Respiratory insufficiency related to copd accelerates systemic inflammation, under-nutrition, and angiogenesis in esophageal malignancies
A number of esophageal cancer patients suffer from respiratory insufficiency due to the coexistence of chronic obstructive pulmonary disease (COPD). Aim: To test the hypothesis that COPD-related systemic hypoxemia may result in accelerated inflammation, malnutrition, and angiogenesis in esophageal c...
Gespeichert in:
| Veröffentlicht in: | Experimental Oncology |
|---|---|
| Datum: | 2008 |
| Hauptverfasser: | , , , , , , , |
| Format: | Artikel |
| Sprache: | English |
| Veröffentlicht: |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
2008
|
| Schlagworte: | |
| Online Zugang: | https://nasplib.isofts.kiev.ua/handle/123456789/139020 |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| Назва журналу: | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| Zitieren: | Respiratory insufficiency related to copd accelerates systemic inflammation, under-nutrition, and angiogenesis in esophageal malignancies / M. Krzystek-Korpacka, M. Matusiewicz, D. Diakowska, K. Grabowski, K. Neubauer, I. Kustrzeba-Wojcicka, G. Terlecki, A. Gamian // Experimental Oncology. — 2008. — Т. 30, № 1. — С. 75–80. — Бібліогр.: 30 назв. — англ. |
Institution
Digital Library of Periodicals of National Academy of Sciences of Ukraine| id |
nasplib_isofts_kiev_ua-123456789-139020 |
|---|---|
| record_format |
dspace |
| spelling |
Krzystek-Korpacka, M. Matusiewicz, M. Diakowska, D. Grabowski, K. Neubauer, K. Kustrzeba-Wojcicka, I. Terlecki, G. Gamian, A. 2018-06-19T18:30:36Z 2018-06-19T18:30:36Z 2008 Respiratory insufficiency related to copd accelerates systemic inflammation, under-nutrition, and angiogenesis in esophageal malignancies / M. Krzystek-Korpacka, M. Matusiewicz, D. Diakowska, K. Grabowski, K. Neubauer, I. Kustrzeba-Wojcicka, G. Terlecki, A. Gamian // Experimental Oncology. — 2008. — Т. 30, № 1. — С. 75–80. — Бібліогр.: 30 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/139020 A number of esophageal cancer patients suffer from respiratory insufficiency due to the coexistence of chronic obstructive pulmonary disease (COPD). Aim: To test the hypothesis that COPD-related systemic hypoxemia may result in accelerated inflammation, malnutrition, and angiogenesis in esophageal cancer patients. Methods: Serum levels of C-reactive protein (CRP), albumin, transferrin, interleukin-1, interleukin-6, interleukin-8, TNF- a, platelet-derived growth factor (PDGF-BB), and midkine and patient BMI and weight-loss rate were determined and compared with blood oxygenation status (pO2, SaO2) in 35 esophageal cancer patients and 42 controls. Results: The incidence of cachexia tended to be higher in patients with systemic hypoxemia (67% vs 40%, p = 0.169). Mean SaO2 level was also significantly decreased in cachectic patients (90.3 vs 93.3%, p = 0.026) and pO2 exhibited a similar trend (58.0 vs 63.4 mmHg, p = 0.120). Transferrin (234 vs 316 mg/dl, p = 0.005) and albumin (31.9 vs 37.1 mg/dl, p = 0.002) concentrations were reduced and CRP was elevated (129.9 vs 54.7 mg/l, p = 0.004) in hypoxemic patients and correlated with pO2 (r = 0.47, p = 0.016; r = 0.48, p = 0.012; r = –0.37, p = 0.064) and SaO2 (r = 0.52, p = 0.006; r = 0.53, p = 0.006; r = –0.40, p = 0.042). Interleukin-6 (9.97 vs 2.21 pg/ml, p = 0.005) and midkine (2101 vs 944 pg/ml, p < 0.001) were elevated and PDGF-BB was decreased (12.2 vs 17.3 pg x 10-6/PLT, p = 0.014) in hypoxemic compared with normoxemic patients. Interleukin-6 and midkine negatively correlated with pO2 (r = –0.44, p = 0.016; r = –0.42, p = 0.011) and SaO2 (r = –0.54, p = 0.003; r = –0.57, p < 0.0001) and PDGF-BB correlated positively (r = 0.53, p = 0.003; r = 0.44, p = 0.020). Interleukin-8 level was affected by pO2 (r = -0.55, p = 0.015) and SaO2 (r = –0.55, p = 0.018) only in hypoxemic patients. Conclusions: COPD-related systemic hypoxemia negatively affects the status of esophageal cancer patients by accelerating inflammation, under-nutrition, and angiogenesis. Многие больные раком пищевода страдают от респираторной недостаточности из-за развития хронического обструктивного легочного заболевания (COPD). Цель: Проверить гипотезу о возможной связи системной гипоксемии, ассоциированной с COPD, с усилением воспалительных процессов, истощением и ангиогенезом у больных раком пищевода. Методы: у 35 больных раком пищевода и 42 здоровых доноров определяли уровень CRP, альбумина, трансферина, интерлейкина-1, интерлейкина-6, интерлейкина-8, TNF-α, PDGF-BB и мидкина в сыворотке крови, показатели BMI и потери веса больных, а также показатели уровня оксигенации крови (pO2 , SaO2 ). Результаты: частота возникновения кахексии была выше у больных с системной гипоксемией (67 против 40%, p = 0,169). Средний уровень SaO2 был также значительно снижен у больных с кахексией (90,3 против 93,3%, p = 0,026), с той же тенденцией и для уровня pO2 (58,0 против 63,4 mmHg, p = 0,120). Концентрации трансферина (234 против 316 мг/дл, p = 0,005) и альбумина (31,9 против 37,1 мг/дл, p = 0,002) были снижены, CRP повышен (129,9 против 54,7 мг/л, p = 0,004) у гипоксемических пациентов, что кореллировало с показателями pO2 (r = 0,47, p = 0,016; r = 0,48, p = 0,012; r = –0,37, p = 0,064) и SaO2 (r = 0,52, p = 0,006; r = 0,53, p = 0,006; r = –0,40, p = 0,042). Уровень интерлейкина-6 (9,97 против 2,21 pg/ml, p = 0,005) и мидкина (2101 против 944 pg/ml, p < 0,001) был также повышен, а уровень PDGF-BB понижен (12,2 против 17,3 pg × 10-6/PLT, p = 0,014) у гипоксемических больных по сравнению с показателями при нормоксемии. Уровни интерлейкина-6 и мидкина негативно кореллировали с показателями pO2 (r = –0,44, p = 0,016; r = –0,42, p = 0,011) и SaO2 (r = –0,54, p = 0,003; r = –0,57, p < 0,0001) и позитивно — с PDGF-BB (r = 0,53, p = 0,003; r = 0,44, p = 0,020). На уровень интерлейкина-8 влияли pO2 (r = –0,55, p = 0,015) и SaO2 (r = –0,55, p = 0,018) только у больных с гипоксемией. Выводы: ассоциированная с COPD системная гипоксемия негативно влияет на состояние больных раком пищевода за счет ускорения воспалительных процессов, истощения и ангиогенеза en Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України Experimental Oncology Uncategorized Respiratory insufficiency related to copd accelerates systemic inflammation, under-nutrition, and angiogenesis in esophageal malignancies Copd-зависимая респираторная недостаточность усиливает системное воспаление, истощение и ангиогенез при злокачественных опухолях пищевода Article published earlier |
| institution |
Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| collection |
DSpace DC |
| title |
Respiratory insufficiency related to copd accelerates systemic inflammation, under-nutrition, and angiogenesis in esophageal malignancies |
| spellingShingle |
Respiratory insufficiency related to copd accelerates systemic inflammation, under-nutrition, and angiogenesis in esophageal malignancies Krzystek-Korpacka, M. Matusiewicz, M. Diakowska, D. Grabowski, K. Neubauer, K. Kustrzeba-Wojcicka, I. Terlecki, G. Gamian, A. Uncategorized |
| title_short |
Respiratory insufficiency related to copd accelerates systemic inflammation, under-nutrition, and angiogenesis in esophageal malignancies |
| title_full |
Respiratory insufficiency related to copd accelerates systemic inflammation, under-nutrition, and angiogenesis in esophageal malignancies |
| title_fullStr |
Respiratory insufficiency related to copd accelerates systemic inflammation, under-nutrition, and angiogenesis in esophageal malignancies |
| title_full_unstemmed |
Respiratory insufficiency related to copd accelerates systemic inflammation, under-nutrition, and angiogenesis in esophageal malignancies |
| title_sort |
respiratory insufficiency related to copd accelerates systemic inflammation, under-nutrition, and angiogenesis in esophageal malignancies |
| author |
Krzystek-Korpacka, M. Matusiewicz, M. Diakowska, D. Grabowski, K. Neubauer, K. Kustrzeba-Wojcicka, I. Terlecki, G. Gamian, A. |
| author_facet |
Krzystek-Korpacka, M. Matusiewicz, M. Diakowska, D. Grabowski, K. Neubauer, K. Kustrzeba-Wojcicka, I. Terlecki, G. Gamian, A. |
| topic |
Uncategorized |
| topic_facet |
Uncategorized |
| publishDate |
2008 |
| language |
English |
| container_title |
Experimental Oncology |
| publisher |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| format |
Article |
| title_alt |
Copd-зависимая респираторная недостаточность усиливает системное воспаление, истощение и ангиогенез при злокачественных опухолях пищевода |
| description |
A number of esophageal cancer patients suffer from respiratory insufficiency due to the coexistence of chronic obstructive pulmonary disease (COPD). Aim: To test the hypothesis that COPD-related systemic hypoxemia may result in accelerated inflammation, malnutrition, and angiogenesis in esophageal cancer patients. Methods: Serum levels of C-reactive protein (CRP), albumin, transferrin, interleukin-1, interleukin-6, interleukin-8, TNF- a, platelet-derived growth factor (PDGF-BB), and midkine and patient BMI and weight-loss rate were determined and compared with blood oxygenation status (pO2, SaO2) in 35 esophageal cancer patients and 42 controls. Results: The incidence of cachexia tended to be higher in patients with systemic hypoxemia (67% vs 40%, p = 0.169). Mean SaO2 level was also significantly decreased in cachectic patients (90.3 vs 93.3%, p = 0.026) and pO2 exhibited a similar trend (58.0 vs 63.4 mmHg, p = 0.120). Transferrin (234 vs 316 mg/dl, p = 0.005) and albumin (31.9 vs 37.1 mg/dl, p = 0.002) concentrations were reduced and CRP was elevated (129.9 vs 54.7 mg/l, p = 0.004) in hypoxemic patients and correlated with pO2 (r = 0.47, p = 0.016; r = 0.48, p = 0.012; r = –0.37, p = 0.064) and SaO2 (r = 0.52, p = 0.006; r = 0.53, p = 0.006; r = –0.40, p = 0.042). Interleukin-6 (9.97 vs 2.21 pg/ml, p = 0.005) and midkine (2101 vs 944 pg/ml, p < 0.001) were elevated and PDGF-BB was decreased (12.2 vs 17.3 pg x 10-6/PLT, p = 0.014) in hypoxemic compared with normoxemic patients. Interleukin-6 and midkine negatively correlated with pO2 (r = –0.44, p = 0.016; r = –0.42, p = 0.011) and SaO2 (r = –0.54, p = 0.003; r = –0.57, p < 0.0001) and PDGF-BB correlated positively (r = 0.53, p = 0.003; r = 0.44, p = 0.020). Interleukin-8 level was affected by pO2 (r = -0.55, p = 0.015) and SaO2 (r = –0.55, p = 0.018) only in hypoxemic patients. Conclusions: COPD-related systemic hypoxemia negatively affects the status of esophageal cancer patients by accelerating inflammation, under-nutrition, and angiogenesis.
Многие больные раком пищевода страдают от респираторной недостаточности из-за развития хронического обструктивного
легочного заболевания (COPD). Цель: Проверить гипотезу о возможной связи системной гипоксемии, ассоциированной
с COPD, с усилением воспалительных процессов, истощением и ангиогенезом у больных раком пищевода.
Методы: у 35 больных раком пищевода и 42 здоровых доноров определяли уровень CRP, альбумина, трансферина,
интерлейкина-1, интерлейкина-6, интерлейкина-8, TNF-α, PDGF-BB и мидкина в сыворотке крови, показатели BMI и
потери веса больных, а также показатели уровня оксигенации крови (pO2
, SaO2
). Результаты: частота возникновения
кахексии была выше у больных с системной гипоксемией (67 против 40%, p = 0,169). Средний уровень SaO2
был также
значительно снижен у больных с кахексией (90,3 против 93,3%, p = 0,026), с той же тенденцией и для уровня pO2
(58,0
против 63,4 mmHg, p = 0,120). Концентрации трансферина (234 против 316 мг/дл, p = 0,005) и альбумина (31,9 против
37,1 мг/дл, p = 0,002) были снижены, CRP повышен (129,9 против 54,7 мг/л, p = 0,004) у гипоксемических пациентов,
что кореллировало с показателями pO2
(r = 0,47, p = 0,016; r = 0,48, p = 0,012; r = –0,37, p = 0,064) и SaO2
(r = 0,52,
p = 0,006; r = 0,53, p = 0,006; r = –0,40, p = 0,042). Уровень интерлейкина-6 (9,97 против 2,21 pg/ml, p = 0,005) и мидкина
(2101 против 944 pg/ml, p < 0,001) был также повышен, а уровень PDGF-BB понижен (12,2 против 17,3 pg × 10-6/PLT,
p = 0,014) у гипоксемических больных по сравнению с показателями при нормоксемии. Уровни интерлейкина-6 и мидкина
негативно кореллировали с показателями pO2
(r = –0,44, p = 0,016; r = –0,42, p = 0,011) и SaO2
(r = –0,54, p = 0,003;
r = –0,57, p < 0,0001) и позитивно — с PDGF-BB (r = 0,53, p = 0,003; r = 0,44, p = 0,020). На уровень интерлейкина-8
влияли pO2
(r = –0,55, p = 0,015) и SaO2
(r = –0,55, p = 0,018) только у больных с гипоксемией. Выводы: ассоциированная
с COPD системная гипоксемия негативно влияет на состояние больных раком пищевода за счет ускорения воспалительных
процессов, истощения и ангиогенеза
|
| issn |
1812-9269 |
| url |
https://nasplib.isofts.kiev.ua/handle/123456789/139020 |
| citation_txt |
Respiratory insufficiency related to copd accelerates systemic inflammation, under-nutrition, and angiogenesis in esophageal malignancies / M. Krzystek-Korpacka, M. Matusiewicz, D. Diakowska, K. Grabowski, K. Neubauer, I. Kustrzeba-Wojcicka, G. Terlecki, A. Gamian // Experimental Oncology. — 2008. — Т. 30, № 1. — С. 75–80. — Бібліогр.: 30 назв. — англ. |
| work_keys_str_mv |
AT krzystekkorpackam respiratoryinsufficiencyrelatedtocopdacceleratessystemicinflammationundernutritionandangiogenesisinesophagealmalignancies AT matusiewiczm respiratoryinsufficiencyrelatedtocopdacceleratessystemicinflammationundernutritionandangiogenesisinesophagealmalignancies AT diakowskad respiratoryinsufficiencyrelatedtocopdacceleratessystemicinflammationundernutritionandangiogenesisinesophagealmalignancies AT grabowskik respiratoryinsufficiencyrelatedtocopdacceleratessystemicinflammationundernutritionandangiogenesisinesophagealmalignancies AT neubauerk respiratoryinsufficiencyrelatedtocopdacceleratessystemicinflammationundernutritionandangiogenesisinesophagealmalignancies AT kustrzebawojcickai respiratoryinsufficiencyrelatedtocopdacceleratessystemicinflammationundernutritionandangiogenesisinesophagealmalignancies AT terleckig respiratoryinsufficiencyrelatedtocopdacceleratessystemicinflammationundernutritionandangiogenesisinesophagealmalignancies AT gamiana respiratoryinsufficiencyrelatedtocopdacceleratessystemicinflammationundernutritionandangiogenesisinesophagealmalignancies AT krzystekkorpackam copdzavisimaârespiratornaânedostatočnostʹusilivaetsistemnoevospalenieistoŝenieiangiogenezprizlokačestvennyhopuholâhpiŝevoda AT matusiewiczm copdzavisimaârespiratornaânedostatočnostʹusilivaetsistemnoevospalenieistoŝenieiangiogenezprizlokačestvennyhopuholâhpiŝevoda AT diakowskad copdzavisimaârespiratornaânedostatočnostʹusilivaetsistemnoevospalenieistoŝenieiangiogenezprizlokačestvennyhopuholâhpiŝevoda AT grabowskik copdzavisimaârespiratornaânedostatočnostʹusilivaetsistemnoevospalenieistoŝenieiangiogenezprizlokačestvennyhopuholâhpiŝevoda AT neubauerk copdzavisimaârespiratornaânedostatočnostʹusilivaetsistemnoevospalenieistoŝenieiangiogenezprizlokačestvennyhopuholâhpiŝevoda AT kustrzebawojcickai copdzavisimaârespiratornaânedostatočnostʹusilivaetsistemnoevospalenieistoŝenieiangiogenezprizlokačestvennyhopuholâhpiŝevoda AT terleckig copdzavisimaârespiratornaânedostatočnostʹusilivaetsistemnoevospalenieistoŝenieiangiogenezprizlokačestvennyhopuholâhpiŝevoda AT gamiana copdzavisimaârespiratornaânedostatočnostʹusilivaetsistemnoevospalenieistoŝenieiangiogenezprizlokačestvennyhopuholâhpiŝevoda |
| first_indexed |
2025-11-25T21:22:33Z |
| last_indexed |
2025-11-25T21:22:33Z |
| _version_ |
1850557515529453568 |
| fulltext |
Experimental Oncology ��� ������ ���� ��arc�� ����� ������ ���� ��arc�� ���arc�� ��� �� ��
Esop�ageal cancer is relatively rare� but nevert�e-
less one of t�e deadliest malignancies� wit� five-year
survival rates not exceeding 1�%. Squamous cell car-
cinoma remains t�e most prevalent type� but adeno-
carcinomas are increasing in number� especially in t�e
developed countries [1]. Tumor resection remains t�e
only effective treatment option; �owever� it is associ-
ated wit� �ig� morbidity and mortality rates [�]. In t�is
respect� t�e accurate identification of �ig�-risk patients
is of great clinical importance. However� prognostication
in esop�ageal malignancies continues to be c�alleng-
ing [�]. A number of models for outcome prediction�
based on various epidemiological� bioc�emical� and
clinico-pat�ological variables� �as been developed.
Preoperative systemic inflammation �as frequently been
recognized as an independent prognosticator of poor
outcome in esop�ageal malignancies [�]. Recently�
abnormal results of functional respiratory test �ave also
been found to be associated wit� postoperative deat�
in patients undergoing esop�agectomy [4].
A considerable number of esop�ageal cancer
patients suffers from c�ronic obstructive pulmonary
disease �COPD�� a condition defined as airflow limita-
tion� w�ic� is not fully reversible. T�e pat�ogeneses
of bot� COPD and esop�ageal cancer� of squamous
origin in particular� are closely linked to tobacco smoke
exposure. It is estimated t�at up to 9�% of patients wit�
esop�ageal cancers [�] and 9�% of COPD patients
[6] are current or former smokers. COPD is a clini-
cally significant causative factor of t�e development
of respiratory insufficiency in patients wit� esop�ageal
malignancies. In turn� respiratory insufficiency may
modify t�e course of cancer.
According to t�e current state of knowledge, bot�
cancer [�] and COPD [�� 9] are considered systemic
inflammatory diseases. T�e mec�anisms of systemic
inflammation in COPD are not fully understood. T�ere
is� �owever� a strong evidence for systemic oxidative
stress� quantitative and functional c�anges in perip�e-
ral blood proinflammatory cells� and an elevation of
proinflammatory cytokines [1�].
T�e results of our previous studies s�owed t�at
t�e coexistence of COPD-related respiratory insuffi-
ciency in patients wit� esop�agogastric malignancies
is linked wit� more aggressive cancer be�avior. Poor
systemic oxygenation status �as been associa ted
wit� locally advanced tumors� in w�ic� t�e key an-
giogenic factor� vascular endot�elial growt� factor A
�VEGF-A�� seems to participate [11]. COPD-related
systemic �ypoxemia may also stimulate t�e production
RESPIRATORY INSUFFICIENCY RELATED TO COPD
ACCELERATES SYSTEMIC INFLAMMATION, UNDER-NUTRITION,
AND ANGIOGENESIS IN ESOPHAGEAL MALIGNANCIES
M. Krzystek-Korpacka1, *, M. Matusiewicz1, D. Diakowska2, K. Grabowski2,
K. Neubauer3, I. Kustrzeba-Wojcicka1, G. Terlecki1, A. Gamian1, 4
1Department of Medical Biochemistry, Wroclaw Medical University, Wroclaw, Poland
2Department of Gastrointestinal and General Surgery, Wroclaw Medical University, Wroclaw, Poland
3Department of Gastroenterology and Hepatology, Wroclaw Medical University, Poland
4Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
A number of esophageal cancer patients suffer from respiratory insufficiency due to the coexistence of chronic obstructive pulmonary
disease (COPD). Aim: To test the hypothesis that COPD-related systemic hypoxemia may result in accelerated inflammation, mal-
nutrition, and angiogenesis in esophageal cancer patients. Methods: Serum levels of C-reactive protein (CRP), albumin, transferrin,
interleukin-1, interleukin-6, interleukin-8, TNF-α, platelet-derived growth factor (PDGF-BB), and midkine and patient BMI and
weight-loss rate were determined and compared with blood oxygenation status (pO2, SaO2) in 35 esophageal cancer patients and
42 controls. Results: The incidence of cachexia tended to be higher in patients with systemic hypoxemia (67% vs 40%, p = 0.169). Mean
SaO2 level was also significantly decreased in cachectic patients (90.3 vs 93.3%, p = 0.026) and pO2 exhibited a similar trend (58.0 vs
63.4 mmHg, p = 0.120). Transferrin (234 vs 316 mg/dl, p = 0.005) and albumin (31.9 vs 37.1 mg/dl, p = 0.002) concentrations were
reduced and CRP was elevated (129.9 vs 54.7 mg/l, p = 0.004) in hypoxemic patients and correlated with pO2 (r = 0.47, p = 0.016;
r = 0.48, p = 0.012; r = –0.37, p = 0.064) and SaO2 (r = 0.52, p = 0.006; r = 0.53, p = 0.006; r = –0.40, p = 0.042). Interleukin-6
(9.97 vs 2.21 pg/ml, p = 0.005) and midkine (2101 vs 944 pg/ml, p < 0.001) were elevated and PDGF-BB was decreased (12.2 vs
17.3 pg × 10-6/PLT, p = 0.014) in hypoxemic compared with normoxemic patients. Interleukin-6 and midkine negatively correlated
with pO2 (r = –0.44, p = 0.016; r = –0.42, p = 0.011) and SaO2 (r = –0.54, p = 0.003; r = –0.57, p < 0.0001) and PDGF-BB
correlated positively (r = 0.53, p = 0.003; r = 0.44, p = 0.020). Interleukin-8 level was affected by pO2 (r = -0.55, p = 0.015) and
SaO2 (r = –0.55, p = 0.018) only in hypoxemic patients. Conclusions: COPD-related systemic hypoxemia negatively affects the status
of esophageal cancer patients by accelerating inflammation, under-nutrition, and angiogenesis.
Key Words: esophageal cancer, COPD, hypoxemia, inflammation, cytokines.
Received: December 17, 2007.
*Correspondence: E-mail: krzystek@bioch.am.wroc.pl
Abbreviations used: APRP — acute phase-response proteins; COPD —
chronic obstructive pulmonary disease; CRP — C-reactive protein;
IL — interleukin; PDGF — platelet-derived growth factor; TNF — tumor
necrosis factor; VEGF-A — vascular endothelial growth factor A.
Exp Oncol ����
��� 1� �����
�6 Experimental Oncology ��� ������ ���� ��arc��
of ot�er inflammatory mediators and be responsible
for nutritional c�anges [1�]. T�erefore� t�e present
study was designed to test t�e �ypot�esis t�at t�e
coexistence of COPD-related �ypoxemia may result
in more pronounced inflammatory response and al-
terations in inflammatory� nutritional� and angiogenic
indices t�an in normoxemic patients wit� esop�ageal
cancer alone.
MATERIALS AND METHODS
Patients. T�e study group consisted of �� sub-
jects: �� esop�ageal cancer patients ��6 wit� squa-
mous cell carcinomas of t�e esop�agus and nine wit�
adenocarcinomas located in t�e lower esop�agus
and gastric cardia� and 4� �ealt�y individuals �con-
trols�. T�e controls were blood donors �6 females and
41 males� mean age: 44.� years�� acknowledged to
be �ealt�y on t�e basis of routine laboratory tests�
w�ose sera were obtained from t�e Regional Center of
Blood Donation and T�erapeutics� Wroclaw� Poland.
T�e cancer patients �� females and �� males� mean
age: 6� years� were clinically staged according to t�e
guidelines of t�e UICC TN� [1�] system on t�e basis of
upper digestive tract �udt� endoscopy wit� biopsy and
pat�ological examination� contrast radiograp�ic studies
of t�e udt wit� barium or gastrografin� posteroanterior
and lateral c�est radiograp�y� ultrasound examination
of t�e abdominal cavity and cervical nodes� t�orax and
abdominal cavity CT� and diagnostic laparotomy and
t�oracotomy. T�ere were seven patients wit� stage
II� 1� wit� stage III� and 1� wit� stage IV. T�e recruited
cancer patients �ad long �istories of �eavy smoking.
Analysis of blood gases was performed as part of t�e
routine pretreatment assessment of t�e patients’ gen-
eral condition. T�e measurement of oxygenation status
was conducted on t�e patients at rest breat�ing room
air. Partial respiratory insufficiency �pO� < 6� mmHg
wit�out �ypercapnia� was found in 19 of t�e cancer
patients and was related to t�e co-existence of COPD.
T�ere were no differences regarding disease stage
distribution ��1 vs 4�%� p = �.����� t�e presence of re-
gional metastasis �lymp� node metastasis� ��� vs �1%�
p = �.1���� or distant metastasis ��� vs ��%� p = �.����
between t�e groups of cancer patients wit�out and wit�
systemic �ypoxemia� respectively. However� t�ere was
a significantly �ig�er incidence of locally advanced
tumors �T4� in t�e �ypoxemic t�an in t�e normoxemic
patients ��9 vs �1%� p = �.����. T�e incidence of mild-
grade anemia �n = 19� was similar in bot� groups �6�%
vs 4�%� p = �.�1��. T�e study protocol was approved
by t�e �edical Et�ics Committee of Wroclaw �edical
University� Wroclaw� Poland.
Analytical methods. All examined indices were
determined in sera obtained from clotted �1� min� RT�
and centrifuged �1� min� ���� rpm� blood� w�ereby
t�e time regime was strictly ad�ered to. Hig�-sensitive
C-reactive protein �CRP� was determined by t�e latex
particle-en�anced immunoturbidimetric met�od wit�
t�e CRPex-HS CRP test provided from Good Biotec�
Corp. �Taiwan�� adjusted to t�e micro-manual proce-
dure. T�e test is based on t�e agglutination of serum
CRP wit� latex particles sensitized wit� t�e ΔFc fragment
of duck anti-CRP IgY antibodies increasing sample
turbidity� measured spectrop�otometrically at ��� nm.
Albumin levels were determined by t�e bromocresol
green met�od� based on t�e colorimetric assessment
�λ = 6�� nm� of t�e albumin-dye complex formed
at acidic pH. T�e reagents were supplied by Stamar
�Poland�. Transferrin was assessed by t�e en�anced
immunoturbidimetric met�od wit� a transferrin assay kit
provided by Stamar �Poland� according to t�e supplier’s
protocol adjusted to micro-assay conditions. T�e test is
based on en�anced reaction between serum transferrin
and rabbit anti-�uman transferrin antibodies causing
increased turbidity� measured spectrop�otometrically
at �9� nm. T�e levels of IL-1� IL-6� IL-�� and TNF-α were
determined wit� PeliKine Compact �uman cytokine
ELISA kits supplied by Sanquin �Holland� according
to t�e manufacturer’s instructions. �idkine concen-
trations were measured wit� a previously described
double-antibody sandwic� indirect ELISA �DASI-ELISA�
in w�ic� rabbit �Gentaur� Belgium� and goat �RnD Sys-
tems� USA� anti-�uman midkine polyclonal antibodies
were employed [14]. PDGF levels �PDGF-BB� were as-
sessed wit� Human PDGF-BB� Stratikine ELISA from
Strat�mann Biotec GmbH �Germany�. Due to t�e strong
relation between serum PDGF level and platelet count
�PLT�� we divided eac� individual PDGF concentration by
t�e subject’s PLT �t�e corrected PDGF factor — cPDGF
[pg x 1�-6/PLT]�.
Statistical analysis. T�e D’Agostino-Pearson test
for normality was applied for data distribution analysis.
Normally distributed data �CRP� transferrin� albumin� are
presented as arit�metic means� data distributed nor-
mally after log-transformation �IL-6� IL-�� midkine� and
cPDGF� as geometric means� and t�e ot�er values �IL-1
and TNF-α� as medians� all accompanied by 9�% CI.
T�e significance of differences between groups was
examined wit� t�e t-test for independent samples or t�e
�ann — W�itney U test wit� respect to data distribution.
Correlation analysis was conducted wit� Spearman’s
or Pearson’s test wit� respect to t�e data type and dis-
tribution. Differences in incidence rates were analyzed
wit� Fis�er’s exact test. All tests were two-sided and p
values ≤ �.�� were considered significant. Statistical
analysis was conducted wit� �edCalc® version 9.�.1.�
statistical software.
RESULTS
Relationship between COPD-related chronic re-
spiratory insufficiency and the nutritional status of
esophageal cancer patients. T�e nutritional status of
cancer patients was evaluated in terms of B�I and sub-
stantial involuntary weig�t loss �≥ �% in a t�ree-mont�
period�. T�ere was no difference �p = �.444� in t�e inci-
dence of underweig�t subjects among normoxemic and
�ypoxemic cancer patients. T�ere was� �owever� a clear
tendency towards diminis�ed pO� levels ��6.1 mmHg
�9�% CI: ��.��6�.�� vs 6�.� mmHg ���.1�66.��� p =
�.1�9� and reduced saturation �9�.�% ��6.4�9�.9� vs
Experimental Oncology ��� ������ ���� ��arc�� ����� ������ ���� ��arc�� ���arc�� ��� �� ��
9�.�% �91.��9�.6�� p = �.1��� in underweig�t cancer
patients compared wit� t�ose wit� correct weig�t.
Forty percent of normoxemic but 6�% of �ypoxemic
cancer patients suffered from substantial weig�t loss�
but t�e difference did not reac� statistical significance
�p = �.169�. Similarly� t�ere was a trend towards re-
duced pO� in t�e cancer patients experiencing weig�t
loss compared wit� t�ose w�ose weig�t remained
unaltered ���.� mmHg ���.��6�.1� vs 6�.4 mmHg
���.��6�.9�� p = �.1���. T�is trend reac�ed statistical
significance w�en SaO� instead of pO� was analyzed
�9�.�% ���.��9�.4� and 9�.�% �91.��94.��� respec-
tively� p = �.��6�.
Relationship between COPD-related chronic re-
spiratory insufficiency and acute-phase response
proteins (APRP) in esophageal cancer patients.
T�e levels of transferrin and albumin were significantly
reduced in cancer patients wit� COPD-related c�ronic
respiratory insufficiency �Table 1� and positively cor-
related wit� pO� and SaO� levels �Table ��. In turn� t�e
le vels of CRP were significantly elevated in cancer
patients wit� respiratory insufficiency �see Table 1�
and negatively correlated wit� pO� and SaO� levels
�see Table ��.
Relationship between COPD-related chronic
respiratory insufficiency and circulating proinflam-
matory and proangiogenic cytokines. T�e levels of
circulating IL-6 and midkine were elevated in cancer
patients wit� respiratory insufficiency� t�e concentra-
tions of IL-� and TNF-α did not differ� w�ile cPDGF was
significantly decreased and IL-1 ex�ibited a similar
tendency �see Table 1�.
IL-6 and midkine negatively correlated wit� pO� and
SaO�� w�ile cPDGF and IL-1 eit�er correlated positively
or ex�ibited suc� a tendency. No correlation between
t�e indices of systemic oxygenation status and t�e levels
of circulating IL-� and TNF-α was found �see Table ��.
However� in t�e subgroup of cancer patients wit� c�ronic
respiratory insufficiency� significant negative correlations
between IL-� and pO� �r = ��.��� p = �.�1�� as well as
SaO� �r = ��.��� p = �.�1�� were demonstrated. T�ere
was also a tendency towards a positive relations�ip be-
tween IL-1 and SaO� �r = �.46� p = �.����.
Relationship between the extent of the primary
tumor (disease T stage), acute-phase proteins,
and proinflammatory and proangiogenic cyto-
kines. T�ere was a direct correlation between pO�
�r = ��.49� p = �.��4� or SaO� �r = ��.��� p = �.����
levels and tumor T stage in t�e esop�ageal cancer
patients. Circulating CRP� IL-6� and midkine concen-
trations increased along wit� increasing tumor extent�
w�ile t�e levels of albumin and transferrin tended
to decrease. T�e extent of t�e primary tumor �ad
no impact on IL-1� IL-�� TNF-α� or cPDGF levels in
t�e examined co�ort of esop�ageal cancer patients
�Table ��.
Table 2. The relationship between the indices of oxygenation status and
serum levels of acute phase proteins, proinflammatory and proangiogenic
cytokines in esophageal cancer patients
Correlation with indices of oxygen status
pO2 SaO2
CRP r = –0.37, p = 0.064 r = –0.40, p = 0.042*
Albumin r = 0.48, p = 0.012* r = 0.53, p = 0.006*
Transferrin r = 0.47, p = 0.016* r = 0.52, p = 0.006
IL-1 r = 0.27, p = 0.145 r = 0.34, p = 0.078
IL-6 r = –0.44, p = 0.016* r = –0.54, p = 0.003*
IL-8 r = –0.02, p = 0.924 r = –0.24, p = 0.179
TNF-α r = –0.04, p = 0.828 r = –0.02, p = 0.905
Midkine r = –0.42, p = 0.011* r = –0.57, p < 0.001*
cPDGF r = 0.53, p = 0.003* r = 0.44, p = 0.020*
*Statistically significant.
Table 3. The relationship between the extent of primary tumor (disease
T stage) and serum levels of acute phase proteins and proinflammatory
and proangiogenic cytokines in esophageal cancer patients
Correlation with tumor T stage
CRP r = 0.67, p < 0.001*
Albumin r = –0.33, p = 0.099
Transferrin r = –0.37, p = 0.066
IL-1 r = 0.14, p = 0.468
IL-6 r = 0.75, p < 0.001*
IL-8 r = 0.26, p = 0.139
TNF-α r = –0.03, p = 0.863
Midkine r = 0.45, p = 0.008*
cPDGF r = –0.19, p = 0.322
*Statistically significant.
Relationship between IL-6 levels and other
variables. Acute-p�ase proteins �ig�ly correlated wit�
IL-6 levels. T�ere was a substantial correlation wit� IL-�
and a moderate correlation wit� midkine �Table 4�.
Table 4. The relationship between circulating IL-6 and serum levels of
acute phase proteins and proinflammatory and proangiogenic cytokines in
esophageal cancer patients
Correlation with circulating IL-6
CRP r = 0.73, p < 0.0001*
Albumin r = –0.60, p = 0.001*
Transferrin r = –0.77, p < 0.0001*
IL-1 r = –0.02, p = 0.901
IL-8 r = 0.56, p = 0.002*
TNF-α r = –0.02, p = 0.932
Midkine r= 0.38, p = 0.042*
cPDGF r = –0.03, p = 0.894
*Statistically significant.
Relationship between COPD-related chronic
respiratory insufficiency and circulating proin-
flammatory cells. T�ere was a significant increase
in t�e number of circulating w�ite blood cells in t�e
cancer patients wit� systemic �ypoxemia� an effect of
t�e elevation of neutrop�ils� but not lymp�ocytes. T�e
Table 1. Alterations in the concentrations of acute-phase proteins and proinflammatory and proangiogenic cytokines in esophageal cancer patients with
respect to their oxygenation status
Healthy controls (C) Esophageal cancer patients p values for pair-wise comparisons
Normoxemic (N) Hypoxemic (H) C vs N C vs H N vs H
CRP [mg/l] 6.8 (0.6–13.1) 54.7 (14.7–95.0) 129.9 (97.3–162.5) 0.024* < 0.0001* 0.004*
Albumin [g/l] 39.4 (36.7–42.0) 37.1 (34.9–39.2) 31.9 (29.4–34.4) 0.173 0.0001* 0.002*
Transferrin [mg/dl] 293 (276–309) 316 (291–342) 234 (184–284) 0.104 0.028* 0.005*
IL-1 [pg/ml] 0.79 (0–2.10) 3.18 (1.96–4.73) 2.58 (1.63–3.87) 0.002* 0.006* 0.254
IL-6 [pg/ml] 0.70 (0.56–0.87) 2.21 (1.13–4.33) 9.97 (4.58–21.74) 0.003* < 0.0001* 0.005*
IL-8 [pg/ml] 9.68 (7.99–11.74) 33.7 (19.5–58.5) 32.8 (19.6–54.9) < 0.001* 0.0001* 0.936
TNF-α [pg/ml] 0.66 (0.33–1.59) 0.89 (0–3.91) 1.02 (0.44–1.99) 0.449 0.275 0.913
Midkine [pg/ml] 25 (10–63) 944 (669–1331) 2101 (1542–2861) < 0.0001* < 0.0001* < 0.001*
cPDGF pgx10-6/PLT 22.5 (19.2–26.3) 17.3 (14.0–21.3) 12.2 (10.0–14.8) 0.055 < 0.0001* 0.014*
*Statistically significant.
�� Experimental Oncology ��� ������ ���� ��arc��
increase in platelet count was not found to be signifi-
cant �Table ��. A significant correlation was observed
only between leukocyte count and bot� pO� �r = ��.���
p = �.�4�� and SaO� �r = ��.4�� p = �.����.
Table 5. Alterations in the counts of proinflammatory cells in esophageal
cancer patients in response to systemic hypoxemia
Esophageal cancer patients p valueNormoxemic Hypoxemic
Leukocyte count [× 103/μl] 8.37 (6.85–9.90) 11.77 (9.80–13.74) 0.009*
Neutrophil count [× 103/μl] 6.09 (4.52–7.65) 9.10 (6.92–11.28) 0.025*
Lymphocyte count [× 103/μl] 1.70 (1.25–2.15) 1.81 (1.45–2.16) 0.700
Platelet count [× 103/μl] 292 (214–370) 322 (279–365) 0.480
*Statistically significant.
Of all t�e studied indices� t�e acute-p�ase proteins
albumin �r = ��.4�� p = �.����� transferrin �r = ��.41�
p = �.���� and CRP �r = �.��� p < �.���1� as well as
IL-6 �r = �.6�� p < �.��1� and midkine �r = �.�6� p =
�.���� correlated wit� leukocyte count. Similarly� only
albumin �r = ��.46� p = �.����� transferrin �r = ��.46�
p = �.��6�� CRP �r = �.��� p < �.���1�� and IL-6 �r =
�.6�� p < �.��1� correlated wit� neutrop�il count. No
significant correlation wit� lymp�ocyte count was
observed� w�ile only CRP �r = �.44� p = �.��6� and
midkine �r = �.��� p = �.���� correlated wit� platelet
count and IL-6 tended to ex�ibit a similar trend �r =
�.��� p = �.�6��.
DISCUSSION
Progressive worsening of a patient’s nutritional
status and loss of body weig�t leading to t�e deve-
lopment of cac�exia is a common consequence of
esop�ageal cancer [1�] and COPD [6� 1�]. Unintended
weig�t loss is observed in about ��% of COPD patients
wit� c�ronic respiratory failure [1�] and in about ��%
of newly diagnosed esop�ageal cancer patients [16].
Tissue �ypoxia� an effect of systemic �ypoxemia� �as
been implicated in increasing t�e metabolic rate [1�].
We t�erefore investigated� w�et�er t�e presence of
COPD-related respiratory insufficiency was associa-
ted wit� a �ig�er prevalence of under-nutrition in
patients wit� esop�ageal malignancies. However� we
failed to demonstrate suc� an association in t�e cur-
rent co�ort of patients. B�I �as been criticized as an
inadequate index of cancer cac�exia since it excludes
t�ose cancer patients w�o ex�ibit normal B�I alt�oug�
t�ey expe rience substantial weig�t loss [1�� 1�]. Ac-
cordingly� t�e measurement of oxygenation status
revealed a clear tendency towards decreased oxygen
partial pressure and saturation in cancer patients wit�
COPD-related respiratory insufficiency. T�e presence
of accelerated and involuntary weig�t loss is consid-
ered a stronger indicator of cancer cac�exia [1�].
Indeed� t�e diffe rences obtained wit� t�is index were
more significant. T�e lack of statistical significance
may result from t�e relatively low number of analyzed
cases� inadequate to demonstrate differences in t�e
incidence of weig�t loss. T�e prevalence of weig�t
loss in esop�agogastric cancer is �ig�� reac�ing ��%
of newly diagnosed cases [1�]. On t�e ot�er �and�
esop�ageal cancer is rare [1] and COPD affects only
1�% of smokers [6]� resulting in a limited number of
patients available for t�e current study.
Supporting t�e t�esis of a worsening of nutritional
status of cancer patients by systemic �ypoxemia�
we found a significant decrease in t�e levels of nutri-
tional markers� transferrin and albumin� in patients wit�
COPD-related respiratory insufficiency. �oreover� t�e
concentrations of bot� markers positively correlated
wit� pO� and SaO� levels. T�e association between
systemic �ypoxemia and cac�exia was furt�er sup-
ported by t�e elevation in IL-6 levels� a procac�ectic
cytokine found to be elevated in esop�agogastric
cancer patients wit� substantial weig�t loss [1�]� and
its negative correlation wit� pO� and SaO�. T�ere was
no difference in t�e levels of t�e ot�er two key pro-
cac�ectic cytokines TNF-α and IL-1. However� t�eir
up-regulation seems to be time limited and to �ave
only a local range� w�ile systemic elevation �as been
rarely detected [19].
Tumor tissue �ypoxia �as been linked wit� ampli-
fied aggressiveness of neoplasms [��]� but t�e effect
of systemic �ypoxemia �as not been extensively stu-
died. We previously linked systemic �ypoxemia wit�
a �ig�er extent of primary tumor and elevated angio-
genic potential� manifested by a significant increase
in circulating VEGF-A [11]. T�e negative impact on
nutritional status reported in t�e present study furt�er
contributes to t�e adverse effects of systemic �ypo-
xemia in esop�ageal cancer patients.
In addition to t�e previously reported VEGF-A
elevation [11]� �ere we revealed a systemic �ypo-
xemia-related increase in t�e concentration of mid-
kine� anot�er mediator of angiogenesis [�1]. We also
confirmed midkine’s relations�ip to disease T stage�
as demonstrated earlier [��]. �idkine’s elevation in
response to �ypoxia t�us provides furt�er evidence for
t�e existence of a link between systemic �ypoxemia
and greater cancer aggressiveness� mediated by an-
giogenic factors. Similarly to VEGF-A [��]� midkine �as
previously been s�own to be up-regulated by �ypoxia-
inducible factor 1α �HIF-1α� [��]� a key redox-sensitive
transcription factor [��]. �oreover� t�e binding sites
for nuclear factor κB �NFκB� and activator protein-1
�AP-1�� ot�er oxygen-dependent transcription factors
[��]� �ave been demonstrated in t�e midkine promoter
sequence as well [�4]. However� midkine oversecretion
in response to systemic �ypoxemia �as not been re-
ported so far. �idkine elevation may reflect t�e ongo-
ing process of repair and restructuring of t�e airways in
t�e course of COPD [��]� since midkine’s involvement
in lung remodeling �as been previously reported [��].
Interestingly� we s�owed IL-� elevation in response to
a tumor-bearing state� but no furt�er rise in �ypoxemic
patients� alt�oug� a gene of t�is proinflammatory and
proangiogenic cytokine is transactivated by NFκB [��].
Nevert�eless� IL-� level increased along wit� worsen-
ing of patients’ oxygenation status� but t�e impact of
systemic �ypoxemia was demonstrated exclusively in
patients wit� respiratory insufficiency.
Surprisingly� some pro-angiogenic cytokines
appear to be inversely regulated. We observed a
decrease in cPDGF-BB levels in cancer patients wit�
Experimental Oncology ��� ������ ���� ��arc�� �9��� ������ ���� ��arc�� �9�arc�� �9� �9 �9
COPD-related respiratory insufficiency� despite t�e
fact t�at PDGF gene �as bot� a �ypoxia-responsive
element �HRE� sequence as well as a binding site for
AP-1 [��]. �oreover� PDGF �as been implicated in t�e
remodeling of t�e airway wall in t�e course of COPD
[�6]. We �ave no explanation for t�is p�enomenon� but
it seems to indeed be related to t�e factor’s diminis�ed
secretion� since platelet count was not significantly
altered. �oreover� despite t�e lack of differences in
mean levels� IL-1 also appears to be negatively af-
fected by t�e decrease in blood oxygenation.
T�e depletion of albumin and transferrin levels may
contribute to en�anced oxidative stress and inflam-
matory response in cancer patients wit� COPD. Cor-
respondingly� we demonstrated an elevation in CRP�
inversely correlating wit� systemic oxygenation status.
CRP elevation �as been found to be an independent
prognostic factor in esop�ageal cancer [�]. Up-regu-
lation of CRP secretion �as also been demonstrated
in COPD� being more pronounced during disease
exacerbation [1�]. Our study s�ows furt�er CRP ele-
vation in cancer patients wit� coexisting respiratory
insufficiency related to COPD. However� t�e impact of
systemic �ypoxemia on CRP concentration� similarly
to transferrin and albumin� mig�t be mediated by IL-6�
a well-known modulator of t�e acute-p�ase response
[��]. Indeed� t�e levels of acute-p�ase proteins more
strongly correlated wit� IL-6 t�an wit� pO� and SaO�
levels. Interestingly� CRP elevation markedly reflected
t�e increase in t�e extent of primary tumor� suggesting
t�at tumor cells mig�t participate in CRP secretion.
T�is is in agreement wit� t�e results of immuno�isto-
c�emical studies by Nozoe et al. [��] demonstrating
CRP expression in esop�ageal squamous cell carci-
noma cancer tissues.
In line wit� CRP elevation� we also observed a sig-
nificant increase in leukocyte and neutrop�il counts�
moderately related to pO� and SaO� levels. T�is obser-
vation is consistent wit� t�e current knowledge on t�e
involvement of perip�eral neutrop�ils in t�e systemic
effects of COPD [1�]. A substantial increase in t�e
number of inflammatory cells as well as en�anced cell
activation �ave been linked to t�e presence of elevated
levels of circulating c�emoattractants [�9]. �idkine�
demonstrated �ere to be oversecreted in cancer
patients wit� systemic COPD-related �ypoxemia� is a
potent neutrop�il and macrop�age c�emoattractant
[��]. Correspondingly� midkine levels correlated wit�
w�ite blood cell counts in t�e examined co�ort of
cancer patients.
We �ypot�esized t�at COPD-related respiratory
insufficiency in patients wit� esop�ageal malignancies
may be associated wit� more pronounced inflamma-
tion� under-nutrition� and angiogenesis. Generally� our
results seem to confirm t�is �ypot�esis. Taking into ac-
count t�e impact t�ese factors �ave on pro gnosis� we
believe t�at our results may contribute not only to a better
understanding of t�e effect systemic �ypoxemia exerts
on t�e course of cancer disease� but may �elp in better
management of esop�ageal cancer patients as well.
REFERENCES
1. Mariette C, Piessen G, Triboulet JP. Therapeutic
strategies in oesophageal carcinoma: role of surgery and other
modalities. Lancet Oncol 2007; 8: 545–53.
2. Crumley ABC, McMillan DC, McKernan M, et al. An ele
vated Creactive protein concentration, prior to surgery, predicts
poor cancerspecific survival in patients undergoing resection for
gastroesophageal cancer. Br J Cancer 2006; 94: 1568–71.
3. Deans DA, Wigmore SJ, de Beaux AC, et al. Clinical
prognostic scoring system to aid decisionmaking in gastro
oesophageal cancer. Br J Surg 2007; 94: 1501–8.
4. Sanz L, Ovejero VJ, Gonzalez JJ, et al. Mortality risk scales
in esophagectomy for cancer: their usefulness in preoperative
patient selection. Hepatogastroenterology 2006; 53: 869–73.
5. Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J
Med 2003; 349: 2241–52.
6. McNee W. Oxidants in COPD. Curr Drug Targ Inflamm
Allergy 2005; 4: 627–41.
7. Aggarwal BB, Shishodia S, Sandur SK, et al. Inflamma
tion and cancer: how hot is the link? Biochem Pharmacol 2006;
72: 1605–21.
8. Oudijk E-JD, Lammers J-WJ, Koenderman L. Systemic
inflammation in chronic obstructive pulmonary disease. Eur
Respir J 2003; 22: 5s–13s.
9. Remels AH, Gosker HR, van der Velden J, et al. Sys
temic inflammation and skeletal muscle dysfunction in chronic
obstructive pulmonary disease: state of the art and novel in
sights in regulation of muscle plasticity. Clin Chest Med 2007;
28: 537–52.
10. Augusti AGN, Noguera A, Sauleda J, et al. Systemic
effects of chronic obstructive pulmonary disease. Eur Respir J
2003; 21: 347–60.
11. Krzystek-Korpacka M, Matusiewicz M, Diakowska D,
et al. Impact of systemic hypoxemia on cancer aggressiveness
and circulating vascular endothelial growth factors A and C in
gastroesophageal cancer patients with chronic respiratory insuf
ficiency. Exp Oncol 2007; 29: 236–42.
12. Dourdado VZ, Tanni SE, Vale SA, et al. Systemic manifes
tations in chronic obstructive pulmonary disease. J Bras Pneumol
2006; 32: 161–71.
13. Sobin LH, Wittekind C. TNM Classification of Malig
nant Tumors, 6th ed. New Jersey: Jon Wiley & Sons, Hoeboken,
2002.
14. Krzystek-Korpacka M, Matusiewicz M, Grabowski K,
et al. Immunoenzymatic method for midkine determination in
serum. Adv Clin Exp Med 2006; 15: 247–52.
15. Ockenga I, Valentini L. Review article: anorexia and
cachexia in gastrointestinal cancer. Aliment Pharmacol Ther
2005; 22: 583–94.
16. Saini A, Al-Shanti N, Stewart CEH. Wastemanagement
cytokines, growth factors and cachexia. Cytokine Growth Factor
Rev 2006; 17: 475–86.
17. Krzystek-Korpacka M, Matusiewicz M, Diakowska D,
et al. Impact of weight loss on circulating IL1, IL6, IL8,
TNFα, VEGFA, VEGFC and midkine in gastroesophageal
cancer patients. Clin Bioch 2007; 40: 1353–60.
18. Inui A. Cancer cachexiaanorexia syndrome: current
issues in research and management. CA Cancer J Clin 2002;
52: 72–91.
19. Lelbach A, Muzes G, Feher J. Current perspectives of
catabolic mediators of cancer cachexia. Med Sci Monit 2007;
13: RA168–73.
20. Vaupel P, Mayer A. Hypoxia and anemia: effects on
tumor biology and treatment resistance. Transfus Clin Biol
2005; 12: 5–10.
�� Experimental Oncology ��� ������ ���� ��arc��
21. Beecken W-D, Kramer W, Jonas D. New molecular me
diators in tumor angiogenesis. J Cell Mol Med 2000; 4: 262–9.
22. Krzystek-Korpacka M, Matusiewicz M, Diakowska D,
et al. Serum midkine depends on lymph node involvement and
correlates with circulating VEGFC in esophageal squamous cell
carcinoma. Biomarkers 2007; 12: 403–13.
23. Reynolds PR, Mucenski ML, Le Cras TD, et al. Midkine
is regulated by hypoxia and causes pulmonary vascular remodel
ling. J Biol Chem 2004; 279: 37124–32.
24. Uehara K, Matsubara S, Kadomatsu K, et al. Genomic
structure of human midkine (MK), a retinoic acidresponsive
growth/differentiation factor. J Biochem 1992; 111: 563–7.
25. Larsson K. Aspects on pathophysiological mechanisms
in COPD. J Intern Med 2007; 262: 311–40.
26. Chung KF. Inflammatory mediators in chronic obstruc
tive pulmonary disease. Curr Drug Targ Inflamm Allergy 2005;
4: 619–25.
27. Gabay C. Interleukin6 and chronic inflammation. Ar
thritis Res Ther 2006; 8 (Suppl 2): S3.
28. Nozoe T, Korenaga D, Futatsugi M, et al. Immunohis
tochemical expression of Creactive protein in squamous cell
carcinoma of the esophagussignificance as a tumor marker.
Cancer Lett 2003; 192: 89–95.
29. Tetley TD. Inflammatory cells and chronic obstructive pulmo
nary disease. Curr Drug Targ Inflamm Allergy 2005; 4: 607–18.
30. Muramatsu T. Midkine and pleiotrophin: two related
proteins involved in development, survival, inflammation and
tumorigenesis. J Biochem 2002; 132: 359–71.
COPD-ЗАВИСИМАЯ РЕСПИРАТОРНАЯ НЕДОСТАТОЧНОСТЬ
УСИЛИВАЕТ СИСТЕМНОЕ ВОСПАЛЕНИЕ, ИСТОЩЕНИЕ
И АНГИОГЕНЕЗ ПРИ ЗЛОКАЧЕСТВЕННЫХ
ОПУХОЛЯХ ПИЩЕВОДА
Многие больные раком пищевода страдают от респираторной недостаточности из-за развития хронического обструк-
тивного легочного заболевания (COPD). Цель: Проверить гипотезу о возможной связи системной гипоксемии, ассоци-
ированной с COPD, с усилением воспалительных процессов, истощением и ангиогенезом у больных раком пищевода.
Методы: у 35 больных раком пищевода и 42 здоровых доноров определяли уровень CRP, альбумина, трансферина,
интерлейкина-1, интерлейкина-6, интерлейкина-8, TNF-α, PDGF-BB и мидкина в сыворотке крови, показатели BMI и
потери веса больных, а также показатели уровня оксигенации крови (pO2, SaO2). Результаты: частота возникновения
кахексии была выше у больных с системной гипоксемией (67 против 40%, p = 0,169). Средний уровень SaO2 был также
значительно снижен у больных с кахексией (90,3 против 93,3%, p = 0,026), с той же тенденцией и для уровня pO2 (58,0
против 63,4 mmHg, p = 0,120). Концентрации трансферина (234 против 316 мг/дл, p = 0,005) и альбумина (31,9 против
37,1 мг/дл, p = 0,002) были снижены, CRP повышен (129,9 против 54,7 мг/л, p = 0,004) у гипоксемических пациентов,
что кореллировало с показателями pO2 (r = 0,47, p = 0,016; r = 0,48, p = 0,012; r = –0,37, p = 0,064) и SaO2 (r = 0,52,
p = 0,006; r = 0,53, p = 0,006; r = –0,40, p = 0,042). Уровень интерлейкина-6 (9,97 против 2,21 pg/ml, p = 0,005) и мидкина
(2101 против 944 pg/ml, p < 0,001) был также повышен, а уровень PDGF-BB понижен (12,2 против 17,3 pg × 10-6/PLT,
p = 0,014) у гипоксемических больных по сравнению с показателями при нормоксемии. Уровни интерлейкина-6 и мидкина
негативно кореллировали с показателями pO2 (r = –0,44, p = 0,016; r = –0,42, p = 0,011) и SaO2 (r = –0,54, p = 0,003;
r = –0,57, p < 0,0001) и позитивно — с PDGF-BB (r = 0,53, p = 0,003; r = 0,44, p = 0,020). На уровень интерлейкина-8
влияли pO2 (r = –0,55, p = 0,015) и SaO2 (r = –0,55, p = 0,018) только у больных с гипоксемией. Выводы: ассоциированная
с COPD системная гипоксемия негативно влияет на состояние больных раком пищевода за счет ускорения воспалительных
процессов, истощения и ангиогенеза.
Ключевые слова: рак пищевода, COPD, гипоксемия, воспаление, цитокины.
Copyright © Experimental Oncology, 2008
|