Yarema R. Factors of the intraperitoneal metastatic cascade in optimizing treatment of gastric cancer

Українська версія

Thesis for the degree of Doctor of Science (DSc)

State registration number

0525U000377

Applicant for

Specialization

  • 14.01.07 - Онкологія

01-10-2025

Specialized Academic Board

Д26. 155. 01

R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology National Academy of Sciences of Ukraine

Essay

The dissertation is devoted to solving the urgent problem of modern oncology – improving the results of combined treatment of patients with gastric cancer with subclinical and manifest peritoneal metastases by applying combined treatment with intraperitoneal hyperthermic chemotherapy (HIPEC) in a bidirectional mode taking into account the factors of the intraperitoneal metastatic cascade. To achieve this goal, the results of treatment of 475 gastric cancer patients with manifest peritoneal metastases or risk of intraperitoneal recurrence were studied. In 226 patients, the clinical, morphological and molecular factors of intraperitoneal recurrence of gastric cancer after radical surgical treatment were studied. In 200 patients with gastric cancer and realized peritoneal metastases who received standard palliative treatment, the possibilities of segregation of the oligometastatic gastric cancer group were studied. Combination therapy using HIPEC in a bidirectional mode was applied to 49 patients with gastric cancer with manifest or subclinical peritoneal metastases. Biological samples of patients were studied using cytological, histological, immunohistochemical methods, enzyme-linked immunosorbent assay, and a biological method for determining the level of cytokines. For the first time, a predictive nomogram of the risk of intraperitoneal recurrence of gastric cancer after radical surgical treatment was proposed, which is a tool for segregation of a group of patients with the need for adjuvant intraperitoneal chemotherapy. The effect of D2 lymphnode dissection on the risk of intraperitoneal recurrence was studied. A reliable relationship between E-cadherin aberrant type of gastric cancer (genomically stable molecular type) and the risk of intraperitoneal recurrence and a negative prognosis of patients was established. The probable dependence of the initiation of progression of gastric cancer on the level of TNF-α in the supernatants of primary tumor cultures, as well as the formation of a pro-inflammatory cytokine intraperitoneal profile and its support of the process of intraperitoneal progression of gastric cancer in a paracrine manner by peritoneal cells, was confirmed. A probable relationship was established between the concentration level in the supernatants of the soluble fraction of ICAM-1 in the mesothelium at the time of radical surgical treatment and the peritoneal recurrence-free survival of patients. Based on the concept of the intraperitoneal metastatic cascade, the clinical efficacy of HIPEC in a bidirectional mode in patients with gastric cancer was substantiated and demonstrated for the first time. A conceptual algorithm for personalized combined treatment of patients with gastric cancer with subclinical and manifest peritoneal metastases was formulated, which has a clear practical direction

Research papers

Ярема Р.Р. Рак шлунка з високим ризиком інтраперитонеального метастазування: особливості перебігу та сучасні методи лікування / Р.Р. Ярема // Львівський медичний часопис. – 2014. – Т. 20, № 2. – С. 69-75 // Б

Ярема Р.Р. Інтраперитонеальний метастатичний каскад: молекулярні та клітинні чинники, механізми // Онкология. – 2016. – Т. 18, №2. – С. 93-103. // Б

Yarema R. Gastric cancer with high risk of intraperitoneal progression: clinical course and current treatments // Curr. Issues Pharm. Med. Sci. – 2017. – 30(4): 190-194. DOI: 10.1515/cipms-2017-0036. // А

Р.Р. Ярема, Т.Г. Фецич, М.А. Огорчак, Г.П. Зубарєв, Ю.Ю. Олійник, М.Б. Матусяк, М.Г. Зубарєв, П.І. Гиря, Ю.Я. Ковальчук, В.І. Сафіян. Інтраопераційна гіпертермічна внутрішньочеревна хіміоперфузія в комбінованому лікуванні пацієнтів із місцево-поширеним та дисемінованим раком шлунка // Клінічна Онкологія. – 2013. – №2. – С. 38-5 // Б

Р.Р. Ярема, Т.Г. Фецич, О. Глеен, Ф.Н. Джиллі, М.А. Огорчак, М.Г. Зубарєв. Інтраперитонеально дисемінований рак: закінчення ери скептицизму? // Онкология. – 2013. – Т. 15, №2. – С. 88-95. // Б

R.R. Yarema, М.А. Ohorchak, G.P. Zubarev, Y.P. Mylyan, Y.Y. Oliynyk, M.G. Zubarev, P.I. Gyrya, Y.J. Kovalchuk, V.I. Safiyan, Т.G. Fetsych. Hyperthermic intraperitoneal chemoperfusion in combined treatment of locally advanced and disseminated gastric cancer: results of a single-centre retrospective study // Int. J. Hyperthermia. – 2014. – 30(3). – С. 159-165. DOI: 10.3109/02656736.2014.893451. // А

Р.Р. Ярема, Д. де Манзоні, Т.Г. Фецич, М.А. Огорчак. D2 лімфодисекція: на шляху до імплементації в європейській популяції хворих на рак шлунка // Клінічна онкологія. – 2015. – № 2(17). – С. 24-29. // Б

R. Yarema, G. de Manzoni, T. Fetsych, М. Ohorchak, M. Pliatsko, M. Bencivenga. On the road to standardization of D2 lymph node dissection in a European population of patients with gastric cancer // World J. Gastrointest. Oncol. – 2016. – 8(6): 489-497. DOI: 10.4251/wjgo.v8.i6.489 // А

V.J. Verwaal, B. Rau, F. Jamali, F.N. Gilly, I. de Hingh, H. Takala, I. Syk, J. Pelz, J. Mulsow, K. van der Speeten, S. Kusamura, L.H. Iversen, F. Mohamed, O. Glehen, R. Younan, R. Yarema, S. Gonzalez-Moreno, S. O'Dwyer, Y. Yonemura, P. Sugarbaker. Registries on peritoneal surface malignancies throughout the world, their use and their options // Int. J. Hyperthermia. – 2017. – 33(5): 528-533. DOI: 10.1080/02656736.2017.1315178. // А

С.І. Кіркілевський, І.В. Жулкевич, А.А. Машуков, В.Є. Максимовський, А. Рибін, О.І. Ткаченко, Р.Р. Ярема, Д.М. Осадчий, М.А. Огорчак, В.В. Пирогов, В.А. Лінькевич. Місце внутрішньочеревної гіпертермічної хіміоперфузії у комплексному лікуванні хворих на перитонеально-дисемінований рак шлунка // Вісник наукових досліджень. - 2018, № 4: 13-25 // Б

R. Yarema, J. Mielko, T. Fetsych, M. Ohorchak, M. Skorzewska, K. Rawicz-Pruszyński, A. Mashukov, V. Maksimovsky, T. Jastrzębski, W. Polkowski, P. Gyrya, Y. Kovalchuk, V. Safiyan, I. Karelin, V. Kopetskiy, O. Kolesnik, Y. Kondratskiy, M. Paskonis. Hyperthermic intraperitoneal chemotherapy (HIPEC) in combined treatment of locally advanced and intraperitonealy disseminated gastric cancer: A retrospective cooperative Central-Eastern European study // Cancer Medicine. – 2019. – 8(6): 2877-2885. DOI: 10.1002/cam4.2204. // А

Gastric cancer with peritoneal metastases: the efficiency of standard treatment methods / R. Yarema, M. Ohorchak, P. Hyrya, Y. Kovalchuk, V. Safiyan, I. Karelin, S. Ferneza, M. Fetsych, M. Matusyak, Y. Oliynyk, Т. Fetsych // World J. Gastrointest. Oncol. – 2020. – 15(5): 569-582. DOI: 10.4251/wjgo.v12.i5.569. // А

Р.Р. Ярема, Т.Г. Фецич, М.А. Огорчак, Н.А. Володько, П.І. Гиря, Ю.Я. Ковальчук, В.І. Сафіян, Ю.П. Милян, М.Б. Матусяк, Ю.Ю. Олійник, Т.І. Новіцька, Л.І. Лаба, М.І. Яриш, М.Т. Фецич, С.Р. Фернеза HIPEC в комбінованому лікуванні інтраперитонеально дисемінованого раку: моноцентровий досвід проведення 215 операцій // Клінічна онкологія. – 2021. – Т.11, №1(41). – С. 1-7. DOI: 10.32471/clinicaloncology.2663-466X.41-1.27758 // Б

R. Yarema, M. Оhorchak, O. Petronchak, R. Huley, P. Hyrya, Y. Kovalchuk, V. Safiyan, O. Rilinh, M. Matusyak. A genomically stable molecular type of gastric cancer as a predictor of peritoneal relapse after radical surgical treatment // General Surgery (Ukraine). – 2022. - 1: 28-34. DOI: 10.30978/GS-2022-1-28 // А

R. Yarema, M. Оhorchak, P. Hyrya, Y. Kovalchuk, V. Safiyan, Y. Oliynyk, O. Rilinh, M. Matusyak. Predictive nomogram of the risk of peritoneal relapse following radical gastric cancer surgery // Proc. Shevchenko Sci. Soc. Med. Sci. – 2022. - 69(2): 18-28. DOI: 10.25040/ntsh2022.02.03 // А

Y.V. Dumanskyi, S.I. Kirkilevskyi, O.M. Sulaeva, V.O. Polyasnyi, A.O. Mashukov, L.A. Kovalevska, R.R. Yarema, M.A. Оhorchak Impact of tumor molecular phenotype on survival of patients with gastric cancer after radical surgery // Exp. Oncol. – 2022. - 44(4): 324-326. DOI: 10.32471/exp-oncology.2312-8852.vol-44-no-4.18903 // А

M. Fetsych, N. Igumentseva, S. Ferneza, R. Yarema, N. Volodko. Cytokine-modulating influence of HIPEC on the intraperitoneal homeostasis formation in patients with ovarian cancer // Proc. Shevchenko Sci. Soc. Med. Sci. – 2023. - 72(2): 1-11. DOI: https://doi.org/10.25040/ntsh2023.02.// А

Р.Р. Ярема, М.А. Огорчак, П.І. Гиря, Ю.Я. Ковальчук, В.І. Сафіян, О.П. Рілінг, Б. Рау. Рак шлунка з імплантаційними метастазами: сучасні стратегії комбінованого лікування (огляд медичної літератури та результати власних досліджень) // Клінічна онкологія. – 2024. – Т.14, №1(53). – С. 1-8. DOI: 10.32471/clinicaloncology.2663-466X.53-1.31940 // Б

V. Kopetskyi, M. Antoniv, R. Yarema, V. Maksymovskyi, V. Chetverikova-Ovchinnik, V. Kryzhevskyi, N. Volodko, V. Gushchin, and A. Nikiforchin Building an efficient peritoneal surface malignancies program despite the lower-middle–income barriers: Ukraine experience // JCO Glob. Oncol. – 2024. - 10: e2300432. DOI:10.1200/GO.23.00432 // А

Пат. № 90205 Україна, МПК А 61 В 17/00; А 61 М 5/44; А 61 Р 31/00. Спосіб лікування хворих на рак шлунка з імплантаційними метастазами з використанням бідирекційної інтраопераційної хіміотерапії / заявник і патентовласник Ярема Р.Р - Опубл. 12.05.2014, Бюл. №9.

Пат. № 90531 Україна, МПК А 61 В 17/00; А 61 М 5/44; А 61 Р 31/00. Апарат для гіпертермічної інтраопераційної внутрішньочеревної хіміоперфузії / заявник і патентовласник Ярема Р.Р - Опубл. 26.05.2014, Бюл. №10.

R. Yarema, T. Fetsych, M. Ohorchak, G. Zubarev, Y. Olijnyk, M. Zubarev, P. Gyrya, Y. Kovalchuk, V. Safiyan. Hyperthermic intraperitoneal chemotherapy in combined treatment of local-advanced and peritoneal disseminated gastric cancer: results of prospective non-randomized study // Eur. J. Cancer. – 2013. – V. 49, suppl. 2. – P. S590. [Special issue: dedicated to 17th ECCO – 38th ESMO – 32th ESTRO European cancer congress, Amsterdam, Nederland, 2013].

R. Yarema, Т. Fetsych, М. Ohorchak, G. Zubarev, Y. Mylyan, Y. Oliynyk, M. Matusak, M. Zubarev, P. Gyrya, Y. Kovalchuk, V. Safiyan, T. Semotuk, T. Novicka, L. Laba, M. Yarysh. Hyperthermic intraperitoneal chemoperfusion in combined treatment of local-advanced and peritoneal disseminated gastric cancer // Ann. Surg. Oncol. – 2014. – V. 25, suppl. 2. – P. ii33. [Special issue: dedicated to the ESMO 16th World Congress on Gastrointestinal Cancer, Barselona, Spain, 2014].

R.R. Yarema, M.A. Ohorchak, G.P. Zubarev, Y.P. Mylyan, Y.Y. Oliynyk, M.G. Zubarev, P.I. Gyrya, Y.Y. Kovalchuk, V.I. Safiyan, T.G. Fetsych Hyperthermic intraperitoneal chemoperfusion in combined treatment of locally advanced and disseminated gastric cancer: results of a single-centre retrospective study // 9th International congress on peritoneal surface malignancies: abstract book. – Amsterdam (Nederland), 2014. – P. 31.

R. Yarema, , М. Ohorchak, Y. Mylyan, Y. Oliynyk, M. Zubarev, P. Gyrya, Y. Kovalchuk, V. Safiyan, Т. Fetsych. Hyperthermic intraperitoneal chemoperfusion in combined treatment of advanced gastric cancer: results of a single-centre study // Eur. J. Cancer. – 2015. – V. 51, suppl. S3. – P. S408. [Special issue: dedicated to the European Cancer Congress, Vienna, Austria, 2015].

Р.Р. Ярема, Т.Г. Фецич, М.А. Огорчак, Ю.П. Милян, Ю.Ю. Олійник, М.Г. Зубарєв, М.Б. Матусяк, П.І. Гиря, Ю.Я. Ковальчук, В.І. Сафіян, І.О. Карелін. Інтраперитонеально дисемінований рак шлунка: чи існує спосіб покращити прогноз? // Укр. радіол. журн. – 2016, №1. – С. 91-92. [Спеціальний випуск: присвячений матеріалам ХІІІ З’їзду онкологів та радіологів України, Київ, 2016].

R. Yarema, М. Ohorchak, Y. Oliynyk, M. Matusak, M. Zubarev, P. Gyrya, Y. Kovalchuk, V. Safiyan, I. Karelin, T. Semotuk, T. Novicka, L. Laba, M. Yarysh, Т. Fetsych. Hyperthermic intraperitoneal chemoperfusion in combined treatment of locally advanced and disseminated gastric cancer: results of a single-centre study // Eur. J. Surg. Oncol. – 2016. – V. 42, issue 9. – P. S75-S76. [Special issue: dedicated to the 36th Congress of the European Society of Surgical Oncology, Krakow, Poland, 2016].

R. Yarema, M. Ohorchak, Y. Oliynyk, M. Matusak, M. Zubarev, P. Gyrya, Y. Kovalchuk, V. Safiyan, I. Karelin, T. Semotuk, T. Novicka, L. Laba, M. Yarysh. Hyperthermic intraperitoneal chemotherapy (HIPEC) in combined treatment of locally advanced and disseminated gastric cancer: results of single-centre study // Ann. Oncol. – 2018. – V. 29, supl. 5. – P - 087. [Special issue: dedicated to the 20th ESMO World Congress on Gastrointestinal Cancer, Barselona, Spain, 2018].

R. Yarema, K. Rawicz-Pruszynski, J. Mielko, T. Fetsych, M. Ohorchak, W. Polkowski. Treatment of peritoneal metastases from gastric carcinoma: experience from Central-Eastern Europe // European Gastric Cancer Congres: abstract book. – Leiden, (Netherlands), 2018. – P. 37-39

R. Yarema, J. Mielko, T. Fetsych, M. Ohorchak, K. Rawicz-Pruszyński, T. Jastrzębski, P. Gyrya, Y. Kovalchuk, V. Safiyan, I. Karelin, A. Mashukov, V. Maksimovsky, V. Kopetskiy, Y. Kondratskiy, M. Paskonis, W. Polkowski. Hyperthermic intraperitoneal chemotherapy (HIPEC) in combined treatment of locally advanced and intraperitonealy disseminated gastric cancer: a retrospective cooperative Central-Eastern European study // Pleura and Peritoneum. – 2018. – V. 3, supl. 1. – P. sA171 – sA172. [Special issue: dedicated to the 11th International Workshop on Peritoneal Surface Malignancy, Paris, France, 2018].

R. Yarema, J. Mielko, T. Fetsych, M. Ohorchak, K. Rawicz-Pruszyński, A. Mashukov, V. Maksimovsky, T. Jastrzębski, P. Gyrya, Y. Kovalchuk, V. Safiyan, V. Kopetskiy, Y. Kondratskiy, M. Paskonis, W. Polkowski. Hyperthermic intraperitoneal chemotherapy (HIPEC) in combined treatment of locally advanced and intraperitoneally disseminated gastric cancer: A retrospective cooperative Central-Eastern European study // Eur. J. Surg. Oncol. – 2019. – 45(2). – P. e144. [Special issue: dedicated to the 38th ESSO Congress, Budapest, Hungary, 2018].

R. Yarema, J. Mielko, T. Fetsych, M. Ohorchak, M. Skorzewska, K. Rawicz-Pruszyński, A. Mashukov, V. Maksimovsky, T. Jastrzębski, P. Gyrya, Y. Kovalchuk, V. Safiyan, V. Kopetskiy, Y. Kondratskiy, M. Paskonis, W. Polkowski. Hyperthermic intraperitoneal chemotherapy (HIPEC) in combined treatment of locally advanced and intraperitonealy disseminated gastric cancer: A retrospective cooperative Central-Eastern European study // 13th International Gastric Cancer Congress (IGCC): abstract book. – Prague, (Czech Republic), 2019. – P. 37-38.

M. Ohorchak, R. Yarema, J. Mielko, T. Fetsych, M. Skorzewska, K. Rawicz-Pruszyński, A. Mashukov, V. Maksimovsky, T. Jastrzębski, P. Gyrya, Y. Kovalchuk, V. Safiyan, V. Kopetskiy, Y. Kondratskiy, M. Paskonis, W. Polkowski. A retrospective cooperative Central-Eastern European study of hyperthermic intraperitoneal chemotherapy (HIPEC) in treatment of locally advanced and intraperitonealy disseminated gastric cancer // Eur. J. Surg. Oncol. – 2022. – V. 48. – P. e180, abstract 0033. [Special issue: dedicated to the 40th ESSO Congress, Lisboa, Portugal, 2021].

R. Yarema, M. Ohorchak, P. Hyrya, Y. Kovalchuk, V. Safiyan, O. Rilinh Predictive nomogram of the risk of peritoneal relapse following radical gastric cancer surgery // Eur. J. Surg. Oncol. – 2023. – V. 49, issue 2. – P. E185. [Special issue: dedicated to the 41th Congress of the European Society of Surgical Oncology, Bordeaux, France, 2022]. DOI: https://doi.org/10.1016/j.ejso.2022.11.513.

R. Yarema, M. Ohorchak, O. Petronchak, R. Huley, P. Hyrya, Y. Kovalchuk, V. Safiyan, O. Rilinh. A genomically stable molecular type of gastric cancer as a predictor of peritoneal relapse after radical surgical treatment // Eur. J. Surg. Oncol. – 2023. – V. 49, issue 2. – P. E185-E186. [Special issue: dedicated to the 41th Congress of the European Society of Surgical Oncology, Bordeaux, France, 2022]. DOI: https://doi.org/10.1016/j.ejso.2022.11.514.

R. Yarema, M. Ohorchak, P. Hyrya, Y. Kovalchuk, V. Safiyan, O. Rilinh, T. Novicka, L. Laba, M. Yarysh, O. Trush. Does D2 lymph node dissection increase the risk of intraperitoneal recurrence of gastric cancer after radical surgery? // Eur. J. Surg. Oncol. – 2023. – V. 49, issue 2. – P. E186. [Special issue: dedicated to the 41th Congress of the European Society of Surgical Oncology, Bordeaux, France, 2022]. DOI: https://doi.org/10.1016/j.ejso.2022.11.515.

R. Yarema, M. Ohorchak, P. Hyrya, Y. Kovalchuk, V. Safiyan, Y. Oliynyk, M. Matusyak, O. Rilinh. Efficacy of standard treatment of gastric cancer with peritoneal metastases // Eur. J. Surg. Oncol. – 2023. – V. 49, issue 2. – P. E197. [Special issue: dedicated to the 41th Congress of the European Society of Surgical Oncology, Bordeaux, France, 2022]. DOI: https://doi.org/10.1016/j.ejso.2022.11.543.

R. Yarema, M. Ohorchak, P. Hyrya, Y. Kovalchuk, V. Safiyan, M. Matusyak, O. Rilinh, T. Novicka, L. Laba, S. Vorobec, V. Luciv. Does D2 lymph node dissection increase the risk of intraperitoneal recurrence of gastric cancer after radical surgery? // 15th International Gastric Cancer Congress (IGCC): abstract book. – Yokohama, (Japan), 2023. – P. P44-1.

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