How to Cite
Abstract
Rzechonek A., Blasiak P., Muszynska-Bernhard B., Adamiak J., Grzegrzółka J., Majchrzak M., Budzynski W., Le Pivert P.
Purpose. To assess the loco-regional distribution pattern of a blue dye tracer, as a surrogate for a chemotherapeutic agent, injected in the invasion edge of resectable lung tumor; to evaluate the technique efficacy at staining the lung-tumor interface and the metastatic pathways. Methods. Between November 2014 and September 2015, we enrolled 33 patients (17 women, 16 men; 52-87 years old) presenting with 31 primary lung carcinomas and 2 metastases. We injected in vivo (n=17) or ex vivo (n=16) the innermost side of the tumor invasion edge with 1.3ml methylene blue dye. We performed the injection alone (n=12) or combined with a focal freezing (n=21). We assessed the stain distribution into the invasion-edge, the tumor, the lung or the node(s) at gross and microscopic examination. Results. At gross examination, we observed a quick, intense staining of the invasion edge, and a concomitant staining of the tumor and the lung. The staining pattern was heterogeneous in the tumor, homogeneous in the invasion edge and the lung irrespective of the focal freezing, tumor type, size, or blood perfusion status. The microscopic examination evidenced the staining of the matrix, vessel lumens, and tumor cells, except for lymph nodes. Conclusions. The inner side of the invasion edge looks a suitable location for directly injecting and distributing the methylene blue tracer within the interstitium and related draining pathways during the resection of primary or secondary lung tumor. Fresh resection specimens are convenient to evaluate new edge-targeting injections techniques for the diagnostic or therapeutic management of cell dissemination during surgery.
Keywords: freezing-assisted injection, lung tumor, methylene blue, surgery, tumor edge injection
ДВОСПРЯМОВАНА МІГРАЦІЯ ФАРБУВАЛЬНОЇ РЕЧОВИНИ, ВВЕДЕНОЇ ІНТРАОПЕРАЦІЙНО, ПРИ ПЕРВИННИХ ТА ВТОРИННИХ ПУХЛИНАХ ЛЕГЕНЬ (ПОЧАТКОВЕ ДОСЛІДЖЕННЯ ЗА УЧАСТЮ 33 ПАЦІЄНТІВ ТА КЛІНІЧНІ ВИСНОВКИ)
Жехонек А., Блашяк П., Мушинський-Бернхард Б., Адамяк Я., Гжегжулка Ю., Майхжак М., Будзинскі В., Ле Півер П.
Мета. Оцінити місцево-регіонарні закономірності розподілу метиленового блакитного барвника як замінника хіміотерапевтичного засобу, що вводиться в край резекції при пухлинах легені; оцінити ефективність методики по фарбуванню прикордонного шару пухлини легені та метастатичного поширення. Методи. У період з листопада 2014 по вересень 2015 року, ми набрали 33 пацієнти (17 жінок, 16 чоловіків; 52-87 років), з яких у 31 був первинний рак легені та у 2 - метастатичне ураження легень. Ми вводили 1,3 мл метиленового блакитного у внутрішній край резекції пухлини in vivo (n = 17) або ex vivo (n = 16). Ін'єкція виконувалася або окремо (n = 12), або в комбінації з місцевим заморожуванням (n = 21). Оцінювалося розподіл барвника по краю резекції, пухлини, легені або лімфатичним вузлам за допомогою макро і мікроскопії. Результати. На макроскопічному рівні було відзначено швидке, інтенсивне забарвлення краю резекції з супутнім фарбуванням пухлини та легені. Характер фарбування був різнорідний в пухлині, однорідний по краю резекції та у легені незалежно від застосування місцевого заморожування, типу та розміру пухлини та ступеню перфузії крові. При мікроскопічному дослідженні виявилося фарбування матриксу, судинних просвітів та пухлинних клітин за винятком лімфатичних вузлів. Висновки. Внутрішня сторона краю резекції представляється гарним місцем для безпосереднього введення та поширення барвника метиленового блакитного в інтерстиціальної тканини та дренажних шляхах при резекції первинних та вторинних пухлин легенів. По свіжих резекційних зразках зручно оцінювати нові методики ін'єкцій, спрямованих на край пухлини, для діагностики або терапевтичного контролю поширення клітин під час операції.
Ключові слова: ін'єкції із заморожуванням, пухлина легенів, метиленовий блакитний, операція, ін'єкція в край резекції пухлини
ДВУНАПРАВЛЕННАЯ МИГРАЦИЯ КРАСЯЩЕГО ВЕЩЕСТВА, ВВЕДЕННОГО ИНТРАОПЕРАЦИОННО ПРИ ПЕРВИЧНЫХ И ВТОРИЧНЫХ ОПУХОЛЯХ ЛЕГКОГО. ПЕРВОНАЧАЛЬНОЕ ИССЛЕДОВАНИЕ С УЧАСТИЕМ 33 ПАЦИЕНТОВ И КЛИНИЧЕСКИЕ ВЫВОДЫ
Жехонек А., Блашяк П., Мушинска-Бернхард Б., Адамяк Я., Гжегжулка Ю., Майхжак М., Будзынски В., Ле Пивер П.
Цель. Оценить местно-регионарные закономерности распределения метиленового голубого красящего вещества как заменителя химиотерапевтического средства, вводимого в край резекции при опухолях легкого; оценить эффективность методики по окрашиванию пограничного слоя опухоли легкого и метастатического распространения. Методы. В период с ноября 2014 по сентябрь 2015 года мы набрали 33 пациента (17 женщин, 16 мужчин; 52-87 лет), из которых у 31 была первичный рак легкого и у 2 – метастатическое поражение легких. Мы вводили 1,3 мл метиленового голубого во внутренний край резекции опухоли in vivo (n=17) или ex vivo (n=16). Инъекция выполнялась либо отдельно (n=12), либо в комбинации с местной заморозкой (n=21). Оценивалось распределение красителя по краю резекции, опухоли, легкому или лимфатическим узлам с помощью макро- и микроскопии. Результаты. На макроскопическом уровне было отмечено быстрое, интенсивное окрашивание края резекции с сопутствующим окрашиванием опухоли и легкого. Характер окрашивания был разнородный в опухоли, однородный по краю резекции и в легком независимо от применения местного замораживания, типа и размера опухоли и степени перфузии крови. При микроскопическом исследовании проявилось окрашивание матрикса, сосудистых просветов и опухолевых клеток за исключением лимфатических узлов. Выводы. Внутренняя сторона края резекции представляется подходящим местом для непосредственного введения и распространения красителя метиленового голубого в интерстициальной ткани и дренажных путях при резекции первичных и вторичных опухолей легких. По свежим резекционным образцам удобно оценивать новые методики инъекций, направленных на края опухоли, для диагностики или терапевтического контроля распространения клеток во время операции.
Ключевые слова: инъекции с заморозкой, опухоль легких, метиленовый голубой, операция, инъекция в край резекции опухоли
References
REFERENCES
Kelsey, C. R., Marks, L. B., Hollis, D., Hubbs, J. L., Ready, N. E., D’Amico, T. A., & Boyd, J. A. (2009). Local recurrence after surgery for early stage lung cancer: An 11-year experience with 975 patients. Cancer, 115(22), 5218–5227. http://doi.org/10.1002/cncr.24625
Matsangou, M., Santos, E. S., Raez, L. E., Gomez, J. E., Dinh, V., & Savaraj, N. (2014). Early-stage non-small-cell lung cancer: Overview of adjuvant chemotherapy and promising advances. Lung Cancer Management, 3(1), 85–99.
Coffey, J. C., Wang, J. H., Smith, M. J. F., Bouchier-Hayes, D., Cotter, T. G., & Redmond, H. P. (2003). Excisional surgery for cancer cure: Therapy at a cost. Lancet Oncology, 4(12), 760–768. http://doi.org/10.1016/S1470-2045(03)01282-8
Polzer, B., & Klein, C. A. (2013). Metastasis Awakening: The challenges of targeting minimal residual cancer. Nature Medicine, 19(3), 274–275. http://doi.org/10.1038/nm.3121
Ceelen, W., Pattyn, P., & Mareel, M. (2014). Surgery, wound healing, and metastasis: Recent insights and clinical implications. Critical Reviews in Oncology/Hematology. http://doi.org/10.1016/j.critrevonc.2013.07.008
Ceelen, W. P., Morris, S., Paraskeva, P., & Pattyn, P. (2007). Surgical trauma, minimal residual disease and locoregional cancer recurrence. Cancer Treatment and Research, 134, 51–69. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/17633047
Baba, T., Uramoto, H., Kuwata, T., Takenaka, M., Chikaishi, Y., Oka, S., … Tanaka, F. (2013). Intrapleural chemotherapy improves the survival of non-small cell lung cancer patients with positive pleural lavage cytology. Surgery Today, 43(6), 648–653. http://doi.org/10.1007/s00595-012-0281-y
Liang, Y., & Wakelee, H. A. (2013). Adjuvant chemotherapy of completely resected early stage non-small cell lung cancer (NSCLC). Translational Lung Cancer Research, 2(5), 403–410. http://doi.org/10.3978/j.issn.2218-6751.2013.07.01
Sawabata, N., Kitamura, T., Nitta, Y., Taketa, T., Ohno, T., Fukumori, T., … Nakamura, T. (2017). Lung cancer biopsy dislodges tumor cells into circulating blood. Journal of Cancer Metastasis and Treatment, 3(1), 16. http://doi.org/10.20517/2394-4722.2016.67
Gaikwad, A., Souza, C. A., Inacio, J. R., Gupta, A., Sekhon, H. S., Seely, J. M., … Gomes, M. M. (2014). Aerogenous metastases: a potential game changer in the diagnosis and management of primary lung adenocarcinoma. American Journal of Roentgenology, 203(6), W570–W582. http://doi.org/10.2214/AJR.13.12088
Pandya, P., Orgaz, J. L., & Sanz-Moreno, V. (2016). Modes of invasion during tumour dissemination. Molecular Oncology, 11, 1–23. http://doi.org/10.1002/1878-0261.12019
Wiig, H., Tenstad, O., Iversen, P., Kalluri, R., Bjerkvig, R., Freitas, I., … Haggerty, A. (2010). Interstitial fluid: the overlooked component of the tumor microenvironment? Fibrogenesis & Tissue Repair, 3(1), 12. http://doi.org/10.1186/1755-1536-3-12
Celikoglu, F., Celikoglu, S. I., & Goldberg, E. P. (2010). Intratumoural chemotherapy of lung cancer for diagnosis and treatment of draining lymph node metastasis. Journal of Pharmacy and Pharmacology, 62(3), 287–293. http://doi.org/10.1211/jpp/62.03.0001
Mehta, H. J., Begnaud, A., Penley, A. M., Wynne, J., Malhotra, P., Fernandez-Bussy, S., … Jantz, M. A. (2015). Restoration of Patency to Central Airways Occluded by Malignant Endobronchial Tumors Using Intratumoral Injection of Cisplatin. Annals of the American Thoracic Society, 12(9), 1345–50. http://doi.org/10.1513/AnnalsATS.201503-131OC
Goldberg, E. P., Hadba, A. R., Almond, B. a, & Marotta, J. S. (2002). Intratumoral cancer chemotherapy and immunotherapy: opportunities for nonsystemic preoperative drug delivery. The Journal of Pharmacy and Pharmacology, 54(2), 159–180. http://doi.org/10.1211/0022357021778268
Tempany, C. M. C., Jayender, J., Kapur, T., Bueno, R., Golby, A., Agar, N., & Jolesz, F. A. (2015). Multimodal imaging for improved diagnosis and treatment of cancers. Cancer, 121(6), 817–27. http://doi.org/10.1002/cncr.29012
Hachey, K. J., & Colson, Y. L. (2014). Current Innovations in Sentinel Lymph Node Mapping for the Staging and Treatment of Resectable Lung Cancer. Seminars in Thoracic and Cardiovascular Surgery, 26(3), 201–209. http://doi.org/10.1053/j.semtcvs.2014.09.001
Meyer, A., Cheng, C., Antonescu, C., Pezzetta, E., Bischof-Delaloye, A., & Ris, H.-B. (2007). Successful migration of three tracers without identification of sentinel nodes during intraoperative lymphatic mapping for non-small cell lung cancer. Interactive Cardiovascular and Thoracic Surgery, 6(2), 214–8. http://doi.org/10.1510/icvts.2006.141911
Mehta, H. J., Begnaud, A., Penley, A. M., Wynne, J., Malhotra, P., Fernandez-Bussy, S., … Jantz, M. A. (2015). Treatment of isolated mediastinal and hilar recurrence of lung cancer with bronchoscopic endobronchial ultrasound guided intratumoral injection of chemotherapy with cisplatin. Lung Cancer, 90(3), 542–547. http://doi.org/10.1016/j.lungcan.2015.10.009
Stylianopoulos, T., Martin, J. D., Snuderl, M., Mpekris, F., Jain, S. R., & Jain, R. K. (2013). Co-evolution of solid stress and interstitial fluid pressure in tumors during progression: Implications for vascular collapse. Cancer Research, 73(13), 3833–3841. http://doi.org/10.1158/0008-5472.CAN-12-4521
Shentu, Y., Zhang, L., Gu, H., Mao, F., Cai, M., Ding, Z., & Wang, Z. (2014). A new technique combining virtual simulation and methylene blue staining for the localization of small peripheral pulmonary lesions. BMC Cancer, 14, 79. http://doi.org/10.1186/1471-2407-14-79
Lim, E. J., Oak, C. H., Heo, J., & Kim, Y. H. (2013). Methylene blue-mediated photodynamic therapy enhances apoptosis in lung cancer cells. Oncology Reports, 30(2), 856–862. http://doi.org/10.3892/or.2013.2494
Shafiei, S., Bagheri, R., Sadri, K., Jafarian, A. H., Attaran, D., Lari, S. M., & Basiri, R. (2015). Sentinel node mapping for intra-thoracic malignancies: systematic review of the best available evidence, 2(2), 52–57. Retrieved from http://rcm.mums.ac.ir/article_3865_556.html
He, X., Xiao, Y., Zhang, X., Du, P., Zhang, X., Li, J., … Le Pivert, P. (2016). Percutaneous Tumor Ablation: Cryoablation Facilitates Targeting of Free Epirubicin-Ethanol-Ioversol Solution Interstitially Co-injected in a Rabbit VX2 Tumor Model. Technology in Cancer Research & Treatment, 15(4), 597–608. http://doi.org/10.1177/1533034615593855
Le Pivert, P. J., Morrison, D. R., Haddad, R. S., Renard, M., Aller, A., Titus, K., & Doulat, J. (2009). Percutaneous tumor ablation: microencapsulated echo-guided interstitial chemotherapy combined with cryosurgery increases necrosis in prostate cancer. Technology in Cancer Research & Treatment, 8(3), 207–216. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/19445538
Vignaud, J.-M., Ménard, O., Weinbreck, N., Siat, J., Borrelly, J., Marie, B., … Martinet, Y. (2006). Evaluation of the spatial diffusion of methylene blue injected in vivo by bronchoscopy into non-small cell lung carcinoma. Respiration; International Review of Thoracic Diseases, 73(5), 658–63. http://doi.org/10.1159/000094392
Boucher, Y., Baxter, L. T., & Jain, R. K. (1990). Interstitial Pressure Gradients in Tissue-isolated and Subcutaneous Tumors: Implications for Therapy. Cancer Research, 50(15), 4478–4484. Retrieved from http://cancerres.aacrjournals.org/content/50/15/4478
Giraud, P., Antoine, M., Larrouy, A., Milleron, B., Callard, P., De Rycke, Y., … Touboul, E. (2000). Evaluation of microscopic tumor extension in non-small-cell lung cancer for three-dimensional conformal radiotherapy planning. International Journal of Radiation Oncology, Biology, Physics, 48(4), 1015–24. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11072158
Munson, J. M., & Shieh, A. C. (2014). Interstitial fluid flow in cancer: implications for disease progression and treatment. Cancer Management and Research, 6, 317–328. http://doi.org/10.2147/CMAR.S65444
Soltani, M., Chen, P., Babich, J., Kierstead, D., & Graham, W. (2011). Numerical Modeling of Fluid Flow in Solid Tumors. PLoS ONE, 6(6), e20344. http://doi.org/10.1371/journal.pone.0020344
Polacheck, W. J., Charest, J. L., & Kamm, R. D. (2011). Interstitial flow influences direction of tumor cell migration through competing mechanisms. Proceedings of the National Academy of Sciences of the United States of America, 108(27), 11115–20. http://doi.org/10.1073/pnas.1103581108
Estourgie, S. H., Nieweg, O. E., Valdés Olmos, R. A., Th Rutgers, E. J., & Kroon, B. B. R. (2003). Intratumoral versus intraparenchymal injection technique for lymphoscintigraphy in breast cancer. Clinical Nuclear Medicine, 28(5), 371–374. http://doi.org/10.1097/01.RLU.0000063409.68758.D4
McGuire, S., & Yuan, F. (2001). Quantitative analysis of intratumoral infusion of color molecules. American Journal of Physiology - Heart and Circulatory Physiology, 281(2), H715–H721. Retrieved from http://ajpheart.physiology.org/content/281/2/H715
Jain, R. K., Martin, J. D., & Stylianopoulos, T. (2014). The role of mechanical forces in tumor growth and therapy. Annual Review of Biomedical Engineering, 16, 321–346. http://doi.org/10.1146/annurev-bioeng-071813-105259
Hohenforst-Schmidt, W., Zarogoulidis, P., Darwiche, K., Vogl, T., Goldberg, E. P., Huang, H., … Brachmann, J. (2013). Intratumoral chemotherapy for lung cancer: re-challenge current targeted therapies. Drug Design, Development and Therapy, 7, 571–83. http://doi.org/10.2147/DDDT.S4639336-
Zhang, X.Y., Luck, J., Dewhirst, M. W., & Yuan, F. (2000). Interstitial hydraulic conductivity in a fibrosarcoma. American Journal of Physiology - Heart and Circulatory Physiology, 279(6).
Le Pivert, P. J. (2017) Translational Cryosurgery in Lung Tumor Therapy, Cryoimmunology, Cryochemotherapy, Nanocryosurgery: basics and applications. In H. Wang, K. Xu, P. Littrup, (Eds.) Cryosurgery for Lung Cancer (to be published). Wien, New York: Springer. Retrieved from https://www.researchgate.net/publication/305620390
Maiwand, M. O., & Asimakopoulos, G. (2004). Cryosurgery for lung cancer: clinical results and technical aspects. Technology in Cancer Research & Treatment, 3(2), 143–50. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/15059020
Polk, W., Fong, Y., Karpeh, M., & Blumgart, L. H. (1995). A technique for the use of cryosurgery to assist hepatic resection. Journal of the American College of Surgeons, 180(2), 171–176.
Hassid, Y., Furman-Haran, E., Margalit, R., Eilam, R., & Degani, H. (2006). Noninvasive magnetic resonance imaging of transport and interstitial fluid pressure in ectopic human lung tumors. Cancer Research, 66(8), 4159–4166. http://doi.org/10.1158/0008-5472.CAN-05-3289
Gatenby, R. A., Gawlinski, E. T., Gmitro, A. F., Kaylor, B., & Gillies, R. J. (2006). Acid-mediated tumor invasion: A multidisciplinary study. Cancer Research, 66(10), 5216–5223. http://doi.org/10.1158/0008-5472.CAN-05-4193
Trédan, O., Galmarini, C. M., Patel, K., & Tannock, I. F. (2007). Drug resistance and the solid tumor microenvironment. Journal of the National Cancer Institute, 99(19), 1441–1454. http://doi.org/10.1093/jnci/djm135
Raghunand, N., & Gillies, R. J. (2000). pH and drug resistance in tumors. Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy, 3(1), 39–47. http://doi.org/10.1054/drup.2000.0119
Morimoto, N., Isoda, N., Takaoka, Y., Hirosawa, T., Watanabe, S., Otake, T., … Yamamoto, H. (2017). Short-Term Results of Laparoscopic Radiofrequency Ablation Using a Multipolar System for Localized Hepatocellular Carcinoma. Liver Cancer, 6(2), 137–145. http://doi.org/10.1159/000450925
"Inter Collegas" is an open access journal: all articles are published in open access without an embargo period, under the terms of the CC BY-NC-SA (Creative Commons Attribution ‒ Noncommercial ‒ Share Alike) license; the content is available to all readers without registration from the moment of its publication. Electronic copies of the archive of journals are placed in the repositories of the KhNMU and V.I. Vernadsky National Library of Ukraine.
Copyright Agreement
1. This Agreement on the transfer of rights to use the work from the Co-authors to the publisher (hereinafter the Agreement) is concluded between all the Co-authors of the work, represented by the Corresponding Author, and Kharkiv National Medical University (hereinafter the University), represented by an authorized representative of the Editorial Board of scientific journals (hereinafter the Editorial Board).
2. This Agreement is an accession agreement within the meaning of clause 1 of Article 634 of the Civil Code of Ukraine: that is, a contract, "the terms of which are established by one of the parties in forms or other standard forms, which can be concluded only by joining the other party to the proposed contract as a whole. The other party cannot offer its terms of the contract." The party that established the terms of this contract is the University.
3. If there is more than one author, the authors choose the Corresponding Author, who communicates with the Editorial Board on his own behalf and on behalf of all Co-authors regarding the publication of a written work of a scientific nature (article or review, hereinafter referred to as the Work).
4. The contract begins from the moment of submission of the manuscript of the Work by the Corresponding Author to the Editorial Board, which confirms the following:
4.1. all Co-authors of the Work are familiar with and agree with its content, at all stages of reviewing and editing the manuscript and the existence of the published Work;
4.2. all Co-authors of the Work are familiar with and agree to the terms of this Agreement.
5. The published Work is in electronic form in public access on the websites of the University and any websites and electronic databases in which the Work is posted by the University and is available to readers under the terms of the "Creative Commons" license (Attribution NonCommercial Sharealike 4.0 International)" or more free licenses "Creative Commons 4.0".
6. The Corresponding Author transfers, and the University receives, the non-exclusive property right to use the Work by placing the latter on the University's websites for the entire term of copyright. The University participates in the creation of the final version of the Work by reviewing and editing the manuscript of the article or review provided to the Editorial Board by the Corresponding Author, translating the Work into any languages. For the participation of the University in the finalization of the Work, the Co-authors agree to pay the invoice issued to them by the University, if such payment is provided by the University. The size and procedure of such payment are not the subject of this contract.
7. The University has the right to reproduce the Work or its parts in electronic and printed forms, to make copies, permanent archival storage of the Work, distribution of the Work on the Internet, repositories, scientometric databases, commercial networks, including for monetary compensation from third parties.
8. The co-authors guarantee that the manuscript of the Work does not use works whose copyright belongs to third parties.
9. The authors of the Work guarantee that at the time of submission of the manuscript of the Work to the Editorial Board, the property rights to the Work belong only to them, neither in whole nor in part have they been transferred to anyone (not alienated), they are not the subject of a lien, litigation or claims by third parties.
10. The Work may not be posted on the University's website if it violates a person's right to the privacy of his personal and family life, harms public order and health.
11. The work may be withdrawn by the Editorial Board from the University websites, libraries and electronic databases where it was placed by the Editorial Board, in cases of detection of violations of the ethics of the authors and researchers, without any compensation for the losses of the Co-authors. At the time of submission of the manuscript to the Editorial Board and all stages of its editing and review, the manuscript must not have already been published or submitted to other editorial offices.
12. The right transferred under this Agreement extends to the territory of Ukraine and foreign countries.
13. The rights of Co-authors include the requirement to indicate their names on all copies of the Work or during any public use or public mention of the Work; the requirement to preserve the integrity of the Work; legal opposition to any distortion or other encroachment on the Work, which may harm the honor and reputation of the Co-authors.
14. Co-authors have the right to control their personal non-property rights by familiarizing themselves with the text (content) and form of the Work before its publication on the University's website, when transferring it to a printing company for reproduction or when using the Work in other ways.
15. The Co-authors, in addition to the property rights not transferred under this Agreement and taking into account the non-exclusive nature of the rights transferred under this Agreement, retain the property rights to finalize the Work and to use certain parts of the Work in other works created by the Co-authors.
16. The Co-authors are obliged to notify the Editorial Board of all errors in the Work, discovered by them independently after the publication of the Work, and to take all measures to eliminate such errors as soon as possible.
17. The University undertakes to indicate the names of the Co-authors on all copies of the Work during any public use of the Work. The list of Co-authors may be shortened according to the rules for the formation of bibliographic descriptions determined by the University or third parties.
18. The University undertakes not to violate the integrity of the Work, to agree with the Corresponding Author on all changes made to the Work during processing and editing.
19. In case of violation of their obligations under this Agreement, its parties bear the responsibility defined by this Agreement and the current legislation of Ukraine. All disputes under the Agreement are resolved through negotiations, and if the negotiations do not resolve the dispute – in the courts of the city of Kharkiv.
20. The parties are not responsible for the violation of their obligations under this Agreement, if it occurred through no fault of theirs. The party is considered innocent if it proves that it has taken all measures dependent on it for the proper fulfillment of the obligation.
21. The Co-authors are responsible for the truthfulness of the facts, quotes, references to legislative and regulatory acts, other official documentation, the scientific validity of the Work, all types of responsibility to third parties who have claimed their rights to the Work. The co-authors reimburse the University for all costs caused by claims of third parties for infringement of copyright and other rights to the Work, as well as additional material costs related to the elimination of identified defects.