Comparison of Local Injection of Fresh Frozen Plasma to Traditional Methods of Hemostasis in Minimally Invasive Procedures.

RATIONALE AND OBJECTIVES: To evaluate different techniques for reducing hemorrhagic complications in coagulopathic patients with elevated international normalized ratio having an image-guided percutaneous invasive procedure; techniques included systemic transfusion of fresh frozen plasma (FFP), local injection of FFP, percutaneous injection of gelatin sponge, and percutaneous placements of angiographic coils. MATERIALS AND METHODS: Retrospective review of 232 consecutive patients with known coagulopathy undergoing image-guided minimally invasive procedures were selected. Ninety-one patients had local FFP injected, 40 patients underwent local synthetic gelatin injection, 16 patients had percutaneous coil embolization, and 85 patients received systemic FFP. The number of bleeds, complications related to bleeds, and systemic complications were recorded. A 30 cc threshold was used to delineate significant bleeding. RESULTS: No patients experienced clinically significant or insignificant bleeding with local FFP injection (P value <.05). Other local hemostatic methods (Gelfoam, systemic FFP, and coil embolization) were associated with higher levels of bleeding (12.5%, 17.1%, 37.5%, respectively) and complications (7.5%, 31.4%, 37.5%, respectively). Systemic FFP infusion was associated with respiratory, infectious, and mortal complications. CONCLUSIONS: Local injection of blood products provides a safe and efficacious hemostatic agent to reduce the incidence of postprocedural bleeding. The technique is associated with lower rates of bleeding and systemic complications when compared to other local and systemic techniques. Further randomized prospective studies with a larger patient cohort need to be performed to corroborate these initial findings.

Efficiency of combined blocking of aerobic and glycolytic metabolism pathways in treatment of N1-S1 hepatocellular carcinoma in a rat model.

BACKGROUND/AIM: The aim of this study was to determine whether the addition of bumetanide (BU), a glycolytic metabolism pathway inhibitor, to arterial embolization improves tumor necrosis of N1-S1 hepatocellular carcinoma in a rat model. MATERIALS AND METHODS: N1-S1 tumors were surgically implanted in the liver of 14 Sprague-Dawley rats. The rats were divided into three groups: In control group (n = 5), 1 ml of normal saline was injected intra-arterially. The tumor in the transarterial embolization group (TAE, n = 4) was embolized using 10 mg of 50-150 µ polyvinyl alcohol (PVA) particles and embolization plus BU group (TAE + BU, n = 5) were embolized with 10 mg of PVA plus 0.04 mg/kg of BU. Tumor volume was measured using two-dimensional ultrasound before intervention and twice a week afterward. Relative tumor volume after the intervention was calculated as the percentage of preinterventional tumor volume. After 4 weeks of observation, the rats were sacrificed for histopathological evaluation. RESULTS: No statistically significant difference was detected in the preintervention tumor sizes between the three groups (P > 0.05). In the control group, the relative tumor volume increased to 142.5% larger than baseline measurements. In the TAE group, the tumor volume decreased by 18.2 ± 12.2%. The tumor volume in the TAE + BU group decrease by 90.4 ± 10.2%, which was 72.2% more than in TAE only group (P < 0.0001). Histopathological evaluation demonstrated no residual tumor in the TAE + BU group. CONCLUSION: Tumor necrosis significantly increased in N1-S1 tumor that received BU at the time of TAE when compared to TAE alone.

Pyogenic liver abscesses: a contemporary analysis of management strategies at a tertiary institution.

BACKGROUND: Despite equivocal evidence, non-surgical management for pyogenic liver abscess (PLA) has become the standard of care at most institutions with surgery relegated to salvage therapy for those who fail less invasive means. The aim of this study was to describe the outcomes of a step-up approach to PLA management. METHODS: A retrospective chart review was conducted at a single institution for patients diagnosed with PLA over a 10-year period. Demographic, radiologic, microbiological, treatment, and outcomes data were collected and analyzed. RESULTS: 64 patients with PLA were identified. Initial treatment included antibiotics alone (n = 9), percutaneous drainage (PD) (n = 54), and surgery (n = 1). Surgery was ultimately required in 8 patients while 50 were cured with PD and 4 with antibiotics alone. Two (3%) patients died. Overall, PD carried an 85% success rate. CONCLUSION: PLA patients should be initially treated non-operatively, barring indications for emergent surgery or inaccessibility for PD. Surgery can be reserved for failure of PD.

Cinnamic Acid Derivatives Enhance the Efficacy of Transarterial Embolization in a Rat Model of Hepatocellular Carcinoma.

INTRODUCTION: We hypothesize that the combination of transarterial embolization (TAE) plus inhibition of lactate export will limit anaerobic metabolism and reduce tumor survival compared to TAE alone. The purpose of this study was to test this hypothesis in a rat model of hepatocellular carcinoma (HCC). METHODS: Rat N1-S1 hepatoma cells were assayed in vitro using the Seahorse XF analyzer to measure extracellular acidification (lactate excretion) comparing effects of the addition of caffeic acid (CA) or ferulic acid (FA) or UK-5099 with control. Monocarboxylate transporter Slc16a3 was knocked down by RNAi. N1S1 tumors were orthotopically implanted in rats and 4 groups evaluated: (1) Control, (2) TAE-only, (3) TAE plus CA, and (4) TAE plus FA. Tumor size was determined by ultrasound and analyzed by repeated measures statistics. Tumors harvested at 4 weeks were examined by microscopy. RESULTS: Seahorse assays showed that CA and FA caused a significant reduction by >90% in lactate efflux by N1S1 tumor cells (p < 0.01). Knockdown of Slc16a3 prevented inhibition by CA. In vivo tumors grew 30-fold in volume over 4 weeks in untreated controls. By comparison, TAE resulted in near cessation of growth (10% in 4-week time period). However, both TAE + CA and TAE + FA caused a significant reduction of tumor volumes (87 and 72%, respectively) compared to control and TAE (p < 0.05). Pathologic evaluation revealed residual tumor in the TAE group but no residual viable tumor cells in the TAE + CA and TAE + FA groups. CONCLUSION: Addition of CA or FA enhances the effectiveness of TAE therapy for HCC in part by blocking lactate efflux.

Direct Injection of Blood Products Versus Gelatin Sponge as a Technique for Local Hemostasis.

PURPOSE: To provide a method of reducing risk of minimally invasive procedures on patients with abnormal hemostasis and evaluate efficacy of direct fresh frozen plasma injection through a procedure needle tract compared to Gelfoam (gelatin sponge) administration. MATERIALS AND METHODS: Eighty patients with elevated international standardized ratio (INR) undergoing minimally invasive procedures using imaging guidance were selected retrospectively. Forty patients had received Gelfoam as a means of tract embolization during the procedure. The other 40 received local fresh frozen plasma (FFP) through the needle tract. The number of complications and clinically significant bleeding events were recorded. A threshold of 30 cc of blood loss after a procedure was used to identify excess bleeding. RESULTS: No patients experienced clinically significant bleeding after administration of FFP. Five patients experienced postoperative drops in hemoglobin or hematomas after administration of Gelfoam. CONCLUSION: Local injection of blood products can reduce postprocedure bleeding in patients undergoing minimally invasive procedures and provides a safe alternative to the use of synthetic fibrin plugs.

Phase I dose-escalation study of stereotactic body radiotherapy (SBRT) for poor surgical candidates with localized renal cell carcinoma.

PURPOSE: To evaluate the tolerability of escalating doses of stereotactic body radiotherapy (SBRT) for primary treatment of localized renal cell carcinoma (RCC) in poor surgical candidates. PATIENTS AND METHODS: Eligible patients included those with clinically staged radiographic and or pathologically confirmed RCC who had not undergone previous abdominal or pelvic radiotherapy. All patients had comorbid medical conditions which precluded surgery. Median (range) patient age was 77.6years (range 59-89) years and all patients had Karnofsky Performance Status of ⩾60. Median tumor volume was 57.9cm(3) (range 13.8-174.7cm(3)). Dose-limiting toxicity (DLT) was defined as grade 3 or worse gastrointestinal/genitourinary toxicity by Common Terminology Criteria of Adverse Events (version 4). Tumor response was assessed by imaging results using Response Evaluation Criteria In Solid Tumors (RECIST) measurement and percutaneous biopsy. RESULTS: A total of 19 patients (13 men and 6 women) were treated on protocol from June 2006 through August 2011. Groups of 3-6 patients received 24, 32, 40, and 48Gy in 4 fractions. Median (range) follow-up was 13. 7months (5.9-34.7months). For possibly treatment-related acute toxicities, one patient developed grade 2 fatigue and one developed grade 4 duodenal ulcer. For possibly treatment-related late toxicities, 2 patients experienced grade 3 renal toxicity (worsening chronic kidney disease), one reported grade 2 urinary incontinence and one developed grade 4 duodenal ulcer. Among the 15 patients with evaluable response, 3 and 12 had partial response and stable disease, respectively, utilizing RECIST criteria. Among the 11 patients who had post-SBRT biopsy, only one (9%) was negative on first biopsy and an additional one (9%) turned negative without further therapy on second biopsy. CONCLUSIONS: Dose escalation to 48Gy in 4 fractions has been achieved successfully without dose-limiting toxicities. A planned extension of this phase I trial is currently underway treating patients to 60Gy in 3 fractions to further evaluate this experimental therapy.

Anti-angiogenic Effects of Bumetanide Revealed by DCE-MRI with a Biodegradable Macromolecular Contrast Agent in a Colon Cancer Model.

PURPOSE: To assess the antiangiogenic effect of bumetanide with dynamic contrast enhanced (DCE)-MRI and a biodegradable macromolecular MRI contrast agent. METHODS: A new polydisulfide containing macrocyclic gadolinium (Gd(III)) chelates, poly([(Gd-DOTA)-DETA]-co-DTBP) (GODP), was synthesized as a safe biodegradable macromolecular MRI contrast agent for DCE-MRI. Nude mice bearing flank HT29 colon cancer xenografts were then treated daily with either bumetanide or saline for a total of 3 weeks. DCE-MRI was performed before and after the treatment weekly. The DCE-MRI data were analyzed using the adiabiatic approximation to the tissue homogeneity (AATH) model to assess the change of tumor vascularity in response to the treatment. Immunohistochemistry (IHC) and western blot were performed to study tumor angiogenic biomarkers and hypoxia. RESULTS: DCE-MRI with GODP revealed that bumetanide reduced vascular permeability and plasma volume fraction by a significantly greater extent than the saline control therapy after 3 weeks of therapy. These changes were verified by the significant decline of CD31 and VEGF expression in the bumetanide treatment group. Despite a significant regression in vascularity, the tumors remained highly proliferative. Overexpression of the transcription factor HIF-1α in response to elevated hypoxia is thought to be the driving force behind the uninterrupted tumor expansion. CONCLUSION: This study demonstrated the effectiveness of DCE-MRI with GODP in detecting vascular changes following the administration of bumetanide. Bumetanide has the potential to curtail growth of the tumor vasculature and can be employed in future therapeutic strategies.

ALPHA glycolytic vasculogenesis better correlates with MRI and CT imaging techniques than the traditional oxygen vasculogenesis theory.

OBJECTIVE: Traditional vasculogenesis has many contradictions related to treatment and imaging. This occurs because cancer also uses glycolysis, which does not need oxygen or arteries. Glycolytic lactate supports many procancer processes but high levels of it inhibit glycolysis. CONCLUSION: To avoid this, lactate induces vascular growth factors that initiate glycolytic vasculogenesis ALPHA (acidic lactate sequentially induces first lymphangiogenesis, phlebogenesis, and then arteriogenesis). The sequence of vessel development is lymphatics, veins, and then arteries. Modern contrast imaging depends more on veins than arteries, which is more consistent with ALPHA than the traditional theory.

Squamous cell carcinoma arising from ovarian mature cystic teratoma and causing small bowel obstruction.

Malignant transformation of mature cystic teratoma (MCT) is a rare phenomenon with incidence of approximately 1-3%. We report a 48-year-old woman who presented to the emergency room with symptoms of bowel obstruction. She underwent computed tomography scan for the evaluation of obstruction, which demonstrated diffuse ascites accompanying a cystic pelvic to lower abdominal mass which had invaded into the adjacent small bowel causing partial small bowel obstruction. Histologically, the mass demonstrated a MCT within which aroused a well-differentiated squamous cell carcinoma. Exploratory laparotomy was performed to confirm the diagnosis and debulking of the mass was performed.

Incidence of hypercoagulable events after image-guided percutaneous cryoablation of renal tumors: a single-center experience.

PURPOSE: To identify retrospectively hypercoagulable events that occurred over time in patients who underwent image-guided percutaneous renal cryoablation and compare the incidence with a cohort of patients who underwent surgical partial nephrectomy (PN) during the same time period. MATERIALS AND METHODS: An electronic medical record database was queried for patients who underwent percutaneous image-guided renal mass cryoablation or PN between September 2006 and June 2012. Records were examined for thrombotic events during the year following the procedure in each group. Incidence rates, Kaplan-Meier estimates, and patient demographic variables were compared using the stratified log-rank test and t test for independent samples. RESULTS: The study comprised 114 cryoablation cases. The cumulative incidence of thrombotic events after 1 year was 4.39%. The incidence per 100 person-years was 4.84. There were 105 PN cases. The cumulative incidence of thrombotic events after 1 year was 1.0%. The incidence per 100 person-years was 1.14. The person-time incidence rate difference for these two groups did not reach statistical significance (P = .0894). CONCLUSIONS: The incidence of thrombotic events in patients who underwent percutaneous renal cryoablation in this study was not significantly different than a comparable cohort who underwent surgical PN during the same time period.

Acidic lactate sequentially induced lymphogenesis, phlebogenesis, and arteriogenesis (ALPHA) hypothesis: Lactate-triggered glycolytic vasculogenesis that occurs in normoxia or hypoxia and complements the traditional concept of hypoxia-based vasculogenesis.

Our hypothesis, ALPHA (Acidic Lactate sequentially induced Lymphogenesis, PHlebogenesis, and Arteriogenesis) proposes that lactate triggers vasculogenesis to manage lactate levels and complements the traditional vasculogenesis hypothesis. The teleologic basis for glycolytic vasculogenesis is primariy to produce drainage vessels, initially lymphatics but subsequently veins.

Pneumodissection: an alternative protective technique for the percutaneous cryoablation of small renal masses.

INTRODUCTION: Percutaneous cryoablation is an emerging treatment option for the small renal mass. It poses a risk of thermal injury to adjacent tissues, limiting its application. We describe pneumodissection, a novel technique for preventing thermal injury during percutaneous cryoablation. MATERIALS AND METHODS: The cases of 4 patients who underwent percutaneous renal cryoablation and pneumodissection were retrospectively reviewed. RESULTS: Pneumodissection mechanically separated four tumors from overlying bowel segments (mean distance 1.2 ± 0.4 cm), permitting successful cryoablation. There were no complications or recurrences with 7.5 months of follow-up. CONCLUSIONS: Pneumodissection is a feasible displacement technique that facilitates percutaneous cryoablation in at-risk patients. Further study is warranted.

Image-guided biopsy of small renal masses in the era of ablative therapies.

OBJECTIVE: To further evaluate the accuracy, safety, and impact of image-guided renal biopsies on clinical decision making and management of the indeterminate small renal masses. METHODS: A total of 145 patients (males 99, females 46) with small renal masses suspicious for malignancy were evaluated during the study period. The patients' mean age was 67.2 (± 11.6) years. Computed tomography guided biopsies were carried out in all cases by an experienced interventional radiologist. An experienced genitourinary pathologist reviewed all pathological specimens. Patients' demographic characteristics, tumor histology and subsequent intervention, as well as periprocedural morbidities were recorded and analyzed. RESULTS: A total of 145 renal biopsy procedures were carried out. The small renal masses mean size was 2.4 ± 1.1 cm. Biopsy was diagnostic in 126 (86.9%) cases and non-diagnostic in 19 (13.1%) cases. Of diagnostic biopsies, 107 (84.9%) were malignant, 84.1% of which were primary renal cell carcinoma. Histological subtyping and grading of tumor was possible in 100% and 52.2% of renal cell carcinomas, respectively. The major renal cell carcinoma subtype was clear cell (63.3%) followed by papillary (24.4%) and chromophobe (8.8%). Repeat biopsy was carried out in nine of 19 non-diagnostic cases, and diagnosis was possible in 66.7%. Sensitivity of percutaneous renal biopsy was 91%, and its accuracy was 85.5%. Overall, patients' age, sex, tumor size, and location were not related to non-diagnostic biopsy results and/or tumor pathology. No cases of hemorrhage, seeding of biopsy tract, infection or mortalities were observed. CONCLUSIONS: Our findings showed that image-guided biopsy of indeterminate small renal masses is safe and can provide the correct diagnosis with a high degree of accuracy. Thus, this procedure can play an important role in establishing a histopathological diagnosis before treatment of enhancing small renal masses with ablative technologies. Furthermore, repeat biopsy can alter the clinical management of non-diagnostic biopsies.

Radiofrequency ablation: effect of tumor- and organ-specific pharmacologic modulation of arterial and portal venous blood flow on coagulation diameter in an N1-S1 tumor model.

PURPOSE: To investigate inherent differences in vasculature of tumors versus normal parenchyma and efficacy of radiofrequency (RF) ablation with glucagon, adenosine, and a combination of the two compared with normal saline solution (NS) controls in an N1-S1 tumor model implanted in Sprague-Dawley rat livers. MATERIALS AND METHODS: A total of 17 tumors were established in the left lobes of rats. Tumor perfusion relative to surrounding liver parenchyma was evaluated with contrast-enhanced ultrasound with intermittent-bolus technique before and after administration of glucagon, adenosine, a combination of the two, or NS. Tumors were ablated with a 22-gauge RF probe with 1 cm of exposed tip at 80 °C for 2 min. Tumor size, zone of necrosis, and viable tumor were measured in tumors after 2,3,5-triphenyltetrazolium chloride staining. Results were compared with degree of tumor perfusion. RESULTS: The normalized tumor perfusion ratio did not significantly change with administration of NS (1.38% ± 3.93). Vasomodulation resulted in significant decreases in normalized tumor perfusion ratio: 66.22% ± 24.57 (P < .01) with glucagon, 71.45% ± 22.72 (P < .01) with adenosine, and 74.98% ± 16.58 (P < .01) with glucagon plus adenosine. After tumor ablation, there was an increase in size of the ablated area by 100%-165% in the three treatment groups compared with NS controls. Differences among treatment groups were not statistically significant. CONCLUSIONS: Tumor blood flow may be significantly altered by using systemic injection of appropriate medications. This tumor- and organ-specific approach to tumor vasomodulation may be used to enhance current therapeutic options.

Differentiation of benign periablational enhancement from residual tumor following radio-frequency ablation using contrast-enhanced ultrasonography in a rat subcutaneous colon cancer model.

Benign periablational enhancement (BPE) response to thermal injury is a barrier to early detection of residual tumor in contrast enhanced imaging after radio-frequency (RF) ablation. The objective of this study was to evaluate the role of quantitative of contrast-enhanced ultrasound (CEUS) in early differentiation of BPE from residual tumor in a BD-IX rat subcutaneous colon cancer model. A phantom study was first performed to test the validity of the perfusion parameters in predicting blood flow of two US contrast imaging modes-contrast harmonic imaging (CHI) and microflow imaging (MFI). To create a simple model of BPE, a peripheral portion of the tumor was ablated along with surrounding normal tissue, leaving part of the tumor untreated. First-pass dynamic enhancement (FPDE) and MFI scans of CEUS were performed before ablation and immediately, 1, 4 and 7 days after ablation. Time-intensity-curves in regions of BPE and residual tumor were fitted to the function y = A(1-exp[-ß{t-t0}])+C, in which A, ß, t0 and C represent blood volume, flow speed, time to start and baseline intensity, respectively. In the phantom study, positive linear correlations were noted between A, ß, Aß and contrast concentration, speed and flow rate, respectively, in both CHI and MFI. On CEUS images of the in vivo study, the unenhanced ablated zone was surrounded by BPE and irregular peripheral enhancement consistent with residual tumor. On days 0, 4 and 7, blood volume (A) in BPE was significantly higher than that in residual tumor in both FPDE imaging and MFI. Significantly greater blood flow (Aß) was seen in BPE compared with residual tumor tissue in FPDE on day 7 and in MFI on day 4. The results of this study demonstrate that qualitative CEUS can be potentially used for early detection of viable tumor in post-ablation assessment.

Hemostasis effects of direct intraparenchymal injection of platelets and fresh frozen plasma before cutting needle biopsy in an animal model.

PURPOSE: To evaluate the effectiveness of direct intraparenchymal injection of platelets or fresh frozen plasma (FFP) into the needle tract before cutting needle biopsy to decrease postprocedural blood loss in pigs with normal and abnormal hemostasis. MATERIALS AND METHODS: A total of 12 Yorkshire-cross pigs were anesthetized and maintained on a respirator. The pigs were divided into three groups: three with normal hemostasis, five treated with warfarin anticoagulation, and four treated with aspirin. Four types of biopsies were performed in the exposed livers and kidneys with 14-gauge Tru-Cut needles. The first was a standard (ie, control) biopsy, and the other three were performed with 2 mL normal saline solution, porcine FFP, or platelet-rich porcine plasma injected into the planned needle tract. Biopsy was then performed in the same needle tract. Blood loss was measured with gauze sponges. RESULTS: Significantly decreased postbiopsy blood loss was noted after FFP and platelet injection in the livers and kidneys of all groups except the kidney biopsy group after platelet injection in pigs with normal hemostasis. There was no significant difference in blood loss between the control and saline solution control groups in any of the pigs. CONCLUSIONS: Local injection of platelets or FFP significantly decreases postbiopsy blood loss in pigs with impaired hemostasis.

Percutaneous cryoablation of renal masses: impact of patient selection and treatment parameters on outcomes.

OBJECTIVES: To evaluate whether the trend in patient selection or perioperative parameters were associated with treatment outcomes after percutaneous cryoablation (PCA) of renal masses. METHODS: We retrospectively analyzed our urological oncology database and identified 52 patients treated for a total of 54 renal masses. Univariate analysis was performed to evaluate whether the variables of age, gender, tumor size, number of probes used, total freezing time, preoperative creatinine, American Society of Anesthesia class, body mass index, or age-adjusted Charlson comorbidity index (CCI) score had an impact on the outcomes of treatment failure or the complication rate. RESULTS: During a mean follow-up of 21 months, recurrence-free, overall, and disease-specific (based on radiographic follow-up and biopsy) survival were 96.2%, 98.1% and 100%, respectively. The mean age-adjusted CCI score for patients with postoperative complications was 6.5, compared with a mean score of 3.0 in patients without postoperative complications (P = .02). The complication rate was also significantly higher when a greater number of cryoprobes were used during PCA (P < .005). None of the variables analyzed were predictive of treatment failure. CONCLUSIONS: Of the pre- and intraoperative variables studied, age-adjusted CCI score and number of cryoprobes used were the only variables with predictive value for outcomes in regard to treatment failure or complications. As investigators continue using cryoablation to treat renal masses, it is important to be able to completely and honestly counsel patients regarding the likelihood of complications and need for subsequent therapy in the setting of treatment failure.

Percutaneous computed tomography guided cryoablation of the celiac plexus as an alternative treatment for intractable pain caused by pancreatic cancer.

Computed Tomography (CT)-guided percutaneous cryoablation was performed in a 43-year-old patient with intractable epigastric abdominal pain caused by advanced adenocarcinoma of the pancreas and extensive celiac trunk involvement. Initial treatment with celiac plexus nerve neurolysis using local ethanol injection was unsuccessful. A 17-gauge 17-cm cryoablation probe (Galil Medical Inc. Plymouth Meeting, PA) was placed into the expected location of the celiac plexus through a left paraspinal approach under CT guidance and two cycles of freeze-thaw were performed. Patient's pain decreased from 10 of 10 (subjective pain scoring using a visual analog scale; VAS; 0-10) to 3. No post-procedure complication was observed. His pain has remained stable after 6 months of follow up. Percutaneous cryoablation appears to be an effective alternative to neurolytic celiac plexus block for palliative treatment of celiac plexus involvement. Further study with larger number of patients is needed to evaluate the safety and efficacy.

Hypoxia--implications for pharmaceutical developments.

Cells sense oxygen availability using not only the absolute value for cellular oxygen in regard to its energetic and metabolic functions, but also the gradient from the cell surface to the lowest levels in the mitochondria. Signals are used for regulatory purposes locally as well as in the generation of cellular, tissue, and humoral remodeling. Lowered oxygen availability (hypoxia) is theoretically important in the consideration of pharmacology because (1) hypoxia can alter cellular function and thereby the therapeutic effectiveness of the agent, (2) therapeutic agents may potentiate or protect against hypoxia-induced pathology, (3) hypoxic conditions may potentiate or mitigate drug-induced toxicity, (4) hypoxia may alter drug metabolism and thereby therapeutic effectiveness, and (5) therapeutic agents might alter the relative coupling of blood flow and energy metabolism in an organ. The prototypic biochemical effect of hypoxia is related to its known role as a cofactor in a number of enzymatic reactions, e.g., oxidases and oxygenases, which are affected independently from the bioenergetic effect of low oxygen on energetic functions. The cytochrome P-450 family of enzymes is another example. Here, there is a direct effect of oxygen availability on the conformation of the enzyme, thereby altering the metabolism of drug substrates. Indirectly, the NADH/NAD+ ratio is increased with 10% inspired oxygen, leading not only to reduced oxidation of ethanol but also to reduction of azo- and nitro-compounds to amines and disulfides to sulfhydryls. With chronic hypoxia, many of these processes are reversed, suggesting that hypoxia induces the drug-metabolizing systems. Support for this comes from observations that hypoxia can induce the hypoxic inducible factors which in turn alters transcription and function of some but not all cytochrome P-450 isoforms. Hypoxia is identified as a cofactor in cancer expression and metastatic potential. Thus, the effects of hypoxia play an important role in pharmacology, and the signaling pathways that are affected by hypoxia could become new targets for novel therapy or avenues for prevention.

Dynamic evolutionary changes in blood flow measured by MDCT in a hepatic VX2 tumor implant over an extended 28-day growth period: time-density curve analysis.

RATIONALE AND OBJECTIVES: The enhancement pattern of malignant tumors has been studied in short-term animal models (7-14 days), but the reported results have been variable and inconsistent. The purpose of this study was to investigate the changing blood flow characteristics of VX2 tumors implanted in rabbit livers with contrast-enhanced multidetector computed tomography (MDCT) to establish a predictable pattern of vascular evolution over an extended 28-day growth period. MATERIALS AND METHODS: VX2 carcinoma was implanted in livers of 10 male New Zealand White rabbits. Dynamic CT (2/seconds x 60 seconds) was conducted on days 7, 14, 21, and 28 after tumor implantation. Enhancement parameters of time-density curve (TDC), time to start (T0), time to peak (TP), maximum enhancement (DeltaH), slope of enhancement (SLe), and washout (SLw) in tumor center, tumor rim, and normal liver were analyzed. Tumor samples corresponding to CT images of one tumor on days 14 and 21 and seven tumors on day 28 were stained with hematoxylin and eosin and anti-CD31 monoclonal antibody. The relationship between enhancement parameters and histology parameters (thickness of tumor border, extent of blood stasis, and luminar vessel density) was analyzed. RESULTS: Consistent growth, appearance, and vascular changes occurred in 7 of 10 animals over the 4-week observation period. Peripheral rim-like enhancement was noted in CT images. TDC analysis showed that tumor rim enhancement was pronounced and more rapid than normal liver initially but this difference diminished with tumor progression. The SLe, SLw, and DeltaH decreased from 10.03 +/- 3.25 Hu/second, 0.42 +/- 0.25 Hu/sec, and 58.00 +/- 25.27 Hu on day 7 to 5.86 +/- 2.73 Hu/second, 0.10 +/- 0.13 Hu/second, and 37.78 +/- 8.89 Hu/second on day 28, respectively. TP increased from 12.71 +/- 4.85 seconds on day 7 to 25.57 +/- 7.75 seconds on day 28. No significant changes were noted on the TDC parameters in normal liver. The maximum density difference between tumor rim and normal liver (D(rim-liver)) appeared 10.5 +/- 2.1 seconds after contrast injection. The maximum D(rim-liver) decreased from 54.33 +/- 37.86 Hu on day 7 to 11.16 +/- 13.03 Hu on day 28. On histological analysis, viable tumor cells were found in tumor rim with few luminar vessels. The tumor border showed desmoplastic reaction, vascular dilation and proliferation, inflammatory cell infiltration, and blood stasis. These findings were more obvious on day 28 than those on day 14. TP showed significant positive correlations with the extent of blood stasis in tumor border and adjacent liver and the maximum thickness of the tumor border (r = 0.945 and 0.893 respectively, P < .05). CONCLUSION: The rabbit VX2 liver tumor is a hypovascular tumor with perilesional enhancement over its lifespan as imaged by MDCT. Consistent changes in the measured vascular parameters correlated with the size/age of the tumor implants. These findings suggest that the accuracy of CT enhancement imaging for VX2 liver tumor detection might be decreased with tumor development.