Comprehensive Characterization of Hearing Loss and Tinnitus in Military-Affiliated and Non-Military-Affiliated Individuals.

PURPOSE: Military-affiliated individuals (MIs) are at a higher risk of developing hearing loss and tinnitus. While these disorders are well-studied in MIs, their impact relative to non-military-affiliated individuals (non-MIs) remains understudied. Our study compared hearing, speech-in-noise (SIN) perception, and tinnitus characteristics between MIs and non-MIs. METHOD: MIs (n = 84) and non-MIs (n = 193) underwent hearing threshold assessment and Quick Speech-in-Noise Test. Participants with tinnitus completed psychoacoustic tinnitus matching, numeric rating scale (NRS) for loudness and annoyance, and Tinnitus Functional Index. Comorbid conditions such as anxiety, depression, and hyperacusis were assessed. We used a linear mixed-effects model to compare hearing thresholds and SIN scores between MIs and non-MIs. A multivariate analysis of variance compared tinnitus characteristics between MIs and non-MIs, and a stepwise regression was performed to identify predictors of tinnitus severity. RESULTS: MIs exhibited better hearing sensitivity than non-MIs; however, their SIN scores were similar. MIs matched their tinnitus loudness to a lower intensity than non-MIs, but their loudness ratings (NRS) were comparable. MIs reported greater tinnitus annoyance and severity on the relaxation subscale, indicating increased difficulty engaging in restful activities. Tinnitus severity was influenced by hyperacusis and depression in both MIs and non-MIs; however, hearing loss uniquely contributed to severity in MIs. CONCLUSIONS: Our findings suggest that while MIs may exhibit better or comparable listening abilities, they were significantly more affected by tinnitus than non-MIs. Furthermore, our study highlights the importance of assessing tinnitus-related distress across multiple dimensions, facilitating customization of management strategies for both MIs and non-MIs.

Spatial morphological and molecular differences within solid tumors may contribute to the failure of vascular disruptive agent treatments.

BACKGROUND: Treatment of solid tumors with vascular disrupting agent OXi4503 results in over 90% tumor destruction. However, a thin rim of viable cells persists in the tumor periphery following treatment, contributing to subsequent recurrence. This study investigates inherent differences in the microenvironment of the tumor periphery that contribute to treatment resistance. METHODS: Using a murine colorectal liver metastases model, spatial morphological and molecular differences within the periphery and the center of the tumor that may account for differences in resistance to OXi4503 treatment were investigated. H&E staining and immunostaining were used to examine vessel maturity and stability, hypoxia and HIF1α levels, accumulation of immune cells, expression of proangiogenic factors/receptors (VEGF, TGF-ß, b-FGF, and AT1R) and expression of EMT markers (ZEB1, vimentin, E-cadherin and ß-catenin) in the periphery and center of established tumors. The effects of OXi4503 on tumor vessels and cell kinetics were also investigated. RESULTS: Significant differences were found between tumor periphery and central regions, including association of the periphery with mature vessels, higher accumulation of immune cells, increased growth factor expression, minimal levels of hypoxia and increased evidence of EMT. OXi4503 treatment resulted in collapse of vessels in the tumor center; however vasculature in the periphery remained patent. Similarly, tumor apoptosis and proliferation were differentially modulated between centre and periphery after treatment. CONCLUSIONS: The molecular and morphological differences between tumor periphery and center may account for the observed differential resistance to OXi4503 treatment and could provide targets for drug development to totally eliminate metastases.

Hyperbaric oxygen therapy reduces the severity of ischaemia, preservation and reperfusion injury in a rat model of liver transplantation.

BACKGROUND: Approaches to increase organ availability for orthotopic liver transplantation (OLT) often result in the procurement of marginal livers that are more susceptible to ischaemia, preservation and reperfusion injury (IPRI). METHODS: The effects of post-OLT hyperbaric oxygen (HBO) therapy on IPRI in a syngeneic rat OLT model were examined at various time-points. The effects of IPRI and HBO on hepatocyte necrosis, apoptosis, proliferation, and sinusoidal morphology and ultrastructure were assessed. RESULTS: Post-OLT HBO therapy significantly reduced the severity of IPRI; both apoptosis [at 12 h: 6.4 ± 0.4% in controls vs. 1.6 ± 0.7% in the HBO treatment group (p < 0.001); at 48 h: 2.4 ± 0.2% in controls vs. 0.4 ± 0.1% in the HBO treatment group (p < 0.001)] and necrosis [at 12 h: 18.7 ± 1.8% in controls vs. 2.4 ± 0.4% in the HBO treatment group (p < 0.001); at 48 h: 8.5 ± 1.3% in controls vs. 3.4 ± 0.9% in the HBO treatment group (P= 0.019)] were decreased. Serum alanine transaminase was reduced [at 12 h: 1068 ± 920 IU/l in controls vs. 370 ± 63 IU/l in the HBO treatment group (P= 0.030); at 48 h: 573 ± 261 IU/l in controls vs. 160 ± 10 IU/l in the HBO treatment group (P= 0.029)]. Treatment with HBO also promoted liver regeneration [proliferation at 12 h: 4.5 ± 0.1% in controls vs. 1.0 ± 0.3% in the HBO treatment group (p < 0.001); at 48 h: 8.6 ± 0.7% in controls vs. 2.9 ± 0.2% in the HBO treatment group (p < 0.01)] and improved sinusoidal diameter and microvascular density index. CONCLUSIONS: Hyperbaric oxygen therapy has persistent positive effects post-OLT that may potentially transfer into clinical practice.

Induction of Th1Immune responses following laser ablation in a murine model of colorectal liver metastases.

BACKGROUND: Preliminary experimental studies have suggested that the in situ destruction of tumor tissue by local laser ablation (LA) may also stimulate host immunity against cancer. We investigated local and systemic induction of immune responses after laser ablation in the setting of residual tumor. METHODS: A murine colorectal cancer (CRC) liver metastasis model was used. Selected tumors of liver CRC bearing mice and livers of mice without tumor induction were treated with LA. Liver and tumor tissues from the ablation sites and from distant sites were collected at various time points following LA and changes in CD3+ T cells and Kupffer cells (F4/80 marker) infiltration and the expression of interferon gamma (IFNγ) were investigated by immunohistochemistry and ELISpot. Base line levels of CD3+ T cells and Kupffer cells were established in untreated mice. RESULTS: The presence of tumor induced significant accumulation of CD3+ T cells and Kupffer cells at the tumor-host interface, within the tumor vascular lakes and increased their baseline concentration within the liver parenchyma. LA of the liver induced accumulation of CD3+ T-cells and Kupffer cells at the site of injury and systemic induction of immune responses as discerned by the presence of IFNγ secreting splenocytes. LA of liver tumors induced significant increase of CD3+ T-cells at site of injury, within normal liver parenchyma, and the tumor-host interface of both ablated and distant tumors. In contrast Kupffer cells only accumulated in ablated tumors and the liver parenchyma but not in distant tumors. IFNγ expression increased significantly in ablated tumors and showed an increasing trend in distant tumors. CONCLUSION: Laser ablation in addition to local tumor destruction induces local and systemic Th1 type immune responses which may play a significant role in inhibiting tumor recurrence from residual micrometastases or circulating tumor cells.

Changes in growth factor levels after thermal ablation in a murine model of colorectal liver metastases.

OBJECTIVES: This study examines changes in the expression of growth factors following thermal ablation (TA) of selected colorectal cancer (CRC) liver metastases. METHODS: Using mice with established CRC liver metastases, two tumours in each animal were thermally ablated. Liver and tumour tissues were collected at various time-points (days 0, 1, 2, 3, 5 and 7) following TA treatment from the ablation site and from sites distant from ablated tumour. Changes in growth factor expression (epidermal growth factor [EGF], vascular endothelial growth factor [VEGF], hepatocyte growth factor [HGF] and transforming growth factor-ß[TGF-ß]) in comparison with baseline levels (non-ablated) were assessed by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry. RESULTS: Baseline TGF-ß and VEGF levels in the liver parenchyma of tumour-bearing mice were significantly higher than levels in naive liver parenchyma. Levels of VEGF and HGF decreased after TA treatment in all tissues. Levels of EGF decreased in ablated and distant tumour tissues, but displayed a tendency to increase in liver tissue. Levels of TGF-ß also decreased during the first 2 days following TA, but later increased in liver and tumour tissues distant from the ablation site to a level that reached significance in tumour tissue at day 7 (P < 0.001). Decreases in growth factor levels were also observed in animals that underwent laparotomy without TA treatment, which indicates that these decreases were caused by the experimental procedure. CONCLUSIONS: Tumour induces upregulation of TGF-ß and VEGF in liver parenchyma. Growth factors decreased after TA, but this appears to be the result of the experimental procedure rather than the TA itself. However, TA resulted in increased levels of TGF-ß, which may contribute to tumour recurrence.

Hyperbaric oxygen improves capillary morphology in severe acute pancreatitis.

OBJECTIVES: This article aims to determine the effect of acute pancreatitis on microvascular morphology and the impact of treatment with hyperbaric oxygen (HBO). METHODS: Sixty-seven male Wistar rats were induced with acute pancreatitis by retrograde bile duct injection. Rats were randomized to 12-hourly HBO or control treatment. Two rats in each group were killed at baseline and 24, 48, and 72 hours postinduction, and a cast of the pancreatic microvasculature was examined using scanning electron microscopy. RESULTS: Normal pancreatic vasculature is a dense network with a consistent capillary diameter. In acute pancreatitis, mean capillary diameter is increased at 24 hours (P < 0.001) and further increased at 48 hours (P = 0.007). From 24 hours, diameter heterogeneity is increased (P < 0.001) and capillary density is reduced (P < 0.001). Hyperbaric oxygen has a significant effect on vascular morphology changes from 48 hours after induction. Capillary diameter and heterogeneity of diameter are decreased by HBO (both P < 0.001). Capillary density is increased by HBO at 48 and 72 hours (P < 0.001). CONCLUSIONS: In acute pancreatitis, structural capillary diameter and heterogeneity of diameter increase and capillary density decreases. These parameters are all improved by HBO treatment. Hyperbaric oxygen treatment normalizes the pancreatic microvasculature after acute pancreatitis and may be a potentially effective treatment of this disease.

Vascular targeting agent Oxi4503 inhibits tumor growth in a colorectal liver metastases model.

BACKGROUND AND AIM: Oxi4503 is a potent vascular targeting agent belonging to the family of combretastatins. These agents produce an acute reduction in tumor blood flow leading to tumor necrosis. Despite evidence of its efficacy in certain malignancies, the effect on colorectal liver metastases remains largely unknown. This study investigates the effect of Oxi4503 on colorectal liver metastases in a murine model. METHODS: The effect of a single dose of Oxi4503 on established tumors in a murine model of colorectal liver metastases was assessed following administration of 1-50 mg/kg Oxi4503. In addition, the effects of continuous, daily and intermittent dosing (1-5 mg/kg) on tumor necrosis and growth were studied by quantitative histological and stereological analysis. The effect of multiple dosing on long-term survival was also assessed using the Kaplan-Meier analysis. The microvascular effects of therapy were studied by scanning electron microscopy of microvascular resin casts. RESULTS: A single dose of 5 or 50 mg/kg of Oxi4503 produced significant tumor necrosis compared to the controls. Subcutaneous continuous dosing infusion with Oxi4503 at 1 mg/kg/day reduced tumor growth compared to the controls, but was associated with marked systemic toxicity. Daily administration over 21 days was associated with significant mortality. Intermittent dosing of Oxi4503 (two doses, 3 days apart) produced the greatest reduction in tumor growth with minimal toxicity and conferred a significant survival advantage. Microvascular casts demonstrated significant disruption of tumor vessels. CONCLUSIONS: A single dose of Oxi4503 produced significant necrosis and microvascular injury in colorectal liver metastases. Intermittent dosing with Oxi4503 produced the maximum reduction in tumor growth, minimal toxicity, and a significant improvement in survival. Oxi4503 is a potential anticancer agent. Further research into its mechanism of action and its synergistic use with other therapies is warranted.

Hyperbaric oxygen therapy for severe acute pancreatitis.

Despite improvements in the supportive management of severe acute pancreatitis over the last decade, the morbidity and mortality rate remains high. The main feature of this condition is pancreatic necrosis leading to sepsis, with both localized and systemic inflammatory response syndromes. Early pathophysiological changes of the pancreas include alterations in microcirculation, ischemia reperfusion injury, and leukocyte and cytokine activation. The efficacy of hyperbaric oxygen (HBO) therapy in improving these pathophysiological disturbances is documented for various conditions. However, its effect in the treatment of severe acute pancreatitis is undetermined. This report documents the case of a 56-year-old woman presenting with severe acute pancreatitis treated by HBO therapy. The severity of disease was based on an Acute Physiology and Chronic Health Evaluation (APACHE II) illness grading score of 11 and a Baltazar based computed tomography severity index (CTSI) score of 9. Administration of 100% oxygen was commenced within 72 h of presentation at a pressure of 2.5 atmospheres for 90 min and given twice daily for a total of 5 days. Therapy was well tolerated with improvements in APACHE II and CTSI grading scores. HBO therapy for severe acute pancreatitis appeared to be safe and may have a role in improving treatment outcomes. Further study is required.

Hyperbaric oxygen therapy reduces severity and improves survival in severe acute pancreatitis.

Severe acute pancreatitis is characterized by pancreatic necrosis, resulting in local and systemic inflammation. Hyperbaric oxygen (HBO) therapy modulates inflammation, but has not been extensively studied in pancreatitis. This study investigates the effects of HBO in a rat model of severe acute pancreatitis. Sixty-four rats were induced with severe pancreatitis using 4% sodium taurocholate and randomized to HBO treatment or control. HBO was commenced 6 h after induction (100% oxygen at 2.5 atmospheres for 90 min) and continued every 12 h for a maximum of eight treatment episodes. Surviving animals were killed at 7 days. Severity of pancreatitis was graded macroscopically and microscopically. Lung edema was calculated using wet and dry lung weights. Macroscopic and microscopic severity scores (mean +/- SE) of HBO-treated animals with pancreatitis (8.3 +/- 0.7; 9.6 +/- 0.4) were lower than those of controls (10.5 +/- 0.5; 11.1 +/- 0.4) (p = 0.02 and p = 0.03, respectively). The HBO-treated group had reduced pancreatic necrosis compared to controls (40 +/- 4% vs. 54 +/- 4%; p = 0.003). There was no difference in pulmonary edema between the groups. Median survival in the HBO-treatment group was 51 h, compared to 26 h in controls. Day-7 survival was significantly improved in the HBO-treated animals compared to controls (40% vs. 27%; p = 0.04). HBO therapy reduces overall severity, decreases the extent of necrosis, and improves survival in severe acute pancreatitis.

Impact of blood flow occlusion on liver necrosis following thermal ablation.

BACKGROUND: Laser, radiofrequency and microwave are common techniques for local destruction of liver tumours by thermal ablation. The main limitation of thermal ablation treatment is the volume of necrosis that can be achieved. Blood flow occlusion is commonly advocated as an adjunct to thermal ablation to increase the volume of tissue necrosis based on macroscopic and histological assessment of immediate or direct thermal injury. This study examines the impact of blood flow occlusion on direct and indirect laser induced thermal liver injury in a murine model using histochemical methods to assess tissue vitality. METHODS: Thermal ablation produced by neodymium yttrium-aluminium-garnet laser (wavelength 1064 nm) was applied to the liver of inbred male CBA strain mice at 2 W for 50 s (100 J). Treatment was performed with and without temporary portal vein and hepatic artery blood flow occlusion. Animals were killed upon completion of the procedure to assess direct thermal injury or at 24, 48 and 72 h to assess the progression of tissue damage. The maximum diameter of necrosis was assessed by vital staining for nicotinamide adenine dinucleotide (NADH) diaphorase. Microvascular changes were assessed by laser Doppler flowmetry, confocal in vivo microscopy and scanning electron microscopy. RESULTS: The direct thermal injury (mean SE) assessed by NADH diaphorase staining was significantly greater following thermal ablation treatment without blood flow occlusion than with blood flow occlusion (3.3 (0.4) mm vs 2.9 (0.3) mm; P = 0.005). Tissue disruption, cracking and vacuolization was more pronounced adjacent to the fibre insertion site in the group treated with thermal ablation combined with blood flow occlusion. There was an equivalent increase in the extent of injury following therapy in both groups that reached a peak at 48 h. The maximum diameter of necrosis in the thermal ablation alone group at 48 h was significantly greater than the thermal ablation combined with blood flow occlusion group (5.8 (0.4) mm vs 5.3 (0.3) mm; P = 0.011). The patterns of microvascular injury were similar in both groups, varying in extent. CONCLUSION: Temporary blood flow inflow occlusion appears to decrease the extent of initial injury measured by vital staining techniques and does not alter the time sequence of progressive tissue injury following thermal ablation therapy.

Progressive microvascular injury in liver and colorectal liver metastases following laser induced focal hyperthermia therapy.

BACKGROUND AND OBJECTIVES: Focal hyperthermia by laser or radiofrequency is currently the preferred method for local ablation of liver tumors. The underlying mechanism of action of focal hyperthermia, in particular the relationship between the microvascular and tissue effect is uncertain and was investigated in a murine model. STUDY DESIGN/MATERIALS AND METHODS: Focal hyperthermia produced by a Neodymium-Yttrium-Aluminium-Garnet laser (wavelength 1,064 nm) was applied to the normal liver and colorectal cancer liver metastases in inbred male CBA strain mice at 2 W for 50 seconds (100 J). Tissue injury was assessed at 0, 24, 48, 72, 120, and 168 hours following therapy by measurements of necrosis in tissue sections stained for nicotinamide adenine dinucleotide (NADH) diaphorase activity. Characteristics of microvascular injury were assessed at the various time points by scanning electron microscopy (SEM) of vascular resin casts, Laser Doppler flowmetry, and confocal in vivo microscopy. RESULTS: Focal hyperthermia produced progressive tissue and vascular injury. There was an initial reduction in blood flow and increased vascular permeability in the microcirculation of both tumor and liver tissue immediately following heat application as assessed by laser Doppler flowmetry and confocal in vivo microscopy, respectively. SEM of vascular casts showed heterogeneous regions of microvascular injury immediately following heat application. The extent of initial vascular disruption or occlusion on SEM of vascular resin casts (mean+/-SE) was significantly less than the tissue necrosis in liver (1.9+/-0.1 mm vs. 3.0 mm+/-0.2 mm P<0.001), but was equivalent to the tissue injury in tumor tissue (3.5 mm+/-0.2 mm vs. 3.6 mm+/-0.1 mm P = 0.907). This was followed by a progressive increase in both microvascular and tissue injury in liver and tumor that peaked by 72 hours following treatment. The peak microvascular injury and tissue damage in liver (6.6 mm+/-0.2 and 6.3 mm+/-0.2 mm, respectively) was significantly greater than the extent of microvascular and tissue damage in tumors (4.8 mm+/-0.2 mm and 4.5 mm+/-0.2 mm, respectively) (P<0.001). The progression of microvascular injury in liver and tumor at times preceded the tissue injury. CONCLUSION: Focal hyperthermia produces both progressive microvascular and tissue damage in liver and colorectal liver metastases. An increase in tissue injury following focal hyperthermia may be a direct result of progressive microvascular damage. Tumor vessels appear more susceptible to direct focal hyperthermia destruction than liver sinusoids. The liver sinusoids are however more susceptible to progressive damage or occlusion following the initial laser thermal stimulus.

Comparison of 980- and 1064-nm wavelengths for interstitial laser thermotherapy of the liver.

OBJECTIVE: Interstitial laser thermotherapy (ILT) of liver tumors is generally performed using neodyium yttrium-aluminium-garnet (Nd-YAG) lasers. More versatile diode units, developed predominantly for other clinical applications, may be equally suitable for ILT. This study compares the efficacy of diode and Nd-YAG lasers in achieving maximum tissue necrosis, at low power, in a murine model. METHODS: Thermal ablation was induced in the liver of CBA strain mice by diode (980-nm wavelength) and Nd-YAG (1064-nm wavelength) lasers using 400-microm diameter bare fibers. Treatment time prior to tissue charring was determined for both lasers at a power output of 2 W. Tissue temperature was recorded upon completion of therapy 3 mm from the fiber insertion site. The maximum diameter of necrosis was accurately assessed by nicotinamide adenine dinucleotide (NADH) diaphorase tissue staining. RESULTS: Maximum diameter of tissue necrosis prior to charring occurred at 20 s (40 J) with the diode laser compared to 50 s (100 J) with the Nd-YAG laser. The maximum diameter of necrosis (mean [SEM]) produced by the diode laser, 5.9 mm (0.14), was equivalent to the necrosis induced by the Nd-YAG laser, 5.9 mm (0.14) (p = 0.963). Tissue temperature 3 mm from the fiber application site immediately following ILT in the diode laser group, 40.8 degrees C (0.93), was not statistically different than that of the Nd-YAG laser group, 39.0 degrees C (0.86) (p = 0.452). Tissue charring consistently prevented treatment beyond 20 s at 2W by the diode laser. CONCLUSION: Low power ILT with diode and Nd-YAG lasers achieves equivalent maximal necrosis when applied to the liver by a bare fiber. Treatment time to produce maximal necrosis is however significantly shorter with the diode laser.

The apoptotic response of liver and colorectal liver metastases to focal hyperthermic injury.

BACKGROUND: Ablation of liver tumours by focal hyperthermia causes tissue injury not only by direct effects, but also by progressive tissue damage following the initial heat application. The mechanism by which this progressive injury occurs remains undefined. Stimulation of apoptosis following the initial heat stimulus may be involved in this progression. The role of apoptosis in the subsequent progression of focal hyperthermia injury was investigated in liver and colorectal liver metastases in a murine model. MATERIALS AND METHODS: Focal hyperthermia produced by laser (Nd-YAG--wavelength 1064 nm) was applied to the liver and colorectal liver metastases in CBA mice (2 Watts for 50 seconds). The animals were killed at 0, 12, 24, 48, 72, 120 and 168 hours after the application of focal hyperthermia. Haematoxylin and eosin staining and immunohistochemistry were performed on paraffin sections to assess the extent of tissue necrosis. Apoptosis was examined by assessment of DNA fragmentation using terminal deoxynucleotidyl transferase d-uridine triphosphate nick end labelling (TUNEL) and activated Caspase 3 immunostaining. The sequence of the apoptotic response was determined at the treated tissue margins and compared to untreated liver and tumour. RESULTS: Focal hyperthermia produced progressive tissue injury in both liver and colorectal liver metastases. TUNEL labelling was less specific than activated Caspase 3 in detecting apoptotic cells. Apoptosis was detected and peaked at 12 hours following therapy based on activated Caspase 3 staining, before returning to baseline at 72 hours. In tumour tissue, the apoptotic response was more sustained, peaking at 24 hours before returning to baseline levels by 96 hours following therapy. CONCLUSION: Increased apoptosis occurs following the application of focal hyperthermia to normal liver and colorectal metastases. The apoptotic response is more sustained in tumour tissue and contributes to the progressive injury that is evident after the initial heat stimulus.

Focal hyperthermia produces progressive tumor necrosis independent of the initial thermal effects.

Focal hyperthermia, produced using laser, radio frequency, and microwave, is used to treat liver tumors. The exact mechanisms of tissue destruction using focal hyperthermia are, however, unknown. Clinical and experimental studies suggest a progression of injury after cessation of the initial heat stimulus. This study investigates the mechanisms and time sequence of progressive tissue necrosis induced using focal hyperthermia in a murine model of colorectal liver metastases. Focal hyperthermia produced using a neodymium-yttrium aluminum garnet (Nd-YAG) laser source was applied to the normal liver and colorectal cancer liver metastases in inbred male CBA strain mice. The extent of direct lethal thermal injury was assessed histochemically using vital stain for nicotinamide adenine dinucleotide (NADH) diaphorase immediately after laser application. Tissue injury at subsequent time points was assessed using both NADH diaphorase staining and routine histology to determine the temporal relationship between tissue necrosis and time. Thermal injury occurring immediately after the application of 100 joules of energy was greater in the tumor tissue than in the normal liver (mean [standard error of the mean (SEM)]), measuring 23.5 (3.4) and 16.3 (2.6) mm(3), respectively (P=0.046), despite similar tissue temperature profiles. There was a significant increase in tissue necrosis after initial injury that was greater in the normal liver than in the tumor tissue. In the normal liver, the peak volume of necrosis was 137.4 (9.8) mm(3) and occurred at 3 days, whereas in the tumor tissue the peak was 49.0 (3.5) mm(3) at 4.5 days (P < 0.001). Focal hyperthermia produces tissue necrosis that occurs in two phases. The first phase is caused by the direct lethal thermal injury followed by a second phase involving a progression of necrosis beyond the initial thermal effects. The normal liver and the tumor tissue responded differently to focal hyperthermia. In the tumor tissue, the direct injury is more pronounced, whereas the progression of injury is more rapid and extensive in the normal liver.

Long-term survival of patients with unresectable colorectal liver metastases treated by percutaneous interstitial laser thermotherapy.

In situ ablation of colorectal cancer (CRC) liver metastases is an accepted form of treatment for selected patients. It is associated with low morbidity and mortality and increases the number of patients who may benefit from therapy compared to resection alone. This study assesses the impact of interstitial laser thermotherapy (ILT) on local tumor control and long-term survival in patients with unresectable CRC liver metastases. Percutaneous ILT was performed in patients with unresectable CRC liver metastases between January 1992 and December 1999 using a bare-tip quartz fiber connected to an Nd:YAG laser source. This was prior to the routine use of a diffusing fiber for ablative therapy. Treatment was monitored with real-time ultrasonography. Tumors were considered unresectable based on their anatomic location or the extent of liver involvement. Patients with extrahepatic disease, more than five liver metastases, or tumors larger than 10 cm in diameter were excluded from this study. Local tumor control was assessed by dynamic computed tomography (CT) 6 months after therapy. Long-term follow-up was undertaken, and the impact of various factors on survival was analyzed. Eighty patients with a mean age of 63.8 years were suitable for ILT. In total, 168 liver tumors with a median diameter of 5 cm (range 1-10 cm) were so treated. There were no procedure-related deaths. The overall complication rate was 16%, with all cases managed conservatively. Bradycardia (n = 5), pneumothorax (n = 3), and persistent pyrexia (n = 3) were the most common complications. Complete tumor ablation was noted in 67% of patients assessed by CT 6 months following the initial therapy. Median follow-up was 35 months (range 4-96 months), with 10 patients alive at the end of this period. Altogether there were 67 deaths, which were related to hepatic disease in 55 cases and to extrahepatic disease in 9; they were unrelated to malignancy in 3 others. Three patients were excluded from follow-up after ILT down-staging of tumors that allowed complete surgical resection. The median disease-free survival of patients treated by ILT was 24.6 months, with a 5-year survival of 3.8%. Poor tumor differentiation and the presence of more than two hepatic metastases were associated with lower overall survival (p < 0.01). Fourteen patients treated by ILT for postoperative hepatic recurrences had the best outcome, with a median overall survival of 36.3 months and a 5-year survival of 17.2%. Percutaneous ILT is a minimally invasive, safe, effective technique that appears to improve overall survival in specific patients with unresectable CRC liver metastases, compared to the natural history of untreated disease reported in the literature.

A model of partial hepatectomy in mice.

A versatile, simple, and reproducible model of hepatectomy is essential for the study of liver regeneration and its effects on various pathological processes. A murine model of liver resection and regeneration suitable for research is described. Male inbred CBA mice 6-8 wk old were used in all experiments. The contribution of the hepatic lobes to the total liver mass was determined by wet weight measurements. Resection of 37% (n = 10) and 70% (n = 10) liver volume was performed using hemostatic clips to ligate the hepatic lobe pedicles. Animals were recovered and subsequently killed 21 days postoperatively Liver mass was determined and compared to control animals (n = 17) to assess the completeness of liver regeneration. There were no operative deaths in animals undergoing either 37% or 70% hepatectomy. The procedures could be performed expediently, and animal recovery was complete. Liver mass (grams) assessed 21 days postoperatively [mean (SE)] in both the 37% resection, 1.76 g (0.07), and 70% resection, 1.56 g (0.05), groups was not significantly different from control animals, 1.64 g (0.07) (p =.265). Thus, partial hepatectomy can be performed safely and rapidly in mice using haemostatic clip ligation of hepatic lobes, with no impairment to the subsequent process of liver regeneration.

Effect of interstitial laser hyperthermia in a murine model of colorectal liver metastases: scanning electron microscopic study.

Interstitial laser hyperthermia (ILH) is an in situ ablative technique used to treat colorectal liver metastases. The relatively high recurrence of tumor after treatment by ILH may be related to incomplete destruction. Little is known about the effectiveness of ILH for destroying tumor microvasculature. The aim of this study was to define the changes to the microvascular architecture of tumors after treatment with ILH, specifically focusing on the completeness of tumor vasculature destruction. An intrasplenic induction model of liver metastases in 4- to 6-week-old male inbred CBA mice was used. Laser hyperthermia was applied to liver and tumor tissue using a bare optical quartz fiber from a Medilas Fibertom 4100 Nd:YAG surgical laser generator. The animals underwent microvascular corrosion casting of the livers immediately after application of ILH. Microvascular casts were then prepared and studied by scanning electron microscopy. ILH produced complete, uniform destruction of the tumor microvasculature with compete hemostasis. Blood flow in vessels larger than 100 microm diameter had a relatively protective effect, although ILH was able to overcome this barrier effectively by increasing the energy applied. ILH produces complete destruction of tumor microvasculature with hemostasis. The protective effect of blood flow in larger vessels can be overcome by the appropriate use of higher energy levels.