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Preservation of tumour oxygen after hyperbaric oxygenation monitored by magnetic resonance imaging

Preservation of tumour oxygen after hyperbaric oxygenation monitored by magnetic resonance imaging British Journal of Cancer (2000) 82(1), 88–92 © 2000 Cancer Research Campaign Article no. bjoc.1999.0882 Preservation of tumour oxygen after hyperbaric oxygenation monitored by magnetic resonance imaging 1 1,2 3 4 1 Y Kinoshita , K Kohshi , N Kunugita , T Tosaki and A Yokota 1 2 3 Departments of Neurosurgery, Hyperbaric Medicine and Environmental Health, University of Occupational and Environmental Health, 1–1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan; Medical Business Group, Daido Hoxan Inc., Tokyo, Japan Summary Hyperbaric oxygen (HBO) has been proposed to reduce tumour hypoxia by increasing the dissolved molecular oxygen in tissue. Using a non-invasive magnetic resonance imaging (MRI) technique, we monitored the changes in MRI signal intensity after HBO exposure because dissolved paramagnetic molecular oxygen itself shortens the T1 relation time. SCCVII tumour cells transplanted in mice were used. The molecular oxygen-enhanced MR images were acquired using an inversion recovery-preparation fast low angle shot (IR-FLASH) sequence sensitizing the paramagnetic effects of molecular oxygen using a 4.7 tesla MR system. MR signal of muscles decreased rapidly and returned to the control level within 40 min after decompression, whereas that of tumours decreased gradually and remained at a high level 60 min after HBO exposure. In contrast, the signal from the tumours in the normobaric oxygen group showed no significant change. Our data suggested that MR signal changes of tumours and muscles represent an alternation of extravascular oxygenation. The preserving tumour oxygen concentration after HBO exposure may be important regarding adjuvant therapy for cancer patients. © 2000 Cancer Research Campaign Keywords: hyperbaric oxygenation; molecular oxygen; paramagnetism; relaxation time; magnetic resonance imaging Tumour oxygenation is known to enhance the efficacy of radio- cancer. We irradiated human malignant gliomas 15 min after HBO therapy, because the presence of hypoxic tumour cells is consid- exposure based on the hypothesis that elevated partial oxygen ered to be one of the major reasons for failure to control tumours tension (PO ) in the tumours was maintained for substantial (Hall, 1994). Regarding hypoxic tumour cells, it is also known that periods after decompression (Kohshi et al, 1996). Using invasive ionizing radiation and some chemotherapeutic agents are less measurements, it was reported that tissue PO increased slowly effective at low oxygen levels. Many studies on tumour oxygen during HBO exposure and that the decline in PO after HBO was tension levels using direct invasive measurements have been slower in subcutaneous tissues than in muscles (Wells et al, 1977), reported (Vaupel et al, 1984; Rampling et al, 1994; Brizel et al, but no study on PO change of tumours after HBO has been 1996; Collingridge et al, 1997; Helmlinger et al, 1997; Al-Hallaq reported. The purpose of this study was to non-invasively monitor et al, 1998). Non-invasively, there has been increasing interest in the tumour PO changes produced by HBO exposure using MRI, measurements of changes in tissue oxygen tension using magnetic and to clarify whether the elevated oxygen level in the tumours is resonance imaging (MRI) methods. Semi-quantitative measure- maintained for substantial periods after decompression. ments of the tumour oxygen level have been discussed using oxygenation-sensitive H-MRI measurements during 100% MATERIALS AND METHODS oxygen inhalation (Karczmar et al, 1994; Kuperman et al, 1995; Edelman et al, 1996; Oikawa et al, 1997; Tadamura et al, 1997; Phantom preparation Obata et al, 1998). These approaches have been used to increase tumour oxygenation sensitizing to radiotherapy and chemo- To investigate the effect of oxygen dissolved in water, we therapy. measured the proton relaxation time of five phantoms. Small tubes Hyperbaric oxygenation (HBO) increases the oxygen supply to were prepared with different oxygen concentrations. The water hypoxic tumour cells independent of its blood flow. Thus, HBO phantoms were as follows: (a) water without oxygen, (b) water has been used clinically in combination with radiotherapy, but the with bubbling oxygen under 1.0 atmosphere absolute (ATA), (c) previous combination method in which irradiation was adminis- water with bubbling oxygen under 1.5 ATA, (d) water with tered during HBO exposure was both hazardous to patients and bubbling oxygen under 2.0 ATA, and (e) water with bubbling complex (Dische, 1978; Jain, 1990). As a result, HBO has not oxygen under 2.5 ATA. MR spectroscopic measurements were been routinely adopted with radiotherapy to treat patients with performed using a Spectroscopy Imaging Systems Corporation (SISCO, Varian NMR Instruments, Palo Alto, CA, USA) 4.7 Tesla, 40 cm bore system. The hydrogen-1 resonant frequency was Received 24 April 1999 200.43 MHz. The T1 relaxation time was measured by alteration Revised 1 July 1999 of the inversion time (TI) using an inversion recovery pulse Accepted 8 July 1999 sequence. An exponential fitting was utilized to calculate T1 Correspondence to: Y Kinoshita relaxation time: 88 Tumour oxygen after HBO monitored by MRI 89 Signal intensity = Mo [1–2 exp (TI/T1)], 0.50 where Mo = longitudinal magnetization at equilibrium. 0.45 Tumour model Ten- to 12-week-old female C3H/He mice were used. The research was conducted according to the principles described in the ‘Guiding Principles for the Care and Use of Animals approved 0.40 by the Faculty Meeting of the University of Occupational Environmental Health’. SCCVII tumour cells, the hypoxic fraction of which was 9.1% (Shibamoto et al, 1994), were maintained in 0.35 culture in RPMI-1640 (Gibco Laboratories, Grand Island, NY, USA) supplemented with 10% fetal bovine serum (Gibco Laboratories) and antibiotics, and trypsinized before making single cell suspensions. The mice were inoculated in the left leg 0.30 1.0 1.5 2.0 2.5 with 3 ´ 10 viable SCCVII tumour cells. Urethane-anaesthetized, ATA oxygen spontaneously breathing mice were studied when the tumour size was about 1 cm in diameter. During MRI measurements, their legs and tumour were restrained in alginate impression material Figure 1 The relaxation rate (R1 = 1/T1) increased logarithmically with pressure at 25°C. ATA: atmosphere absolute without occluding the blood supply on the table graduating scale. The mice were transferred with the table into a small experimental hyperbaric chamber. We attempted to set the same position, within every 2.5 min. Finally, T1- and T2-weighted SE images were 0.5 mm difference between pre- and post-HBO exposure. The obtained. Subsequently, after gadopentetate dimeglumine (Gd- temperature was maintained using warm oxygen forced through a –1 DTPA, 0.4 ml kg ) (Magnevist, Berlex Laboratories, Wayne, NJ, hyperbaric chamber during HBO exposure. USA) was administered intravenously, the Gd-enhanced image was taken. Tumours with a haemorrhagic lesion on the T1- MRI measurements of tumours weighted SE image or necrotic tissue on the T2-weighted SE MRI measurements were performed using the same MR system image were excluded from this study. A region of interest described above. MR images were taken with a bird cage-type encompassing the tumour image was chosen and the average pixel resonator (inner diameter, 8.9 cm) in a magnet fitted with an intensity was calculated. –1 actively shielded gradient coil (1.8 G cm ). The molecular oxygen-enhanced MR images were acquired using an inversion RESULTS recovery-preparation fast low angle shot (IR-FLASH) sequence. The acquisition parameters for the IR-FLASH sequence were as Phantom study follows: repetition time (TR), 30 ms; echo time (TE), 8 ms; flip T1 relaxation time of water protons was related to the presence angle, 30°; field of view (FOV), 80 ´ 80 mm; matrix, 128 ´ 128; of paramagnetic molecular oxygen dissolved in water. The T1 one excitation; slice thickness, 2.0 mm. The inversion time was relaxation time for each water phantom at 25°C was as follows: 1000 ms to sensitize the acquisition to the paramagnetic effects of 3.12 ± 0.06 s without oxygen, 2.83 ± 0.04, 2.36 ± 0.01, molecular oxygen. Each image of IR-FLASH took about 5 s to 2.20 ± 0.02, 2.09 ± 0.02 s with oxygen under 1.0, 1.5, 2.0 and acquire. The acquisition parameters for the spin echo (SE) 2.5 ATA respectively. The relaxation rate (R1 = 1/T1) of pure sequence were as follows: FOV, 80 ´ 80 mm; matrix, 256 ´ 128; water without dissolved oxygen was 0.32, and a non-linear two excitation average; slice thickness, 2.0 mm. For T1-weighted relationship (r = 0.981) was observed between R1 and ATA images and gadolinium (Gd)-enhanced images, TR was 300 ms (Figure 1). The phantom study indicated that the T1 relaxation and TE was 20 ms; for the T2-weighted images TR was 2000 ms time was shortened by dissolved molecular oxygen under the and TE was 80 ms. The resonance frequency and shimming did high-pressure environment. not change between the pre- and post-HBO exposure. Experimental schedule Tumour study For T1-weighted images, a slice was selected through the centre of T1-weighted SE images of pre- and post-treatment of HBO the tumour and two baseline IR-FLASH images were initially exposure revealed the same registration (Figure 2 A,B), and acquired while the mice were breathing air. For the HBO-treated T2-weighted SE images demonstrated no necrotic lesions group (n = 6), HBO exposure was given in a small experimental (Figure 2C). The Gd-enhanced image showed a homogeneous hyperbaric chamber according to the following schedule: 10 min enhanced tumour of 1 cm in diameter (Figure 2D). The patho- of compression with oxygen, 60 min of 100% oxygen inhalation at logical specimen stained haematoxylin and eosin (Figure 2E) 2.0 ATA, and 10 min of decompression with oxygen inhalation. showed no evidence of haemorrhage or necrosis. Immediately For the normobaric group (n = 5), oxygen inhalation was given in after HBO exposure, IR-FLASH signals from the tumours of the same schedule as above but without compression. With air HBO-treated mice showed a signal increase in the tumour inhalation, the acquisition of IR-FLASH images was started 5 min compared with the pre-HBO image (Figure 2 F–K). Compared to after decompression, and images in both groups were obtained the two baseline IR-FLASH images, the average signals of © 2000 Cancer Research Campaign British Journal of Cancer (2000) 82(1), 88–92 -1 R1 (s ) 90 Y Kinoshita et al AB C D E FG H I J K Figure 2 Demonstrative MR images of tumour-bearing hind leg of HBO-treated (2.0 ATA 100% O ) mice. T1-weighted SE images (A: pretreatment, B: post-treatment) revealed the same registration and slight signal increase on the image after HBO exposure. T1-weighted SE image (A, B), T2-weighted image (C), Gd-enhanced image (D) and haematoxylin and eosin-stained pathological specimen (E) showed no evidence of haemorrhagic or necrotic tissue. Temporal signal changes were demonstrated on IR-FLASH images (F: pretreatment, G: 5 min after HBO, H: 15 min, I: 30 min, J: 60 min, K: 90 min) T1-weighted imaging during air-inhalation after HBO decompres- Air Oxygen sion. The first study using this non-invasive method examined the effect of hyperoxia on T2*-weighted images of rat R3230AC Tumour (HBO) n=6 mammary adenocarcinomas (Karczmar et al, 1994). The same Tumour (control) n=5 Muscle (HBO) n=6 group reported that T2*-weighted images differentiated tumours from normal tissue (Kuperman et al, 1995). They reported that significant signal increases were observed within the tumour centre and rim, while little change was observed in muscle during hyperoxia. Using the same T2*-weighted gradient echo images, another study on the responses of six rodent tumours to carbogen (95% oxygen/ 5% carbon dioxide) suggested that the MR signals were consistent with an increase in oxygen content of blood, tumour cell oxygenation and tumour blood flow (Robinson et al, 1997). On the other hand, using T1-weighted images instead of T2*-weighted images, semi-quantitative measurements of the –10 tumour oxygen level have been discussed (Edelman et al, 1996; 0 20 40 60 80 100 (min) Tadamura et al, 1997; Obata et al, 1998). Tadamura (1997) Time after HBO reported that there was no significant change in the T2 value Figure 3 Temporal signal change of tumours after 2.0 ATA 100% O (open during oxygen inhalation in the tissues, including the spleen and circles), muscles after 2.0 ATA 100% O (open triangles), and tumours after 1.0 ATA 100% O (filled circles). After the HBO treatment, the signals of myocardium, in which T1 shortening was observed. These results tumours and muscles were logarithmically decreased, but the tumour signal indicate that T1-weighted imaging is more useful to evaluate the showed a slower decline than that of the muscle signal. The mean signal effect of tissue oxygenation compared to T2*-weighted imaging elevation of the tumours after 100% 2.0 ATA O compression lasted for more than 60 min which was affected by blood oxygenation, blood flow and tissue oxygenation. tumours exposed to HBO showed 20%, 18%, 15%, 13% and 10% increases and those of the muscles demonstrated 18%, 11%, 5%, Mechanisms affecting MR signal intensity 0% and –2% in each image intensity at 5, 15, 30, 60 and 90 min Two major mechanisms affect MR signal changes in tissue after decompression respectively. There was a logarithmic rela- oxygenation. The first mechanism is blood oxygenation level- tionship (r = 0.929) between the MR signal intensity of tumours dependent (BOLD) contrast based on paramagnetic deoxyhaemo- and time. Similarly, the average signals from muscles exposed to globin and the second is paramagnetic molecular oxygen itself HBO showed a logarithmic relationship (r = 0.946). In contrast, containing two unpaired electrons. Paramagnetic deoxyhaemo- the signals from the tumours in the normobaric group showed no globin in blood creates magnetic susceptibility gradients near significant change during the course of measurement with air blood vessels that produce phase dispersion of water proton breathing. It is also noteworthy that the MR signal increase of the magnetization in the surrounding tissue, so the gradient recalled tumours lasted over 60 min after decompression in the HBO- echo-type sequences are very sensitive to the BOLD effect treatment group, unlike that of the muscle tissues (Figure 3). (Ogawa et al, 1990). This BOLD contrast has been utilized to evaluate regional blood flow and/or tissue oxygenation on func- DISCUSSION tional MR imaging. During oxygen inhalation, the mean enhance- Non-invasively, we detected that the decline of MR signal ment on T2*-weighted brain images in the grey matter and the intensity of the tumour was slower than that of muscle using white matter were 4.23% and 1.92% respectively, but T1-weighted British Journal of Cancer (2000) 82(1), 88–92 © 2000 Cancer Research Campaign Signal change (%) Tumour oxygen after HBO monitored by MRI 91 turbo-FLASH images demonstrated no significant changes with a carbogen caused no significant change in tumour oxygenation, conventional MR scanner at 1.5 Tesla (Berthezéne et al, 1995). whereas HBO and hyperbaric carbogen led to improvement of This result demonstrated that these local signal increases were oxygenation (Brizel et al, 1995). Moreover, hyperbaric carbogen attributed to changes in net conversion of deoxyhaemoglobin to was less effective than HBO in increasing the tumour because of oxyhaemoglobin and cerebral blood volume on T2*-weighted the result of adrenergic stimulation from the inspired carbon images. Although deoxyhaemoglobin is paramagnetic, it does not dioxide. HBO might be the most effective method to reduce cause significant T1 shortening. Since the electron spin relaxation tumour hypoxia by increasing the amount of dissolved oxygen in time of deoxyhaemoglobin is very short and because water mole- the plasma and tumour cells. cules are unable to approach the haem iron within a distance of The changes in tissue PO reduction after HBO exposure depend 3 Å, the T1 of an aqueous solution of deoxyhaemoglobin is not on blood flow and/or oxygen consumption in tissues. Wells short (Singer and Crooks, 1978). Therefore, T2*-weighted MR (1977), using a mass spectrometer probe that quantified the images were mainly affected by the BOLD effect of intravascular duration and magnitude of the HBO effect, found that tissue PO deoxyhaemoglobin, but T1-weighted MR images were affected by changed slowly during and after HBO exposure and that the paramagnetic molecular oxygen itself. Moreover, on T1-weighted decline in PO was slower in subcutaneous tissue than in muscle. turbo-FLASH images, no signal change during oxygen inhalation They concluded that the different PO changes in tissues were suggested a nearly stable concentration of free oxygen in blood affected by differences in tissue perfusion. On the other hand, Hall (Berthezéne et al, 1995). Free oxygen in blood represents less than (1994) emphasized poor tissue perfusion in the presence of 0.3% and is not significantly modified by oxygen inhalation until hypoxic tumour cells (Thomlinson and Gray, 1955). In this study, the haemoglobin is fully saturated. The molecular oxygen is an increased oxygen level in the tumour continued for a substantial dissolved into the fluid in proportion to Henry’s law and is period despite fast oxygen reduction in the muscle. Although the expressed as PO ´ 0.003. If PO values of the arterial blood before oxygen metabolism in tumours and muscles was not measured in 2 2 and during inhalation of 100% oxygen are ~100 mmHg and this condition, one of the reasons for the slower PO decline in ~500 mmHg, respectively, the concentration of dissolved molec- tumours was probably the lower blood flow in tumours. ular oxygen will increase by approximately five times. Under 2.5 ATA, the PO value of the arterial blood was ~1500 mmHg and the concentration of dissolved oxygen will increase by approximately Clinical application of HBO 15 times (Wells et al, 1977). It was considered that a large quantity Most malignant tumours appear to have a hypoxic core, and the of dissolved molecular oxygen shortened the T1 relaxation time of elimination of this core may destroy cells which are not killed by blood in proportion to ATA. Our in vitro study using water usual radiation procedures and which may be responsible for phantom demonstrated that it shortened the T1 relaxation time by recurrence. It is well known that hypoxic tumour cells are resistant about 3 s to 2 s according 1–2.5 ATA at 4.7 Tesla magnetic field. to some types of chemotherapy and radiotherapy. Tumour Our MR parameters of the IR-FLASH sequence were sensitive to oxygenation is a critical determinant of many forms of cancer these T1 changes because the image contrast was acquired about therapy. Clinical trials of radiotherapy during HBO showed 3 s after the inversion pulse. improvements in the local cure and survival rates of cancers in the Our observed T1 changes, however, reflected alterations of head, neck, and uterine cervix and evidence of HBO benefits has dissolved oxygen not only in intravascular blood but also in the been obtained in carcinomas of the bronchus, but not of the fluid of extravascular spaces. We did not measure the intravascular bladder (Dische, 1978). Since HBO has an enhancing radiation blood PO but Wells (1977) demonstrated rapid PO decline of the 2 2 effect on normal tissues as well as tumours, controversy remains arterial blood and it reached a baseline level within a few minutes concerning the actual improvement in the therapeutic efficacy of after the end of HBO exposure. Since we started the acquisition of HBO. In addition, the dose correction of radiation absorbed in the IR-FLASH images 5 min after decompression, our observed MR chamber wall is complex. But our new protocol that involved irra- signal changes did not seem to be affected by the arterial blood diation immediately after HBO exposure was simple and safe PO , but indicated an alternation of extravascular oxygenation. It is compared to radiotherapy during HBO exposure (Kohshi et al, noteworthy that oxygen in the extravascular space is important for 1996). The results of the present non-invasive study supported the the effectiveness of radiotherapy. theory that elevated MR signal intensity indicates tissue PO in the tumours was maintained for substantial periods after decompres- Tumour oxygenation method sion. Therefore, irradiation immediately after decompression is considered to be effective for malignant tumours without exerting Many studies to improve tumour oxygenation have been the influence of radiation on normal tissue. Furthermore, multi- performed. Some investigators have reintroduced the clinical use variate analysis in our small series revealed that combination with of carbogen to improve tumour oxygenation. Carbogen breathing HBO was a good predictive prognostic factor for survival (Kohshi may improve tumour blood oxygenation in two ways: (1) the 95% et al, 1999). oxygen may simply increase the arterial blood PO ; (2) 5% carbon dioxide may induce vasodilation of afferent tumour vessels (Robinson et al, 1995). Carbogen breathing caused increases of up ACKNOWLEDGEMENTS to 100% in normalized MR image intensity in GH3 prolactinomas grown in rats, and reversion to air breathing caused a subsequent This work was supported by a grant from Daido Hoxan Inc., fall in MR image intensity. These changes in signal intensity are Tokyo, Japan, and a Grant-in-Aid for Scientific Research consistent with an increase in oxygen content of the blood, tumour 10877221, from the Ministry of Education, Science and Culture, cell oxygenation and blood flow of the tumour. Using the Japan. We thank Rieko Maeda for preparing the histological Eppendorf PO histography, however, normobaric oxygen and sections and Norio Iriguchi for expert technical assistance. © 2000 Cancer Research Campaign British Journal of Cancer (2000) 82(1), 88–92 92 Y Kinoshita et al Kuperman V, River JN, Lewis MZ, Lubich LM and Karczmar GS (1995) Changes in REFERENCES T2*-weighted images during hyperoxia differentiate tumors from normal tissue. 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Br J Radiol 51: 888–894 75: 1000–1006 Edelman RR, Hatabu H, Tadamura E, Li W and Prasad PV (1996) Noninvasive Shibamoto Y, Kitakabu Y, Murata R, Oya N, Shibata T, Sasai K, Takahashi M and assessment of regional ventilation in the human lung using oxygen-enhanced Abe M (1994) Reoxygenation in the SCCVII tumor after KU-2285 magnetic resonance imaging. Nat Med 2: 1236–1239 sensitization plus single or fractionated irradiation. Int J Radiat Oncol Biol Hall EJ (1994) Radiobiology for the Radiologist, pp. 133–152. Lippincott: Phys 29: 583–586 Philadelphia Singer JR and Crooks LE (1978) Some magnetic studies of normal and leukemic Helmlinger G, Yuan F, Dellian M and Jain RK (1997) Interstitial pH and PO blood. Clin Eng 3: 357–363 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of Tadamura E, Hatabu H, Li W, Prasad PV and Edelman RR (1997) Effect of oxygen correlation. Nat Med 3: 177–182 inhalation on relaxation times in various tissues. J Magn Reson Imaging 7: Jain KK (1990) Texbook of hyperbaric medicine, pp. 408–417. Hogrefe & Huber 220–225 Publishers: Toronto Thomlinson RH and Gray LH (1955) The histological structure of some human lung Karczmar GS, River JN, Li J, Vijayakumar S, Goldman Z and Lewis MZ (1994) cancers and the possible implications for radiotherapy. Br J Cancer 9: 539–549 Effects of hyperoxia on T2* and resonance frequency weighted magnetic Vaupel P, Frinak S and O’Hara M (1984) Direct measurement of reoxygenation in resonance images of rodent tumours. NMR Biomed 7: 3–11 malignant mammary tumors after a single large dose of irradiation. Adv Exp Kohshi K, Kinoshita Y, Terashima H, Konda N, Yokota A and Soejima T (1996) Med Biol 180: 773–782 Radiotherapy after hyperbaric oxygenation for malignant gliomas: a pilot study. Wells CH, Goodpasture JE, Horrigan DJ and Hart GB (1977) Tissue gas J Cancer Res Clin Oncol 122: 676–678 measurements during hyperbaric oxygen exposure. In: Proceedings of the 6th Kohshi K, Kinoshita Y, Imada H, Kunugita N, Abe H, Terashima H, Tokui N and International Congress on Hyperbaric Medicine, Smith (ed), pp. 118–124. Uemura S (1999) Effects of radiotherapy after hyperbaric oxygenation on Aberdeen University Press: Aberdeen malignant gliomas. Br J Cancer 80: 236–241 British Journal of Cancer (2000) 82(1), 88–92 © 2000 Cancer Research Campaign http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Cancer Springer Journals

Preservation of tumour oxygen after hyperbaric oxygenation monitored by magnetic resonance imaging

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Springer Journals
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Copyright © 2000 by The Author(s)
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Biomedicine; Biomedicine, general; Cancer Research; Epidemiology; Molecular Medicine; Oncology; Drug Resistance
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0007-0920
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1532-1827
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10.1054/bjoc.1999.0882
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Abstract

British Journal of Cancer (2000) 82(1), 88–92 © 2000 Cancer Research Campaign Article no. bjoc.1999.0882 Preservation of tumour oxygen after hyperbaric oxygenation monitored by magnetic resonance imaging 1 1,2 3 4 1 Y Kinoshita , K Kohshi , N Kunugita , T Tosaki and A Yokota 1 2 3 Departments of Neurosurgery, Hyperbaric Medicine and Environmental Health, University of Occupational and Environmental Health, 1–1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan; Medical Business Group, Daido Hoxan Inc., Tokyo, Japan Summary Hyperbaric oxygen (HBO) has been proposed to reduce tumour hypoxia by increasing the dissolved molecular oxygen in tissue. Using a non-invasive magnetic resonance imaging (MRI) technique, we monitored the changes in MRI signal intensity after HBO exposure because dissolved paramagnetic molecular oxygen itself shortens the T1 relation time. SCCVII tumour cells transplanted in mice were used. The molecular oxygen-enhanced MR images were acquired using an inversion recovery-preparation fast low angle shot (IR-FLASH) sequence sensitizing the paramagnetic effects of molecular oxygen using a 4.7 tesla MR system. MR signal of muscles decreased rapidly and returned to the control level within 40 min after decompression, whereas that of tumours decreased gradually and remained at a high level 60 min after HBO exposure. In contrast, the signal from the tumours in the normobaric oxygen group showed no significant change. Our data suggested that MR signal changes of tumours and muscles represent an alternation of extravascular oxygenation. The preserving tumour oxygen concentration after HBO exposure may be important regarding adjuvant therapy for cancer patients. © 2000 Cancer Research Campaign Keywords: hyperbaric oxygenation; molecular oxygen; paramagnetism; relaxation time; magnetic resonance imaging Tumour oxygenation is known to enhance the efficacy of radio- cancer. We irradiated human malignant gliomas 15 min after HBO therapy, because the presence of hypoxic tumour cells is consid- exposure based on the hypothesis that elevated partial oxygen ered to be one of the major reasons for failure to control tumours tension (PO ) in the tumours was maintained for substantial (Hall, 1994). Regarding hypoxic tumour cells, it is also known that periods after decompression (Kohshi et al, 1996). Using invasive ionizing radiation and some chemotherapeutic agents are less measurements, it was reported that tissue PO increased slowly effective at low oxygen levels. Many studies on tumour oxygen during HBO exposure and that the decline in PO after HBO was tension levels using direct invasive measurements have been slower in subcutaneous tissues than in muscles (Wells et al, 1977), reported (Vaupel et al, 1984; Rampling et al, 1994; Brizel et al, but no study on PO change of tumours after HBO has been 1996; Collingridge et al, 1997; Helmlinger et al, 1997; Al-Hallaq reported. The purpose of this study was to non-invasively monitor et al, 1998). Non-invasively, there has been increasing interest in the tumour PO changes produced by HBO exposure using MRI, measurements of changes in tissue oxygen tension using magnetic and to clarify whether the elevated oxygen level in the tumours is resonance imaging (MRI) methods. Semi-quantitative measure- maintained for substantial periods after decompression. ments of the tumour oxygen level have been discussed using oxygenation-sensitive H-MRI measurements during 100% MATERIALS AND METHODS oxygen inhalation (Karczmar et al, 1994; Kuperman et al, 1995; Edelman et al, 1996; Oikawa et al, 1997; Tadamura et al, 1997; Phantom preparation Obata et al, 1998). These approaches have been used to increase tumour oxygenation sensitizing to radiotherapy and chemo- To investigate the effect of oxygen dissolved in water, we therapy. measured the proton relaxation time of five phantoms. Small tubes Hyperbaric oxygenation (HBO) increases the oxygen supply to were prepared with different oxygen concentrations. The water hypoxic tumour cells independent of its blood flow. Thus, HBO phantoms were as follows: (a) water without oxygen, (b) water has been used clinically in combination with radiotherapy, but the with bubbling oxygen under 1.0 atmosphere absolute (ATA), (c) previous combination method in which irradiation was adminis- water with bubbling oxygen under 1.5 ATA, (d) water with tered during HBO exposure was both hazardous to patients and bubbling oxygen under 2.0 ATA, and (e) water with bubbling complex (Dische, 1978; Jain, 1990). As a result, HBO has not oxygen under 2.5 ATA. MR spectroscopic measurements were been routinely adopted with radiotherapy to treat patients with performed using a Spectroscopy Imaging Systems Corporation (SISCO, Varian NMR Instruments, Palo Alto, CA, USA) 4.7 Tesla, 40 cm bore system. The hydrogen-1 resonant frequency was Received 24 April 1999 200.43 MHz. The T1 relaxation time was measured by alteration Revised 1 July 1999 of the inversion time (TI) using an inversion recovery pulse Accepted 8 July 1999 sequence. An exponential fitting was utilized to calculate T1 Correspondence to: Y Kinoshita relaxation time: 88 Tumour oxygen after HBO monitored by MRI 89 Signal intensity = Mo [1–2 exp (TI/T1)], 0.50 where Mo = longitudinal magnetization at equilibrium. 0.45 Tumour model Ten- to 12-week-old female C3H/He mice were used. The research was conducted according to the principles described in the ‘Guiding Principles for the Care and Use of Animals approved 0.40 by the Faculty Meeting of the University of Occupational Environmental Health’. SCCVII tumour cells, the hypoxic fraction of which was 9.1% (Shibamoto et al, 1994), were maintained in 0.35 culture in RPMI-1640 (Gibco Laboratories, Grand Island, NY, USA) supplemented with 10% fetal bovine serum (Gibco Laboratories) and antibiotics, and trypsinized before making single cell suspensions. The mice were inoculated in the left leg 0.30 1.0 1.5 2.0 2.5 with 3 ´ 10 viable SCCVII tumour cells. Urethane-anaesthetized, ATA oxygen spontaneously breathing mice were studied when the tumour size was about 1 cm in diameter. During MRI measurements, their legs and tumour were restrained in alginate impression material Figure 1 The relaxation rate (R1 = 1/T1) increased logarithmically with pressure at 25°C. ATA: atmosphere absolute without occluding the blood supply on the table graduating scale. The mice were transferred with the table into a small experimental hyperbaric chamber. We attempted to set the same position, within every 2.5 min. Finally, T1- and T2-weighted SE images were 0.5 mm difference between pre- and post-HBO exposure. The obtained. Subsequently, after gadopentetate dimeglumine (Gd- temperature was maintained using warm oxygen forced through a –1 DTPA, 0.4 ml kg ) (Magnevist, Berlex Laboratories, Wayne, NJ, hyperbaric chamber during HBO exposure. USA) was administered intravenously, the Gd-enhanced image was taken. Tumours with a haemorrhagic lesion on the T1- MRI measurements of tumours weighted SE image or necrotic tissue on the T2-weighted SE MRI measurements were performed using the same MR system image were excluded from this study. A region of interest described above. MR images were taken with a bird cage-type encompassing the tumour image was chosen and the average pixel resonator (inner diameter, 8.9 cm) in a magnet fitted with an intensity was calculated. –1 actively shielded gradient coil (1.8 G cm ). The molecular oxygen-enhanced MR images were acquired using an inversion RESULTS recovery-preparation fast low angle shot (IR-FLASH) sequence. The acquisition parameters for the IR-FLASH sequence were as Phantom study follows: repetition time (TR), 30 ms; echo time (TE), 8 ms; flip T1 relaxation time of water protons was related to the presence angle, 30°; field of view (FOV), 80 ´ 80 mm; matrix, 128 ´ 128; of paramagnetic molecular oxygen dissolved in water. The T1 one excitation; slice thickness, 2.0 mm. The inversion time was relaxation time for each water phantom at 25°C was as follows: 1000 ms to sensitize the acquisition to the paramagnetic effects of 3.12 ± 0.06 s without oxygen, 2.83 ± 0.04, 2.36 ± 0.01, molecular oxygen. Each image of IR-FLASH took about 5 s to 2.20 ± 0.02, 2.09 ± 0.02 s with oxygen under 1.0, 1.5, 2.0 and acquire. The acquisition parameters for the spin echo (SE) 2.5 ATA respectively. The relaxation rate (R1 = 1/T1) of pure sequence were as follows: FOV, 80 ´ 80 mm; matrix, 256 ´ 128; water without dissolved oxygen was 0.32, and a non-linear two excitation average; slice thickness, 2.0 mm. For T1-weighted relationship (r = 0.981) was observed between R1 and ATA images and gadolinium (Gd)-enhanced images, TR was 300 ms (Figure 1). The phantom study indicated that the T1 relaxation and TE was 20 ms; for the T2-weighted images TR was 2000 ms time was shortened by dissolved molecular oxygen under the and TE was 80 ms. The resonance frequency and shimming did high-pressure environment. not change between the pre- and post-HBO exposure. Experimental schedule Tumour study For T1-weighted images, a slice was selected through the centre of T1-weighted SE images of pre- and post-treatment of HBO the tumour and two baseline IR-FLASH images were initially exposure revealed the same registration (Figure 2 A,B), and acquired while the mice were breathing air. For the HBO-treated T2-weighted SE images demonstrated no necrotic lesions group (n = 6), HBO exposure was given in a small experimental (Figure 2C). The Gd-enhanced image showed a homogeneous hyperbaric chamber according to the following schedule: 10 min enhanced tumour of 1 cm in diameter (Figure 2D). The patho- of compression with oxygen, 60 min of 100% oxygen inhalation at logical specimen stained haematoxylin and eosin (Figure 2E) 2.0 ATA, and 10 min of decompression with oxygen inhalation. showed no evidence of haemorrhage or necrosis. Immediately For the normobaric group (n = 5), oxygen inhalation was given in after HBO exposure, IR-FLASH signals from the tumours of the same schedule as above but without compression. With air HBO-treated mice showed a signal increase in the tumour inhalation, the acquisition of IR-FLASH images was started 5 min compared with the pre-HBO image (Figure 2 F–K). Compared to after decompression, and images in both groups were obtained the two baseline IR-FLASH images, the average signals of © 2000 Cancer Research Campaign British Journal of Cancer (2000) 82(1), 88–92 -1 R1 (s ) 90 Y Kinoshita et al AB C D E FG H I J K Figure 2 Demonstrative MR images of tumour-bearing hind leg of HBO-treated (2.0 ATA 100% O ) mice. T1-weighted SE images (A: pretreatment, B: post-treatment) revealed the same registration and slight signal increase on the image after HBO exposure. T1-weighted SE image (A, B), T2-weighted image (C), Gd-enhanced image (D) and haematoxylin and eosin-stained pathological specimen (E) showed no evidence of haemorrhagic or necrotic tissue. Temporal signal changes were demonstrated on IR-FLASH images (F: pretreatment, G: 5 min after HBO, H: 15 min, I: 30 min, J: 60 min, K: 90 min) T1-weighted imaging during air-inhalation after HBO decompres- Air Oxygen sion. The first study using this non-invasive method examined the effect of hyperoxia on T2*-weighted images of rat R3230AC Tumour (HBO) n=6 mammary adenocarcinomas (Karczmar et al, 1994). The same Tumour (control) n=5 Muscle (HBO) n=6 group reported that T2*-weighted images differentiated tumours from normal tissue (Kuperman et al, 1995). They reported that significant signal increases were observed within the tumour centre and rim, while little change was observed in muscle during hyperoxia. Using the same T2*-weighted gradient echo images, another study on the responses of six rodent tumours to carbogen (95% oxygen/ 5% carbon dioxide) suggested that the MR signals were consistent with an increase in oxygen content of blood, tumour cell oxygenation and tumour blood flow (Robinson et al, 1997). On the other hand, using T1-weighted images instead of T2*-weighted images, semi-quantitative measurements of the –10 tumour oxygen level have been discussed (Edelman et al, 1996; 0 20 40 60 80 100 (min) Tadamura et al, 1997; Obata et al, 1998). Tadamura (1997) Time after HBO reported that there was no significant change in the T2 value Figure 3 Temporal signal change of tumours after 2.0 ATA 100% O (open during oxygen inhalation in the tissues, including the spleen and circles), muscles after 2.0 ATA 100% O (open triangles), and tumours after 1.0 ATA 100% O (filled circles). After the HBO treatment, the signals of myocardium, in which T1 shortening was observed. These results tumours and muscles were logarithmically decreased, but the tumour signal indicate that T1-weighted imaging is more useful to evaluate the showed a slower decline than that of the muscle signal. The mean signal effect of tissue oxygenation compared to T2*-weighted imaging elevation of the tumours after 100% 2.0 ATA O compression lasted for more than 60 min which was affected by blood oxygenation, blood flow and tissue oxygenation. tumours exposed to HBO showed 20%, 18%, 15%, 13% and 10% increases and those of the muscles demonstrated 18%, 11%, 5%, Mechanisms affecting MR signal intensity 0% and –2% in each image intensity at 5, 15, 30, 60 and 90 min Two major mechanisms affect MR signal changes in tissue after decompression respectively. There was a logarithmic rela- oxygenation. The first mechanism is blood oxygenation level- tionship (r = 0.929) between the MR signal intensity of tumours dependent (BOLD) contrast based on paramagnetic deoxyhaemo- and time. Similarly, the average signals from muscles exposed to globin and the second is paramagnetic molecular oxygen itself HBO showed a logarithmic relationship (r = 0.946). In contrast, containing two unpaired electrons. Paramagnetic deoxyhaemo- the signals from the tumours in the normobaric group showed no globin in blood creates magnetic susceptibility gradients near significant change during the course of measurement with air blood vessels that produce phase dispersion of water proton breathing. It is also noteworthy that the MR signal increase of the magnetization in the surrounding tissue, so the gradient recalled tumours lasted over 60 min after decompression in the HBO- echo-type sequences are very sensitive to the BOLD effect treatment group, unlike that of the muscle tissues (Figure 3). (Ogawa et al, 1990). This BOLD contrast has been utilized to evaluate regional blood flow and/or tissue oxygenation on func- DISCUSSION tional MR imaging. During oxygen inhalation, the mean enhance- Non-invasively, we detected that the decline of MR signal ment on T2*-weighted brain images in the grey matter and the intensity of the tumour was slower than that of muscle using white matter were 4.23% and 1.92% respectively, but T1-weighted British Journal of Cancer (2000) 82(1), 88–92 © 2000 Cancer Research Campaign Signal change (%) Tumour oxygen after HBO monitored by MRI 91 turbo-FLASH images demonstrated no significant changes with a carbogen caused no significant change in tumour oxygenation, conventional MR scanner at 1.5 Tesla (Berthezéne et al, 1995). whereas HBO and hyperbaric carbogen led to improvement of This result demonstrated that these local signal increases were oxygenation (Brizel et al, 1995). Moreover, hyperbaric carbogen attributed to changes in net conversion of deoxyhaemoglobin to was less effective than HBO in increasing the tumour because of oxyhaemoglobin and cerebral blood volume on T2*-weighted the result of adrenergic stimulation from the inspired carbon images. Although deoxyhaemoglobin is paramagnetic, it does not dioxide. HBO might be the most effective method to reduce cause significant T1 shortening. Since the electron spin relaxation tumour hypoxia by increasing the amount of dissolved oxygen in time of deoxyhaemoglobin is very short and because water mole- the plasma and tumour cells. cules are unable to approach the haem iron within a distance of The changes in tissue PO reduction after HBO exposure depend 3 Å, the T1 of an aqueous solution of deoxyhaemoglobin is not on blood flow and/or oxygen consumption in tissues. Wells short (Singer and Crooks, 1978). Therefore, T2*-weighted MR (1977), using a mass spectrometer probe that quantified the images were mainly affected by the BOLD effect of intravascular duration and magnitude of the HBO effect, found that tissue PO deoxyhaemoglobin, but T1-weighted MR images were affected by changed slowly during and after HBO exposure and that the paramagnetic molecular oxygen itself. Moreover, on T1-weighted decline in PO was slower in subcutaneous tissue than in muscle. turbo-FLASH images, no signal change during oxygen inhalation They concluded that the different PO changes in tissues were suggested a nearly stable concentration of free oxygen in blood affected by differences in tissue perfusion. On the other hand, Hall (Berthezéne et al, 1995). Free oxygen in blood represents less than (1994) emphasized poor tissue perfusion in the presence of 0.3% and is not significantly modified by oxygen inhalation until hypoxic tumour cells (Thomlinson and Gray, 1955). In this study, the haemoglobin is fully saturated. The molecular oxygen is an increased oxygen level in the tumour continued for a substantial dissolved into the fluid in proportion to Henry’s law and is period despite fast oxygen reduction in the muscle. Although the expressed as PO ´ 0.003. If PO values of the arterial blood before oxygen metabolism in tumours and muscles was not measured in 2 2 and during inhalation of 100% oxygen are ~100 mmHg and this condition, one of the reasons for the slower PO decline in ~500 mmHg, respectively, the concentration of dissolved molec- tumours was probably the lower blood flow in tumours. ular oxygen will increase by approximately five times. Under 2.5 ATA, the PO value of the arterial blood was ~1500 mmHg and the concentration of dissolved oxygen will increase by approximately Clinical application of HBO 15 times (Wells et al, 1977). It was considered that a large quantity Most malignant tumours appear to have a hypoxic core, and the of dissolved molecular oxygen shortened the T1 relaxation time of elimination of this core may destroy cells which are not killed by blood in proportion to ATA. Our in vitro study using water usual radiation procedures and which may be responsible for phantom demonstrated that it shortened the T1 relaxation time by recurrence. It is well known that hypoxic tumour cells are resistant about 3 s to 2 s according 1–2.5 ATA at 4.7 Tesla magnetic field. to some types of chemotherapy and radiotherapy. Tumour Our MR parameters of the IR-FLASH sequence were sensitive to oxygenation is a critical determinant of many forms of cancer these T1 changes because the image contrast was acquired about therapy. Clinical trials of radiotherapy during HBO showed 3 s after the inversion pulse. improvements in the local cure and survival rates of cancers in the Our observed T1 changes, however, reflected alterations of head, neck, and uterine cervix and evidence of HBO benefits has dissolved oxygen not only in intravascular blood but also in the been obtained in carcinomas of the bronchus, but not of the fluid of extravascular spaces. We did not measure the intravascular bladder (Dische, 1978). Since HBO has an enhancing radiation blood PO but Wells (1977) demonstrated rapid PO decline of the 2 2 effect on normal tissues as well as tumours, controversy remains arterial blood and it reached a baseline level within a few minutes concerning the actual improvement in the therapeutic efficacy of after the end of HBO exposure. Since we started the acquisition of HBO. In addition, the dose correction of radiation absorbed in the IR-FLASH images 5 min after decompression, our observed MR chamber wall is complex. But our new protocol that involved irra- signal changes did not seem to be affected by the arterial blood diation immediately after HBO exposure was simple and safe PO , but indicated an alternation of extravascular oxygenation. It is compared to radiotherapy during HBO exposure (Kohshi et al, noteworthy that oxygen in the extravascular space is important for 1996). The results of the present non-invasive study supported the the effectiveness of radiotherapy. theory that elevated MR signal intensity indicates tissue PO in the tumours was maintained for substantial periods after decompres- Tumour oxygenation method sion. Therefore, irradiation immediately after decompression is considered to be effective for malignant tumours without exerting Many studies to improve tumour oxygenation have been the influence of radiation on normal tissue. Furthermore, multi- performed. Some investigators have reintroduced the clinical use variate analysis in our small series revealed that combination with of carbogen to improve tumour oxygenation. Carbogen breathing HBO was a good predictive prognostic factor for survival (Kohshi may improve tumour blood oxygenation in two ways: (1) the 95% et al, 1999). oxygen may simply increase the arterial blood PO ; (2) 5% carbon dioxide may induce vasodilation of afferent tumour vessels (Robinson et al, 1995). Carbogen breathing caused increases of up ACKNOWLEDGEMENTS to 100% in normalized MR image intensity in GH3 prolactinomas grown in rats, and reversion to air breathing caused a subsequent This work was supported by a grant from Daido Hoxan Inc., fall in MR image intensity. 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British Journal of CancerSpringer Journals

Published: Dec 10, 1999

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