment protocols are not well established. A better prognosis might be possible with early diagnosis and treatment strategies incorporating 2

4 3 chemotherapy along with oncological radical surgery and/or radiotherapy as part of a multimodality approach.. Comment #2: Because of the rareness of a small cell esophageal carcinoma, the histopathological differential diagnosis should be worked out more in detail. Although chromogranin occurs in small cell lung cancer, it is a typical marker of neuroendocrine tumors. Did you screen for other tumor markers, e.g. NSE or Cyfra-21-1? Were the margins of the specimen free of tumor?. Answer #2: We would like to thank the reviewer for his comment. Apart from chromogranin, we also screened for NSE which was also positive. We did not screen for Cyfra In addition, the margins of the specimen were free of tumor. As stated in the Case presentation section of the revised version, 3 rd paragraph, 2 nd sentence, page 5: The margins of the specimen were free of tumor.. Additionally, in the Case presentation section, 3 rd paragraph, last sentence, page 5 it is mentioned: Immunohistochemical staining of the tumor cells was positive for chromogranin and neuron-specific enolase (NSE).. Comment #3: "Endoscopic US was not helpful". What does this mean: not conclusive, not feasible? Did you use a PET-scan?. Answer #3: We appreciate the reviewer s comment. Unfortunately, endoscopic US was not feasible because of esophageal lumen obstruction. The 6 th sentence of the 1 st paragraph, in the Case presentation section, in page 5 of the initial manuscript: Due to esophageal lumen obstruction, endoscopic US was not helpful. has been corrected to: Due to esophageal 3

5 4 lumen obstruction, endoscopic US was not feasible. in the revised text. Regarding PET-scan, we did not use this modality in this case. Comment #4: What was the rational for the chosen chemotherapy? Did you treat the patient similar to a small cell cancer of the lung? What did you use for the postoperative chemotherapy?. Answer #4: We appreciate the reviewer s comment. Indeed, based on the literature regarding the histology, biologic behavior, systemic nature, chemosensitivity, and treatment of this rare neoplasm, we treated the patient similar to a small cell cancer of the lung. As stated in the revised manuscript, in the Discussion section, 4 th paragraph, 1 st and 2 nd sentence, page 7: Although treatment protocols are not well established because of the paucity of cases and the lack of large studies, chemotherapy remains the treatment of choice given the systemic nature of the disease [1,2]. Since small cell carcinoma of the esophagus is histologically identical to small cell carcinoma of the lung and, furthermore, their aggressive behavior but also chemosensitivity are similar, the chemotherapeutic agents used for small cell esophageal carcinoma are similar to those for its lung counterpart [1,2].. Furthermore, we used the same agents (cisplatine and etoposide) for the postoperative chemotherapy. In the Abstract section of the revised paper in page 2, in Case presentation, 5 th sentence, it is stated: Preoperative chemotherapy with cisplatine and etoposide for 3 months resulted in a significant reduction of the tumor.. In addition, in the Abstract section, Case presentation, last sentence, page 2, it is stated: The patient received another 3 months course of postoperative chemotherapy with the same agents and remains free of disease for 12 months.. 4

6 5 In the Case presentation section of our revised paper, page 5, 2 nd paragraph, 1 st sentence, it is also stated: The patient received preoperative chemotherapy with cisplatine and etoposide for 3 months that resulted in a significant reduction of the tumor size (Figure 2).. Regarding postoperative chemotherapy, in the Case presentation section, page 6, last sentence, it is stated: The patient received another 3 months course of postoperative chemotherapy with the same agents (cisplatine and etoposide) and remains free of disease for 12 months.. Finally, in the Discussion section, 2 nd paragraph, from the 2 nd to 4 th sentence, page 8, it is stated: Our initial treatment consisted of a 3 months preoperative chemotherapy course with cisplatine and etoposide that resulted in a significant reduction of the neoplasm. Given the response to chemotherapy and since no metastatic disease was identified in the postchemotherapy investigation, radical surgical resection, including en block esophagectomy with two field lymph node dissection and proximal gastrectomy, was then performed. Based on the promising results of preoperative chemotherapy, another 3 months course of postoperative chemotherapy with the same agents was administered.. Comment #5: The conclusion that multicenter-approaches are needed to establish a treatment protocol for such a rare entity is right. But is it really feasible? Perhaps the discussion and conclusion should focus more on your treatment of this tumor.. Answer #5: We appreciate the reviewer s comment. Small cell esophageal carcinoma is a very infrequent neoplasm. Since the rarity of this entity has impeded statistical evaluation and treatment protocols are not well established because of the paucity of cases and the lack of large studies, multicenter-approaches are probably needed to obtain sufficiently large populations for optimization of therapy. However, we agree with the reviewer that this might not be really feasible. According to the reviewer s suggestion, we have focused more on our 5

7 6 treatment of this neoplasm in the presented patient in the discussion and conclusion of the revised version of our manuscript. As stated in the Discussion section, 2 nd paragraph, in page 8: The reported patient presented with a large tumor of the distal esophagus. Our initial treatment consisted of a 3 months preoperative chemotherapy course with cisplatine and etoposide that resulted in a significant reduction of the neoplasm. Given the response to chemotherapy and since no metastatic disease was identified in the post-chemotherapy investigation, radical surgical resection, including en block esophagectomy with two field lymph node dissection and proximal gastrectomy, was then performed. Based on the promising results of preoperative chemotherapy, another 3 months course of postoperative chemotherapy with the same agents was administered. Although conclusions regarding treatment of such a rare clinical entity can not be drawn from a case report, the effects of our treatment strategy seem encouraging since our patient remains free of disease for 12 months.. In the revised Conclusions section, page 9, 2 nd sentence, it is also stated: Our treatment strategy of preoperative chemotherapy followed by radical surgical resection and postoperative chemotherapy in the reported patient may have yielded promising results.. Comment #6: Make sure the CT scan is of the same level in the pre- and post-chemotherapy picture, it looks as they are not from the same level now.. Answer #6: We would like to thank the reviewer for his comment. Indeed, the pre- (Figure 1) and post-chemotherapy (Figure 2) pictures are not exactly from the same level. We feel terribly sorry and would like to apologise for this event. We, therefore, meticulously reviewed all pictures of the pre- and post-chemotherapy CT scans. Unfortunately, though, we have not found a post-chemotherapy picture that is from the identically same level of the pre- 6

8 7 chemotherapy one. However, it should be taken into consideration that there is a slight difference between the two presented pictures and that they very clearly demonstrate the significant reduction of the tumor size following chemotherapy. Reviewer #2: Comments to authors: No further comments.. Revisions necessary for publication: None.. Answer: We would like to thank the reviewer. All authors have contributed to, and read the paper, have given permission for their name to be included as a co-author, and take public responsibility for it. We also state that the present manuscript is original, is submitted solely to this Journal, has not been previously published, nor accepted for publication elsewhere, nor is it under consideration for publication elsewhere, and will not be submitted elsewhere. We declare that we do not have any financial support or relationships that may pose conflict of interest. In addition, written consent was obtained from the patient for publication for this case report. We would like to thank you for your interest in our paper. Please do not hesitate to contact us if you have any further questions or comments. Yours sincerely, Haridimos Markogiannakis, MD; Dimitrios Theodorou, MD, PhD; Konstantinos G Toutouzas, MD, PhD; Andreas Larentzakis, MD; Michael Pattas, MD; Angeliki Bousiotou, 7

9 8 MD, PhD; Pavlos Papacostas, MD, PhD; Konstantinos Filis, MD, PhD; Stilianos Katsaragakis, MD, PhD Corresponding author: Dr. Haridimos Markogiannakis, MD Aristeidou 239 street, Kallithea, Athens, Greece Tel: Fax:

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