Liver resection and ablation for squamous cell carcinoma liver metastases.

BACKGROUND: Limited evidence exists to guide the management of patients with liver metastases from squamous cell carcinoma (SCC). The aim of this retrospective multicentre cohort study was to describe patterns of disease recurrence after liver resection/ablation for SCC liver metastases and factors associated with recurrence-free survival (RFS) and overall survival (OS). METHOD: Members of the European-African Hepato-Pancreato-Biliary Association were invited to include all consecutive patients undergoing liver resection/ablation for SCC liver metastases between 2002 and 2019. Patient, tumour and perioperative characteristics were analysed with regard to RFS and OS. RESULTS: Among the 102 patients included from 24 European centres, 56 patients had anal cancer, and 46 patients had SCC from other origin. RFS in patients with anal cancer and non-anal cancer was 16 and 9 months, respectively (P = 0.134). A positive resection margin significantly influenced RFS for both anal cancer and non-anal cancer liver metastases (hazard ratio 6.82, 95 per cent c.i. 2.40 to 19.35, for the entire cohort). Median survival duration and 5-year OS rate among patients with anal cancer and non-anal cancer were 50 months and 45 per cent and 21 months and 25 per cent, respectively. For the entire cohort, only non-radical resection was associated with worse overall survival (hazard ratio 3.21, 95 per cent c.i. 1.24 to 8.30). CONCLUSION: Liver resection/ablation of liver metastases from SCC can result in long-term survival. Survival was superior in treated patients with liver metastases from anal versus non-anal cancer. A negative resection margin is paramount for acceptable outcome.

Preoperative Aspartate Aminotransferase-to-Platelet Ratio Index Predicts Perioperative Liver-Related Complications Following Liver Resection for Colorectal Cancer Metastases.

BACKGROUND AND AIMS: There are limited data on the potential role of preoperative non-invasive markers, specifically the aspartate-to-alanine aminotransferase ratio and the aspartate aminotransferase-to-platelet ratio index, in predicting perioperative liver-related complications after hepatectomy for colorectal cancer metastases. METHODS: Patients undergoing liver resection for colorectal cancer metastases in a European institution during 2003-2010 were retrospectively enrolled. Relevant data, such as neoadjuvant chemotherapy, preoperative liver function tests, and perioperative complications, were collected from medical records. The nontumorous liver parenchyma in the surgical specimens of 31 patients was re-evaluated. RESULTS: Overall, 215 patients were included. In total, 40% underwent neoadjuvant chemotherapy and 47% major resection, while 47% had perioperative complications (6% liver-related). In multivariate regression analysis, the aspartate aminotransferase-to-platelet ratio index was independently associated with liver-related complications (odds ratio: 1.149, p = 0.003) and perioperative liver failure (odds ratio: 1.155, p = 0.012). The latter was also true in the subcohort of patients with neoadjuvant chemotherapy (odds ratio: 1.157, p = 0.004) but not in those without such therapy (p = 0.062). The aspartate-to-alanine aminotransferase ratio was not related to liver-related complications (p = 0.929). The area under the receiver operating characteristics curve for the aspartate aminotransferase-to-platelet ratio index as a predictor of liver-related complications was 0.857 (p = 0.008) in patients with neoadjuvant chemotherapy. Increasing aspartate aminotransferase-to-platelet ratio index was observed with an increase in degrees of sinusoidal obstruction syndrome (p = 0.01) but not for fibrosis (p = 0.175) or steatosis (p = 0.173) in the nontumorous liver in surgical specimens. CONCLUSION: The preoperative aspartate aminotransferase-to-platelet ratio index, but not the aspartate-to-alanine aminotransferase ratio, predicts perioperative liver-related complications following hepatectomy due to colorectal cancer metastases, in particular after neoadjuvant chemotherapy. The aspartate aminotransferase-to-platelet ratio index is related to sinusoidal obstruction syndrome in the nontumorous liver.

Impact of a fast-track surgery programme for pancreaticoduodenectomy.

BACKGROUND: Fast-track (FT) programmes are multimodal, evidence-based approaches to optimize patient outcome after surgery. The aim of this study was to evaluate the safety, clinical outcome and patients' experience of a FT programme after pancreaticoduodenectomy (PD) in a high-volume institution in Sweden. METHODS: Consecutive patients undergoing PD were studied before and after implementation of the FT programme. FT changes included earlier mobilization, standardized removal of the nasogastric tube and drain, and earlier start of oral intake. Patient experience was evaluated with European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-PAN26 questionnaires 2 weeks before and 4 weeks after surgery. RESULTS: Between 2011 and 2014, 100 consecutive patients undergoing PD were studied, of whom 50 received standard care (controls), followed by 50 patients treated after implementation of the FT programme. The nasogastric tube was removed significantly earlier in the FT group, and these patients were able fully to tolerate fluids and solid food sooner after PD. Delayed gastric emptying was significantly reduced in the FT group (26 versus 48 per cent; P = 0.030). Overall morbidity remained unchanged and there were no deaths in either group. Postoperative length of hospital stay was reduced from 14 to 10 days and hospital costs were decreased significantly. Health-related quality-of-life questionnaires showed similar patterns of change, with no significant difference between groups before or after surgery. CONCLUSION: The FT programme after PD was safe. Delayed gastric emptying, hospital stay and hospital costs were all reduced significantly. Although patients were discharged 4 days earlier in the FT group, this did not influence health-related quality of life compared with standard care.

Prolonged chemotherapy impairs liver regeneration after portal vein occlusion - an audit of 26 patients.

AIM: The aim of the present retrospective study was to investigate the influence of neoadjuvant chemotherapy on liver regeneration after portal vein occlusion before major hepatectomy. METHOD: Between 2003 and 2007, 26 patients underwent portal vein occlusion, of whom 22 had portal vein embolisation and 4 portal vein ligation. 15 of 23 patients with colorectal liver metastases had neoadjuvant chemotherapy. RESULTS: After portal vein occlusion, the ratio of the future liver remnant volume to total parenchymal liver volume (FLR%) was reduced in patients receiving neoadjuvant chemotherapy (27 +/- 1% vs 32 +/- 1%, p = 0.03). A smaller future liver remnant before portal vein occlusion resulted in a greater degree of hypertrophy (r(2) = 0.18, p = 0.04). Patients with tumour size greater than 60 mm showed a decreased degree of hypertrophy (7 +/- 1)% as compared to patients with smaller tumours (13 +/- 1%, p = 0.01). There was one death shortly after portal vein embolisation. 19/26 patients were resected with zero operative mortality. CONCLUSION: Prolonged neoadjuvant chemotherapy has a small negative effect on liver regeneration induced by portal vein occlusion. Liver regeneration induced by portal vein occlusion is relatively large when tumour burden is small.

Comparison of poly(acryl starch) and poly(lactide-co-glycolide) microspheres as drug delivery system for a rotavirus vaccine.

Drug delivery systems allowing controlled release of antigen are of particular interest in the development of vaccines. We have compared poly(acrylic starch) microspheres (PAS) and poly(lactide-co-glycolide) microspheres (PLG) as drug delivery systems for a rotavirus vaccine. The polymers are both biodegradable but have different degradation mechanisms and antigen release profiles. PAS are enzymatically degraded and have a continuous fast antigen release rate compared to the hydrolytically degraded PLG which release the incorporated antigen in a pulsatile manner. In this study mice were immunised intramuscularly and orally on three occasions with formalin-inactivated rotavirus (FRRV) incorporated in PAS and PLG and with FFRV alone. Serum and faeces samples were collected and analysed by ELISA for rotavirus specific IgG and IgA antibodies. A neutralising assay was also conducted on both serum and faeces antibodies. The two different polymer drug delivery systems induced different immune responses depending on administration route. PAS elicited significant antibody levels and neutralising effect after oral administration while PLG showed high antibody levels after intramuscular administration. The immune response appears to be dependent on the differences in antigen release and degradation mechanism for the two polymer systems.

Incorporation of protein in PLG-microspheres with retention of bioactivity.

The enzyme urease was incorporated into poly(lactide-co-glycolide) microspheres using a double emulsion solvent removal technique. Ethyl acetate was used as organic solvent since it is less toxic than the more commonly used methylene chloride. The effect of the two solvents on urease was compared. Although this preparation technique is well established, it is often associated with reduced bioactivity and low entrapment efficiency of proteins. In order to retain a high degree of bioactivity, the well known protein stabilisers: sucrose, trehalose and poloxamer 407, were added to the urease in the preparation. The bioactivity of the entrapped urease was reduced more by methylene chloride than by ethyl acetate. The gelled form of poloxamer was shown to highly favour the retention of bioactivity, demonstrated by an increase of 41% compared to preparations without poloxamer. Moreover, the presence of poloxamer strongly increased the in vitro release rate of urease from the microspheres. The entrapment efficiency was increased by 44% using the sugars in the preparation. These results clearly show the great potential of small quantities of additive in the formulation to control the properties of the microspheres. The amount and type of additive could be adjusted according to the therapeutic application of the preparation.

Encapsulation of rotavirus into poly(lactide-co-glycolide) microspheres.

Two small-scale double emulsion techniques for incorporation of formaldehyde-inactivated rotavirus particles (FRRV) into poly(lactide-co-glycolide) (PLG) microspheres were developed and optimised. The effects of high-speed homogenisation versus vortex mixing on the double emulsion stability, microsphere size, entrapment efficiency and in vitro release of FRRV in the second emulsification step were studied. A stable double emulsion was verified only when using vortex mixing in this step. Slow removal of the organic phase allowed measurement of the size of the emulsion droplets and subsequent prediction of the size of the resulting microspheres. Microspheres in the size range of 1-10 microm were prepared using both techniques. The homogenisation technique was sensitive to changes in the operating time, the emulsification energy and the volume of the outer aqueous phase, while the vortex technique was more robust. Rotavirus was released in vitro in a triphasic manner with both techniques. The more robust vortex technique was selected for preparation of PLG microspheres containing rotavirus for in vivo studies. After immunisation of mice with a single intramuscular injection, the PLG-FRRV microspheres elicited an IgG antibody response in serum detected by ELISA equally high as that elicited with FRRV alone. These results indicate that the antigenicity of FFRV was retained after incorporation into PLG microspheres using the vortex technique.

Changes in local hepatic blood perfusion during interstitial laser-induced thermotherapy of normal rat liver measured by interstitial laser Doppler flowmetry.

Interstitial laser Doppler flowmetry was used to measure the effect of interstitial laser-induced thermotherapy on local blood perfusion in normal rat liver in the peripheral treatment region elevated to hyperthermic temperatures. The Nd:YAG laser emitting at 1064 nm was utilised as heat generation source. The plane-cut tip of an optical fibre was placed in the middle of the exteriorised left liver lobe. Blood perfusion and temperature were measured in the liver parenchyma 4 mm from the laser fibre. The temperature at the location of the liver temperature sensor was maintained at 41 or 44°C during 30 min by regulating the power of the heating laser. The laser Doppler signal was recorded during and after heat treatment, for a total time of 60 min. At 41°C, a significant increase in perfusion up to 1.3 times the initial value was observed 2-16 min after start of treatment. At 44°C, perfusion decreased continuously during and after treatment, and was significantly different from control 40 min after start of treatment. The results may be valuable in assessing the thermal response of tissues surrounding the target in interstitial laser-induced thermotherapy of liver tumours during conditions of normal blood flow.

Optimizing transurethral microwave thermotherapy: a model for studying power, blood flow, temperature variations and tissue destruction.

OBJECTIVE: To examine the role of microwave power and blood flow on temperature variations and tissue destruction in the prostate, using a theoretical model of transurethral microwave thermotherapy (TUMT), and thus compare fixed-energy TUMT with no intraprostatic temperature monitoring (constant microwave power applied over a fixed period) with 'feedback' TUMT in which the microwave power is adjusted according to the monitored intraprostatic temperature. MATERIALS AND METHODS: The temperature distribution in the prostate was modelled for a typical TUMT catheter at various blood flow rates. The volume of tissue destroyed was simultaneously calculated from cell survival data after thermal exposure. The calculated quantity of tissue destroyed at the different microwave power levels and blood flow rates was used to describe qualitatively the simulated treatments. RESULTS: Treatment monitoring and consistency were better during feedback TUMT than fixed-energy TUMT, in that the former compensated for variations in blood flow rate. The modelled values agreed with observations during real TUMT. CONCLUSIONS: Blood flow rate is a key factor in the outcome of TUMT. Only by measuring intraprostatic temperature is it possible to compensate for the large variations in prostatic blood flow and obtain consistent treatment results. Repeated interruptions prompted by high rectal temperatures should be minimized and preferably avoided, as the quantity of tissue destroyed is then greatly reduced, and in extreme cases the treatment is totally ineffective.

Feedback interstitial diode laser (805 nm) thermotherapy system: ex vivo evaluation and mathematical modeling with one and four-fibers.

BACKGROUND AND OBJECTIVE: In this study a newly developed microprocessor controlled power regulation and thermometry system integrated with a diode laser (805 nm wavelength) was evaluated with respect to temperature distribution, effectiveness of regulation, and ability to predict temperature distributions by computer simulation. STUDY DESIGN/MATERIALS AND METHODS: Experiments were performed in ground bovine muscle using either a single laser fiber or four-fibers. The target temperature at one (feedback) thermistor, placed 5 mm from one of the laser fibers, was set to 50 degrees C and was maintained by means of stepwise power regulation. The temperature distribution was monitored using multiple thermistor probes. A numerical model based on the bioheat equation was used to calculate the temperature distributions. RESULTS: Temperature regulation was excellent with a tendency towards better regulation in the four-fiber than in the single-fiber experiments. Agreement between calculated and measured temperatures was good. The coagulated (> 55 degrees C) and hyperthermic (> 45 degrees C) volumes were 6 and 10-11 times larger, respectively, with four-fibers than with a single fiber. CONCLUSION: It is concluded that the stepwise power regulation system was efficient in maintaining a stable target temperature. The results indicate that the system can produce lesion volumes adequate for treating a relatively large tumor in a single session and that computer simulation may be useful for predicting temperature distribution.

Interstitial laser-induced thermotherapy: influence of carbonization on lesion size.

BACKGROUND AND OBJECTIVE: The size of laser-induced coagulated lesions produced in porcine muscle in vitro using a cylindrical diffusing fiber tip and a conductive heat source, made by covering the diffuser with a hollow steel needle, were compared to investigate the influence of charring. MATERIALS AND METHODS: Light from a Nd:YAG laser was utilized for thermotherapy. A theoretical model for calculating tissue temperature was used to predict the experimental results and to simulate in vivo treatments. RESULTS: The metal-covered tip produced carbonization and tissue vaporization that was not found with the diffuser. After 20 min of irradiation at a laser power of 7 W, the coagulated volumes with and without carbonization were found to be 13.1 cm3 (range 12.4-14.1 cm3, n = 4) and 12.2 cm3 (range 11.5-13.4 cm3, n = 4), respectively. Mathematical simulations showed that in unperfused tissue, a diffusing laser heat source produces smaller lesions than does a conductive heat source at the same power, the difference in coagulated volume becoming smaller with increased treatment time and increased power. CONCLUSION: Using cylindrical diffusers, interstitial laser-induced thermotherapy without carbonization at the fiber tip can be as efficient as treatment with carbonization.

Changes in spectral shape of tissue optical properties in conjunction with laser-induced thermotherapy.

We measured the optical properties on samples of rat liver tissue before and after laser-induced thermotherapy performed in vivo with Nd:YAG laser irradiation. This made it possible to monitor not only the influence of coagulation on the scattering properties but also the influence of damages to vessels and heat-induced damage to blood on the absorption properties. An experimental integrating-sphere arrangement was modified to allow the determination of the g factor and the absorption and scattering coefficients versus the wavelength in the 600-1050-nm spectral region, with the use of a spectrometer and a CCD camera. The results show a relative decrease in the g factor of on average 21 ? 7% over the entire spectral range following thermotherapy, and a corresponding relative increase in the scattering and absorption coefficients of 23 ? 8% and 200 ? 100%, respectively. An increase of on average 200 ? 80% was consequently found for the reduced scattering coefficient. The cause of these changes in terms of the Mie-equivalent average radius of tissue scatterers as well as of the distribution and biochemistry of tissue absorbers was analyzed, utilizing the information yielded by the g factor and the spectral shapes of the reduced scattering and absorption coefficients. These results were correlated with the alterations in the ultrastructure found in the histological evaluation. The average radius of tissue scattering centers, determined by using either the g factors calculated on the basis of Mie theory or the spectral shape of reduced scattering coefficients calculated on the Mie theory, was estimated to be 21-32% lower in treated than in untreated liver samples. The Mie-equivalent average radii of scattering centers in untreated liver tissue deduced by the two methods corresponded well and were found to be 0.31 and 0.29 mum, respectively, yielding particle sizes in the same range as the size of a mitochondrion.

Hepatic inflow occlusion increases the efficacy of interstitial laser-induced thermotherapy in rat.

Interstitial laser-induced thermotherapy (ILT) destroys tumors thermally. ILT was performed for treatment of liver tumors in rats to investigate the effect of hepatic inflow occlusion on temperature distribution and lesion size. Tumors were irradiated for 20 min with near-infrared light from a neodymium:yttrium-aluminum-garnet (Nd:YAG) laser. The laser light at a power of 1.5 W was delivered through a plane-cut optical fiber, the tip of which was placed in the tumor. Rats in group I received ILT without interruption of hepatic blood flow. Those in group II received ILT during hepatic inflow occlusion. Liver temperatures were measured during treatment. After 3 days the animals were sacrificed and the size of the lesions was measured. Occlusion of the hepatic inflow during ILT increased the maximum lesion diameter, as measured at the liver surface, by 47%. Linear interpolation between the temperatures measured at 6 and 12 mm distance from the fiber tip revealed that the temperature at the necrotic border just before the end of treatment was approximately 45 degrees C in both the occluded and nonoccluded groups, indicating that the hepatic inflow occlusion caused no increase in tissue thermal sensitivity. This study shows that occlusion of the hepatic inflow during interstitial laser-induced thermotherapy causes a significant increase in lesion size, which could have implications for the treatment of hepatic tumors.

Tissue temperature control using a water-cooled applicator: implications for transurethral laser-induced thermotherapy of benign prostatic hyperplasia.

A prototype to a water-cooled applicator to be used in transurethral laser-induced thermotherapy of benign prostatic hyperplasia was developed. The flexible applicator was made of Teflon tubes except for the distal outer part which was made of glass, providing a transparent medium for laser radiation and enabling efficient cooling of the surrounding tissue. For heating, laser light from a Nd:YAG laser emitting at 1064 nm, which was coupled into an optical fiber with an institutionally made diffusing tip, was used. Cooling was performed by flushing water through the applicator. By using a mathematical model it was possible to connect the temperature rise of the water in the applicator to the maximum tissue temperature. Tissue light absorption was calculated using Monte Carlo simulations and the heat conduction equation was solved numerically using a finite-difference technique. Experiments on porcine liver in vitro showed that the maximum tissue temperature could be estimated with an average accuracy of 0.4 degree C by measuring the difference in outlet and inlet applicator water temperature and using the thermal model. The results presented suggest that the described method for temperature control can be used during laser prostatectomy to maximize the lesion size while preventing carbonization.

Tumour vessel damage resulting from laser-induced hyperthermia alone and in combination with photodynamic therapy.

This study examined tumour vessel injury resulting from laser-induced hyperthermia alone and in combination with photodynamic therapy (PDT) in the treatment of rat liver tumours by means of scanning electron microscopy. A total of 18 Wistar rats were divided into three groups. Group I (six animals) underwent hyperthermia for 15 min (15-min hyperthermia). Group II (six animals) underwent hyperthermia for 30 min (30-min hyperthermia). Group III (six animals) received the combined treatment of PDT and 30-min hyperthermia. For PDT, delta-amino laevulinic acid at a dose of 60 mg/kg of body weight was intravenously administered 60 min before irradiation at 635 nm. The morphological results indicated that 15-min hyperthermia gave rise to an increase in permeability of the vessels in the treated tumour. Thirty-min hyperthermia caused extreme oedema of vascular endothelial cells and restrictive openings of tumour branch vessels. The combined therapy of PDT and hyperthermia destroyed tumour vasculature. Large breaks of the inner wall of the treated tumour vessels were deeply involved in the basement membrane of the vessel. The results indicate that there may be a close link between inhibition of tumour growth and degree of damage to tumour vessels.

Mathematical modelling of dynamic cooling and pre-heating, used to increase the depth of selective damage to blood vessels in laser treatment of port wine stains.

Based on the assumption that the maximum irradiance allowed during laser treatment of port wine stains is limited by the temperature rise at the dermoepidermal junction, we theoretically investigated how much the irradiance could be increased by dynamically cooling the skin surface. The heat condution equation was solved numerically in cylindrical coordinates using a skin model composed of four layers. The laser-light absorption was calculated using Monte Carlo simulations. The transient thermal behaviour of the skin was modelled when cooling with water at a temperature of 0 degrees C and with liquid nitrogen at a temperature of -196 degrees C. With cooling, an increase in the maximum irradiance by a factor of 2.3-3.6 was theoretically permitted depending on the irradiation time, wavelength and mode of cooling. The corresponding increase in vessel selective damage depth was predicted to be 0.4-0.5 mm. A new concept for increasing the depth of vessel selective damage is introduced where the initial temperature profile of the skin is reshaped by using not only surface cooling but also laser irradiation. By pre-irradiating the skin with near-infrared light without selective absorption by the tissue chromophores in conjunction with surface cooling, a maximum temperature at a depth of 1 mm from the dermoepidermal junction was theoretically achieved. A subsequent 0.1 s pulse from a frequency doubled Nd:YAG laser is theoretically shown to selectively destroy vessels up to a depth of 0.8 mm from the dermoepidermal junction. By pre-heating at 1064 nm and treating at 532 nm in conjunction with surface cooling, the theoretical results indicate that the Nd:YAG laser can compete in effectiveness with the flashlamp-pumped dye laser in the treatment of port wine stains.

Theoretical analysis of transurethral laser-induced thermo-therapy for treatment of benign prostatic hyperplasia. Evaluation of a water-cooled applicator.

A mathematical model for predicting the temperature rise in transurethral laser-induced thermo-therapy for benign prostatic hyperplasia was developed. In the model an optical line source emitting light from an Nd:YAG laser isotropically was placed in the urethra. Water cooling of the urethral epithelium was modelled using a two-tube system. The relationship between the difference in outlet and inlet water temperatures and the highest tissue temperature level reached was theoretically investigated. It was found that the water temperature difference was linearly dependent on the steady-state maximum tissue temperature. The theoretical calculations suggest that the water-cooled applicator can be used to measure the maximum tissue temperature. With temperature control, the prostatic tissue temperature can be prevented from exceeding the boiling point of water, excluding tissue carbonization. The model was also used to evaluate the influence of a number of different parameters on the damaged tissue volume. Increasing the urethral lumen radius by a factor of two by means of inserting different sized tubes was found to augment the tissue volume raised to therapeutic temperatures by up to 50%. The calculations showed that cooling of the urethral epithelium can result in an increase in the damaged volume by 80% as compared to not applying any cooling. The temperature of the cooling water was found to influence the tissue temperature only to a small extent.

A mathematical model for predicting the temperature distribution in laser-induced hyperthermia. Experimental evaluation and applications.

A time-dependent mathematical model for the heat transfer in laser-induced hyperthermia has been developed. The model calculates the temperature distribution in surface-irradiated tissues. Good agreement was found between the predictions of the model and in vitro experimental results obtained for bovine liver irradiated with an expanded beam from a Nd:YAG laser. Surface evaporation of water was included in the model and experimentally verified. The discrepancy between the measured and the calculated rise in temperature at three different depths on the axis of symmetry of the irradiating beam was found to be less than 5% after 15 min of irradiation. When irradiating in air and not accounting for the surface evaporation in the model, the accuracy of the model predictions was only 75-80%. The model was then used to investigate the influence of surface evaporation of water on the total temperature distribution theoretically in a clinically relevant case. From the numerical simulations, it was shown that, simply by providing a moistened liver surface, the maximum steady-state temperature could be forced into the tissue to a depth of 4 mm. It was also shown that, by employing the numerical model during the initial phase of hyperthermia treatment, overshooting of the temperature during the transient thermal build-up time could be prevented.