MR-guided laser thermal ablation of primary and secondary liver tumours.

AIM: To test the hypothesis that magnetic resonance (MR)-guided hepatic tumour ablation is (i) safe and feasible, (ii) is associated with favourable patient survival, and (iii) decreases viable tumour. MATERIALS AND METHODS: One hundred and twenty-five MR-guided laser thermal ablations (LTA) were performed on 35 patients with hepatocellular carcinoma (HCC, n=19), hepatic metastases (n=11, mainly colorectal) and carcinoid liver tumours (n=5). RESULTS: Mean overall survival was 14.8 months (HCCs 14.6 months, metastases 15.2 months). Near real-time T1-weighted colourized thermal maps correlated moderately with follow-up gadolinium-enhanced MR imaging in predicting ablated tumour area (Pearson correlation coefficient=0.5). There was a significant difference in percentage enhancing pre- and post-LTA (Wilcoxon signed ranks test=0.0001). An average of 50.7% of tumour was ablated by each treatment. In patients with multiple liver tumours ablated tumours grew significantly less than untreated tumours (108%compared with 196% growth, follow-up period 5.8 months, WSRTp=0.07). CONCLUSION: MR- guided LTA of primary and secondary liver tumours is safe, feasible, and significantly decreased amount of enhancing or viable tumour. MR-guided LTA produces a better survival in patients with HCC than would be expected in untreated patients, and has a mean survival in patients with metastases at least equal to the longest median survival in untreated patients.

Magnetic resonance imaging-guided laser thermal ablation of renal tumours.

OBJECTIVE: To test the hypothesis that magnetic resonance imaging (MRI)-guided laser thermal ablation (LTA) of inoperable renal tumours is a safe, tolerable and potentially effective treatment. PATIENTS AND METHODS: Nine patients (aged 56-81 years) with malignant renal tumours underwent percutaneous LTA under MRI guidance in a 0.5 T open magnet. Real-time colour thermal mapping was used to monitor tumour ablation, and the follow-up was with gadolinium-enhanced MRI at 6 weeks and (where appropriate) 3-4 months after the procedure. Tumour volume and percentage tumour enhancement before and after ablation were compared. The percentage of tumour ablated on real-time T1-weighted thermal maps was compared with that on gadolinium-enhanced follow-up MRI. RESULTS: The mean (range) follow-up was 16.9 (3-32) months after the first ablation. The mean tumour size did not change significantly, but the mean percentage of viable tumour decreased significantly from 73.7% before to 29.5% after ablation (P = 0.012, Wilcoxon signed-ranks test). Thermal maps correlated moderately well with follow-up MRI in predicting the extent of tumour ablation (Pearson correlation coefficient 0.55). There were two minor and one major complication. CONCLUSION: In this pilot study of patients unsuitable for surgery, MRI-guided LTA of renal tumours was safe, feasible (being well tolerated by the patient) and significantly reduced enhancing tumour volume by a mean of 45%.

The value of MnDPDP enhancement during MR guided laser interstitial thermoablation of liver tumors.

Magnetic resonance (MR)-guided thermal ablation procedures are feasible in modern open low field strength MR scanners. The compromises for rapid imaging in this configuration worsen liver lesino conspicuity. To overcome this, we utilize liver-specific contrast Mangafodipir Trisodium (MnDPDP) to improve lesion recognition and targeting and allow a longer contrast-assisted window. Three observers assessed pre- and post-contrast MR scans of 14 liver ablation patients. They assessed the number of lesions, ease of puncture planning, conspicuity of lesions, gallbladder, vessels, and surrounding bowel. There was a significant improvement in lesion conspicuity and ease of puncture planning when MnDPDP was used. In two of the observers, there was also a significant improvement in the number of lesions seen and in bowel conspicuity. No significant difference was shown in the detection of the gallbladder or vessels. We conclude that the liver-specific contrast agent MnDPDP improves the overall accuracy and safety of MR-guided thermal ablation of liver tumors facilitating this procedure at lower field strengths. J. Magn. Reson. Imaging 2001;13:37-41.

Significantly increased lesion size by using the near-infrared photosensitizer 5,10,15,20-tetrakis (m-hydroxyphenyl)bacteriochlorin in interstitial photodynamic therapy of normal rat liver tissue.

BACKGROUND AND OBJECTIVE: Penetration of tissues by activating light ultimately limits the size of the lesions achievable in interstitial photodynamic therapy. Measurements of the wavelength-dependence of tissue optical properties suggest that substantial improvements may be possible, particularly in pigmented organs such as the liver, by using drugs absorbing at near infrared wavelengths. STUDY DESIGN/MATERIALS AND METHODS: In this study, the extent of light induced necrosis with the photosensitive agents Photofrin (activated at 632 nm), meta-tetra(hydroxyphenyl)chlorin (mTHPC) (activated at 652 nm) and 5,10,15,20-tetrakis(m-hydroxyphenyl)bacteriochlorin (mTHPBC) (activated at 740 nm) are compared in normal rat liver. Interstitial irradiation of mTHPBC-sensitized liver tissue resulted in significantly larger necrotic areas than irradiation of Photofrin and mTHPC-sensitised livers. CONCLUSION: The results illustrate the advantage of near-infrared photosensitizer activation and point to a specific role for mTHPBC in the interstitial treatment of liver tumours.

In vivo photodynamic characteristics of the near-infrared photosensitizer 5,10,15,20-tetrakis(M-hydroxyphenyl) bacteriochlorin.

This paper describes the photodynamic characteristics of the new near-infrared photosensitizer 5,10,15,20-tetrakis(m-hydroxyphenyl)bacteriochlorin (mTHPBC or SQN400) in normal rat and mouse tissues. A rat liver model of photodynamic tissue necrosis was used to determine the in vivo action spectrum and the dose-response relationships of tissue destruction with drug and light doses. The effect of varying the light irradiance and the time interval between drug administration and light irradiation on the biological response was also measured in the rat liver model. Photobleaching of mTHPBC was measured and compared with that of its chlorine analog (mTHPC) in normal mouse skin and an implanted mouse colorectal tumor. The optimum wavelength for biological activation of mTHPBC in rat liver was 739 nm. mTHPBC was found to have a marked drug-dose threshold of around 0.6 mg kg-1 when liver tissue was irradiated 48 h after drug administration. Below this administered drug dose, irradiation, even at very high light doses, did not cause liver necrosis. At administered doses above the photodynamic threshold the effect of mTHPBC-PDT was directly proportional to the product of the drug and light doses. No difference in the extent of liver necrosis produced by mTHPBC was found on varying the light irradiance from 10 to 100 mW cm-2. The extent of liver necrosis was greatest when tissue was irradiated shortly after mTHPBC administration and necrosis was absent when irradiation was performed 72 h or later after drug administration, suggesting that the drug was rapidly cleared from the liver. In vivo photobleaching experiments in mice showed that the rate of bleaching of mTHPBC was approximately 20 times greater than that of mTHPC. It is argued that this greater rate of bleaching accounts for the higher photodynamic threshold and this could be exploited to enhance selective destruction of tissues which accumulate the photosensitizer.

Upright dynamic MR defaecating proctography in an open configuration MR system.

We describe our experience evaluating an MR proctography technique using an open 0.5 T MR system. Evacuation of a gadolinium-containing rectal contrast agent was dynamically imaged in the upright position using a fast gradient echo sequence. Anatomical and functional abnormalities were documented. Results from 40 patients who underwent this technique are reported. The method is proposed as an alternative to conventional fluoroscopic proctography.

Biodistribution and bioactivity of tetra-pegylated meta-tetra(hydroxyphenyl)chlorin compared to native meta-tetra(hydroxyphenyl)chlorin in a rat liver tumor model.

It has been proposed that the construction of a photosensitizer-polymer conjugate would lead to an increased selective retention of the drug in tumor tissue resulting in an enhancement of selective tumor destruction by light in photodynamic therapy. In this study the kinetics of a tetra-pegylated derivative of meta-tetra(hydroxyphenyl)chlorin (mTHPC-PEG) were compared with those of native meta-tetra(hydroxyphenyl)chlorin (mTHPC) in a rat liver tumor model. In addition, the time course of bioactivity of both drugs was studied in normal liver tissue. Pegylation of mTHPC resulted in a two-fold increase in the plasma half-life time, a five-fold decrease in liver uptake and an increase in the tumor selectivity at early time intervals after drug administration. However, although mTHPC concentrations in liver decrease rapidly with time, mTHPC-PEG liver concentrations increased as a function of time. This led to a loss of tumor selectivity at all but the earliest time points, whereas with mTHPC tumor selectivity increased with time. For both drugs the time course of bioactivity in the liver parallels drug concentration levels with extensive necrosis after irradiation of mTHPC-PEG-sensitized liver tissue up to drug-light intervals of 120 h. It is concluded that on balance mTHPC-PEG does not appear to show any benefits over native mTHPC for the treatment of liver tumors, as normal liver tissue accumulates the compound. However, pegylation is a potentially promising strategy with an increase in tumor selectivity and reduced liver uptake if accumulation in the liver can be prevented.

Monte carlo simulations of light distributions in an embedded tumour model: studies of selectivity in photodynamic therapy.

It is well known that photosensitisers in photodynamic therapy (PDT) tend to localise in greater concentrations in tumours. This attractive feature may help confer on PDT the potential to selectivity destroy tumours while sparing the surrounding normal tissue. In this paper Monte Carlo simulations were used to study light distributions in a simple model consisting of tumour embedded in surrounding normal tissue subjected to superficial irradiance. The Monte Carlo model was coded to allow modelling of arbitrary geometries and multiple tissue types. This permitted the use of different optical properties for tumour and normal tissue. Two simulations were run using optical coefficients appropriate to breast carcinoma in adipose tissue and liver tumour in liver. Contours of equal fluence were plotted against depth for both simulations. Contours of equal photodynamic dose (fluence×drug concentration) were plotted for various tumour/normal drug ratios. By assuming a threshold for necrosis it was possible to estimate the depth of damage in the normal tissue and tumour simultaneously. A greater depth of selective tumour damage was observed in the breast tissue simulation for a given drug ratio due to the higher penetration of light compared to the liver. For a tumour to normal ratio of 4:1 selective damage to a depth greater than 4 mm was observed in the breast simulation compared to almost 3 mm in the case of the liver model.

MR-guided laser thermoablation of inoperable renal tumors in an open-configuration interventional MR scanner: preliminary clinical experience in three cases.

A minimally invasive technique for performing magnetic resonance (MR)-guided laser interstitial thermoablation (LITT) for inoperable renal tumors is described. Three patients were treated using a percutaneous technique with real-time MR guidance in an open access interventional MR scanner. Laser therapy was delivered using a neodymium-YAG source via a water-cooled applicator system. Thermal lesions were monitored in real time using a color thermometry sequence. All patients were discharged the following day with no complications. Follow-up with gadolinium-enhanced MRI in a conventional high-field system confirmed necrosis in targeted tissue, and further treatment is planned for one patient. We concluded that LITT can be useful in treating inoperable renal malignancy and merits further evaluation. J. Magn. Reson. Imaging 1999;10:545-549.

MRI guidance of infra-red laser liver tumour ablations, utilising an open MRI configuration system: technique and early progress.

BACKGROUND/AIMS: Primary and secondary liver tumours are a common clinical problem, with a poor prognosis in most cases. Surgical resection offers the best outcome, but is only appropriate for the minority. Thermal ablation techniques have been described, but the lack of an optimal means of monitoring has limited their use. We undertook a pilot study to assess the feasibility and safety of an integrated MR-guided laser thermoablation technique under local anaesthesia using a real-time colourisation thermal monitoring technique in a newly developed open MR scanner. METHODS: Liver tumours were punctured after the administration of intravenous Mangafodipir trisodium (MnDPDP) using real-time MR image guidance under local or general anaesthesia, and treated using a water-cooled interstitial fibre and a Nd-YAG laser source. Twenty-seven procedures were performed in 12 patients. Therapy was monitored using a real-time MR colourisation sequence. Thermoablation was followed by a colour change in a region of interest. RESULTS: Thermal lesions of mean size 3 cm in diameter were produced with a maximum size of 5 cm. Eight out of 12 patients were discharged the next day with few significant complications. Repeat procedures have been performed in seven of 12 patients. Two patients with lesions of 3 cm diameter have had complete tumour ablation with only one procedure. CONCLUSION: Percutaneous laser thermoablation for liver tumours performed as an integrated one-step technique in an open configuration MR scanner is described. It can be safely performed under local anaesthesia in the majority of patients, with few side effects. MR control shows the site and size of the evolving thermal lesions, allowing appropriate action to be taken in terms of further burns, time of application and power applied.

mTHPC Polymer Conjugates: The In Vivo Photodynamic Activity of Four Candidate Compounds.

The in vivo photodynamic activities of four poly(ethylene glycol) (PEG) conjugates of the photosensitiser 5,10,15,20-tetrakis-(m-hydroxyphenyl)chlorin (mTHPC, temoporfin, Foscan(®)) were compared with that of mTHPC over a range of drug-light intervals using acute tumour necrosis and skeletal muscles swelling in a mouse model in order to ascertain the influence of linking group stability and PEG chain length on the photodynamic activity. The four compounds examined contained either PEG 2000 or PEG 5000 attached by carbonate or triazine linkages at the phenol hydroxyl groups of the mTHPC.All compounds tested caused tumour necrosis at drug-light intervals of between one and four days. mTHPC produced tumour necrosis of over 5 mm at drug-light intervals of 1 and 2 days with limited muscle damage at early drug-light intervals. The relatively labile carbonate-linked conjugates gave tumour necrosis similar to mTHPC but produced severe muscle and systemic phototoxicity on irradiation at 4-24 h after injection. The more stable triazine-linked conjugates produced no significant muscle damage at any of the drug-light intervals tested, but gave only limited tumour necrosis under the conditions tested. PEG chain length had relatively little effect on the patterns of bioactivity.It is concluded that both classes of mTHPC PEG conjugates may be suitable for photodynamic therapy if the problems of stability and early photosensitivity in the case of the carbonates and reduced potency in the case of the triazines can be overcome through improved formulations and PDT treatment regimens.

Characterization of a murine model for the rapid assessment of acute photodynamic response in tumour and muscle.

A murine implanted colorectal tumour model is described in which a measurement of tumour depth of necrosis is combined with a simultaneous measurement of muscle damage. The response of this model to a range of photodynamic therapy parameters was characterized using the chlorin photosensitizer mTHPC (temoporfin, Foscan(R)R). Both tumour depth of necrosis (measured directly and on histology) and muscle swelling correlate with the dose of photosensitizer and light, and are shown to be repeatable and consistent with published values obtained under similar conditions using established models.

Tissue photosensitizer detection by low-power remittance fluorimetry.

A simple adaptation of a commercial spectrofluorimeter which allows the semiquantitative determination of photodynamic therapy photosensitizer fluorescence in accessible tissues is described. Light from a xenon lamp is directed via a monochromator onto the tissue surface by a bifurcated random fibre bundle. Tissue fluorescence is directed to the emission monochromator and photomultiplier of the fluorimeter by the second limb of the fibre bundle. Although relatively simple, this device can be used to carry out a wide range of useful measurements in clinical and experimental photodynamic therapy. The sensitivity and reproducibility of the measurements were determined using mouse tumour and muscle tissue fluorescence measured in vivo compared with photosensitizer content measured by high performance liquid chromatography. As an illustration of the potential applications of such systems, the time courses of fluorescence in the skin of patients treated with the photosensitizers Photofrin(R) and metatetra(hydroxyphenyl)chlorin (mTHPC) (temoporfin) and the photobleaching of 5-aminolaevulinic acid-derived protoporphyrin IX during treatment, are described.

A comparison of novel light sources for photodynamic therapy.

A diode laser, light-emitting diode (LED) array bandwidth 25 nm, full width half maximum (FWHM) and filtered arc lamp (bandwidth 40 nm, FWHM), all with peak emission at about 650 nm, suitable for the photosensitizer tetra(meta-hydroxyphenyl)chlorin (mTHPC), were compared with a copper vapour laser pumped dye laser, using depth of necrosis in normal rat liver as a measure of photodynamic effect.A three-way comparison between a DL10K dye laser, the LED array and the filtered arc lamp resulted in mean depths of necrosis of 4.64, 4.29 and 4.04 mm, respectively, at 20 J cm(-2), the values for the laser and arc lamp being significantly different at the 5% level. A further comparison of a narrower linewidth DL20K dye laser with the LED array, using a light dose of 20 J cm(-2), showed a significant difference between the mean depths of necrosis of 4.97 and 4.05 mm, respectively (p=0.01).A final study, comparing the DL20K dye laser with the diode laser and a light dose of 10 J cm(-2), demonstrated no significant difference in depths of necrosis (3.23 and 3.25 mm, respectively). The results obtained in the three studies are attributed to the relative bandwidths of light emission for the various sources. A simple mathematical model is presented explaining the results in terms of the relative activation of the photosensitizer and the consequent threshold fluence required for the induction of necrosis.It is concluded that, in order to achieve the same depth of effect as a laser when using the broad band sources, the incident fluence would have to be approximately doubled. However, when the low cost and ease of use of the non-laser sources are taken into consideration, these devices are likely to find widespread applications in clinical photodynamic therapy.