U Un ni iv ve er rs si it ty y o of f P Pr re et to or ri ia a e et td d --D Dv vi ir r, , E E ( ... more U Un ni iv ve er rs si it ty y o of f P Pr re et to or ri ia a e et td d --D Dv vi ir r, , E E ( (2 20 00 05 5) ) CHAPTER 6: DISCUSSION 38 6.1 Electrocardiographic changes 38 6.2 Cardiac pathology 49 CHAPTER 7: CONCLUSIONS 54 REFERENCES 56
Spirocerca lupi is a nematode infesting the canine oesophagus, where it induces the formation of ... more Spirocerca lupi is a nematode infesting the canine oesophagus, where it induces the formation of a nodule that may transform into a malignant sarcoma. The current, retrospective study compared the clinical presentation, haematology, serum albumin and globulin and radiology of benign cases (n = 31) and malignant cases (n = 31) of spirocercosis.
A retrospective study of 39 dogs with spirocercosis is described, emphasizing radiographic and co... more A retrospective study of 39 dogs with spirocercosis is described, emphasizing radiographic and computed tomographic aspects and clinical presentation. Dogs were classified as complicated or uncomplicated, both clinically and radiographically. Besides the expected upper gastrointestinal signs, a high incidence of respiratory (77%) and locomotor (23%) complications were present. All dogs had thoracic radiographs. Esophageal masses were radiographically classified as typical or atypical according to their location. Twenty-seven dogs had a typical caudal esophageal mass. Six dogs had a mass atypically located in the hilar region. These masses were smaller and more difficult to visualize radiographically. The remaining 6 dogs did not have a radiographically detectable esophageal mass. Radiology as an initial diagnostic tool was effective in detecting and localizing the mass and to detect early respiratory abnormalities such as pleuritis, mediastinitis, pneumonia, and bronchial displacement. Endoscopy was the modality of choice to confirm antemortem esophageal masses. In dogs where the mass filled the whole esophageal lumen, endoscopy failed to give essential information necessary for surgical excision of neoplastic masses, such as the extent of esophageal wall attachment. Caudal esophageal sphincter involvement was difficult to determine endoscopically with large caudal esophageal masses. Computed tomography was performed on 3 dogs and did not address the latter problems completely, but was found to be a sensitive tool to detect focal aortic mineralization and early spondylitis, both typical for the disease, and essential in the diagnosis of non- or extramural esophageal abnormalities.
In this prospective study, the effect of thoracic positioning on the visibility and size of cauda... more In this prospective study, the effect of thoracic positioning on the visibility and size of caudal esophageal masses caused by spirocercosis was investigated. Dorsoventral (DV), ventrodorsal (VD) as well as left lateral recumbent (LLR) and right lateral recumbent (RLR) thoracic radiographs of 28 dogs, diagnosed endoscopically with spirocercosis, were evaluated. The radiographic findings were compared with those of esophageal endoscopy. Masses were seen equally well in left vs. right recumbency as well as in DV vs. VD positions but in DV/VD views 86% of masses were detected whereas in lateral views only 50% of masses were identified. In spirocercosis-endemic areas DV and RLR views are advised as they also allow for better visualization of descending aorta aneurysms and to avoid interpreting the potentially normally visible esophagus in LLR in large dogs as a mass.
Otitis media/interna was diagnosed in a 20-month-old German shepherd with the assistance of magne... more Otitis media/interna was diagnosed in a 20-month-old German shepherd with the assistance of magnetic resonance (MR) imaging. The MR images were acquired primarily to exclude a brain lesion responsible for vestibular signs. No brain lesion was detected, but obvious signs of chronic changes in the left bulla and external ear canal were confirmed. Thickening of the epithelium and soft tissue surrounding the external ear canal and a laminated appearance of high and low T2 intensities in the tympanic bulla's mucosa were present. The hypointense lines were suspected to be fibrous tissue, indicating chronic changes. This report suggests that MR imaging may serve as a useful imaging tool for otitis media and that it supplies information not obtained with radiography or computed tomography.
This study compared the sensitivity of ECG and cardiac troponins to predict cardiac histopatholog... more This study compared the sensitivity of ECG and cardiac troponins to predict cardiac histopathological changes, clinical severity, and survival in canine babesiosis. One control group (n = 9) and 4 groups of dogs with mild uncomplicated babesiosis (n = 8), severe uncomplicated babesiosis (n = 9), complicated babesiosis (n = 8), and babesiosis and concurrent immune-mediated he-molytic anemia (IMHA) (n = 9) were studied. A 1-minute lead II ECG was recorded, and cardiac troponin I (cTnl) and T (cTnT) concentrations in plasma were measured. cTnl concentrations were significantly higher in the complicated (mean, 9.9; SE, ±5.76) and concurrent IMHA (mean, 6.53; SE, ±4.32) groups and in the 3 dogs that died of the disease (mean, 22.17; SE, ±12.85) than in the control dogs (concentration below detection limit of test, —0.3 ng/mL). The 3 nonsurvivors had the most severe cardiac histopathological changes, but no arrhythmia and minimal other ECG changes. Dogs with babesiosis developed a variety of ECG abnormalities, but the abnormalities were not associated with disease severity, outcome, or plasma cardiac troponin concentrations. The exception was the presence of ventricular premature complexes (VPCs), which were associated with high cardiac troponin concentrations. This study showed an association between cTnl concentration and histological changes, clinical severity, and survival and no correlation between ECG abnormalities and histological changes or biochemical evidence of myocardial damage as reflected by cTnl concentrations. From this study, it was concluded that the analysis of plasma cTnl is a feasible and sensitive test and is superior to cTnT in diagnosing cardiac involvement in dogs with babesiosis.
The main purpose of this study was to describe electrocardiographic (ECG) changes in canine babes... more The main purpose of this study was to describe electrocardiographic (ECG) changes in canine babesiosis, and to relate these to clinical severity, outcome and cardiac pathology.
This study compared the sensitivity of ECG and cardiac troponins to predict cardiac histopatholog... more This study compared the sensitivity of ECG and cardiac troponins to predict cardiac histopathological changes, clinical severity, and survival in canine babesiosis. One control group (n = 9) and 4 groups of dogs with mild uncomplicated babesiosis (n = 8), severe uncomplicated babesiosis (n = 9), complicated babesiosis (n = 8), and babesiosis and concurrent immune-mediated hemolytic anemia (IMHA) (n = 9) were studied. A 1-minute lead II ECG was recorded, and cardiac troponin I (cTnI) and T (cTnT) concentrations in plasma were measured. cTnI concentrations were significantly higher in the complicated (mean, 9.9; SE, +/-5.76) and concurrent IMHA (mean, 6.53; SE, +/-4.32) groups and in the 3 dogs that died of the disease (mean, 22.17; SE, +/-12.85) than in the control dogs (concentration below detection limit of test, -0.3 ng/mL). The 3 nonsurvivors had the most severe cardiac histopathological changes, but no arrhythmia and minimal other ECG changes. Dogs with babesiosis developed a variety of ECG abnormalities, but the abnormalities were not associated with disease severity, outcome, or plasma cardiac troponin concentrations. The exception was the presence of ventricular premature complexes (VPCs), which were associated with high cardiac troponin concentrations. This study showed an association between cTnI concentration and histological changes, clinical severity, and survival and no correlation between ECG abnormalities and histological changes or biochemical evidence of myocardial damage as reflected by cTnI concentrations. From this study, it was concluded that the analysis of plasma cTnI is a feasible and sensitive test and is superior to cTnT in diagnosing cardiac involvement in dogs with babesiosis.
DP-155 is a lipid prodrug of indomethacin that comprises the latter conjugated to lecithin at pos... more DP-155 is a lipid prodrug of indomethacin that comprises the latter conjugated to lecithin at position sn-2 via a 5-carbon length linker. It is cleaved by phospholipase A2 (PLA)2 to a greater extent than similar compounds with linkers of 2, 3, and 4 carbons. Indomethacin is the principal metabolite of DP-155 in rat serum and, after DP-155 oral administration, the half-life of the metabolite was 22 and 93 h in serum and brain, respectively, compared to 10 and 24 h following indomethacin administration. The brain to serum ratio was 3.5 times higher for DP-155 than for indomethacin. In vitro studies demonstrated that DP-155 is a selective cyclooxygenase (COX)-2 inhibitor. After it is cleaved, its indomethacin derivative nonselectively inhibits both COX-1 and -2. DP-155 showed a better toxicity profile probably due to the sustained, low serum levels and reduced maximal concentration of its indomethacin metabolite. DP-155 did not produce gastric toxicity at the highest acute dose tested (0.28 mmol/kg), while indomethacin caused gastric ulcers at a dose 33-fold lower. Furthermore, after repeated oral dosing, gastrointestinal and renal toxicity was lower (10- and 5-fold, respectively) and delayed with DP-155 compared to indomethacin. In addition to reduced toxicity, DP-155 had similar ameliorative effects to indomethacin in antipyretic and analgesia models. Moreover, DP-155 and indomethacin were equally efficacious in reducing levels of amyloid ß (Aß)42 in transgenic Alzheimer's disease mouse (Tg2576) brains as well as reducing Aß42 intracellular uptake, neurodegeneration, and inflammation in an in vitro AD model. The relatively high brain levels of indomethacin after DP-155 administration explain the equal efficacy of DP-155 despite its low systemic blood concentrations. Compared to indomethacin, the favored safety profile and equal efficacy of DP-155 establish the compound as a potential candidate for chronic use to treat AD-related pathology and for analgesia.
Purpose: To investigate a novel mechanism for oral controlled release of drugs involving a contin... more Purpose: To investigate a novel mechanism for oral controlled release of drugs involving a continuous degradation of a phospholipid prodrug along the intestine. An indomethacin-lecithin conjugate with the drug attached to the sn-2 position of the phospholipid through a 5-carbon linker (DP-155) was used as a model molecule. Methods: The pharmacokinetics of DP-155 and free indomethacin liberated from the prodrug following intravenous, oral or intra-colon administration was investigated in rats, and evaluated in comparison to free indomethacin administration. Degradation by phospholipase A 2 (PLA 2 ) enzymes was assessed in-vitro. The impact of the linker length was evaluated in comparison to an indomethacin-phospholipid conjugate with a shorter linker (2-carbons). Results: Following oral or intra-colon DP-155 administration, free indomethacin was liberated along the intestine and absorbed into the systemic circulation, resulting in a controlled release profile of indomethacin in the plasma. The shorter linker caused a 20-fold decrease in the subsequent indomethacin absorption. DP-155 in-vitro degradation by PLA 2 was over 60%, while shorter linkers were profoundly less degradable. Conclusions: DP-155 caused a continuous input of free indomethacin into the plasma following degradation by PLA 2 in the gut lumen. Since the rate of drug release is not formulation dependent, the prodrug can be compounded even in a liquid dosage form. The phospholipid-drug conjugate is thus a potential novel mechanism for oral controlled release of drugs.
This study aims to outline the histological progression of the Spirocerca lupi nodule from infect... more This study aims to outline the histological progression of the Spirocerca lupi nodule from infection to neoplastic transformation. Sixty-two spirocercosis-induced nodules, 42 nonneoplastic and 20 neoplastic, were stained with HE. Ten non-overlapping high power fields per nodule were examined and non-neoplastic and neoplastic nodules were compared. Inflammation was scored 0-3 and revealed a score of 1.91 AE 0.52 in the non-neoplastic and 0.97 AE 0.5 in the neoplastic cases (p < 0.01). In most non-neoplastic cases the inflammatory infiltrate was lymphoplasmacytic and in the neoplastic cases neutrophils predominated. Necrosis was scored 0-3 and revealed a score of 0.88 AE 0.41 in the non-neoplastic and 1.47 AE 0.5 in the neoplastic cases (p < 0.01). The average number of mitoses over 10 high power fields per nodule was 1.31 AE 1.55 in the non-neoplastic compared to 42.85 AE 30.79 in the neoplastic cases (p < 0.01). The average number of multinucleated giant cells over 10 high power fields per nodule was 0.9 AE 1.45 in the non-neoplastic compared to 13.9 AE 14.66 in the neoplastic cases (p < 0.01). In the non-neoplastic cases, collagen, immature fibroblasts and fibroblast activation (excessively plump euchromatic nuclei with single or multiple prominent nucleoli) were scored 0-3 and a combined score, fibroblasts + activation score À collagen was calculated. The non-neoplastic cases were divided into a combined score of 1 (n = 15) or >1 (n = 27). The 2 groups had similar scores for inflammation and necrosis, but were significantly different (p < 0.01) in mitotic index (0.26 AE 0.46 vs. 1.89 AE 1.65) and number of multinucleated cells (0 vs. 1.4 AE 1.6). These results indicate 2 stages in the non-neoplastic nodules: early inflammation, characterized by fibrocytes and abundant collagen, and a pre-neoplastic stage, characterized by activated fibroblasts and reduced collagen. ß
U Un ni iv ve er rs si it ty y o of f P Pr re et to or ri ia a e et td d --D Dv vi ir r, , E E ( ... more U Un ni iv ve er rs si it ty y o of f P Pr re et to or ri ia a e et td d --D Dv vi ir r, , E E ( (2 20 00 05 5) ) CHAPTER 6: DISCUSSION 38 6.1 Electrocardiographic changes 38 6.2 Cardiac pathology 49 CHAPTER 7: CONCLUSIONS 54 REFERENCES 56
Spirocerca lupi is a nematode infesting the canine oesophagus, where it induces the formation of ... more Spirocerca lupi is a nematode infesting the canine oesophagus, where it induces the formation of a nodule that may transform into a malignant sarcoma. The current, retrospective study compared the clinical presentation, haematology, serum albumin and globulin and radiology of benign cases (n = 31) and malignant cases (n = 31) of spirocercosis.
A retrospective study of 39 dogs with spirocercosis is described, emphasizing radiographic and co... more A retrospective study of 39 dogs with spirocercosis is described, emphasizing radiographic and computed tomographic aspects and clinical presentation. Dogs were classified as complicated or uncomplicated, both clinically and radiographically. Besides the expected upper gastrointestinal signs, a high incidence of respiratory (77%) and locomotor (23%) complications were present. All dogs had thoracic radiographs. Esophageal masses were radiographically classified as typical or atypical according to their location. Twenty-seven dogs had a typical caudal esophageal mass. Six dogs had a mass atypically located in the hilar region. These masses were smaller and more difficult to visualize radiographically. The remaining 6 dogs did not have a radiographically detectable esophageal mass. Radiology as an initial diagnostic tool was effective in detecting and localizing the mass and to detect early respiratory abnormalities such as pleuritis, mediastinitis, pneumonia, and bronchial displacement. Endoscopy was the modality of choice to confirm antemortem esophageal masses. In dogs where the mass filled the whole esophageal lumen, endoscopy failed to give essential information necessary for surgical excision of neoplastic masses, such as the extent of esophageal wall attachment. Caudal esophageal sphincter involvement was difficult to determine endoscopically with large caudal esophageal masses. Computed tomography was performed on 3 dogs and did not address the latter problems completely, but was found to be a sensitive tool to detect focal aortic mineralization and early spondylitis, both typical for the disease, and essential in the diagnosis of non- or extramural esophageal abnormalities.
In this prospective study, the effect of thoracic positioning on the visibility and size of cauda... more In this prospective study, the effect of thoracic positioning on the visibility and size of caudal esophageal masses caused by spirocercosis was investigated. Dorsoventral (DV), ventrodorsal (VD) as well as left lateral recumbent (LLR) and right lateral recumbent (RLR) thoracic radiographs of 28 dogs, diagnosed endoscopically with spirocercosis, were evaluated. The radiographic findings were compared with those of esophageal endoscopy. Masses were seen equally well in left vs. right recumbency as well as in DV vs. VD positions but in DV/VD views 86% of masses were detected whereas in lateral views only 50% of masses were identified. In spirocercosis-endemic areas DV and RLR views are advised as they also allow for better visualization of descending aorta aneurysms and to avoid interpreting the potentially normally visible esophagus in LLR in large dogs as a mass.
Otitis media/interna was diagnosed in a 20-month-old German shepherd with the assistance of magne... more Otitis media/interna was diagnosed in a 20-month-old German shepherd with the assistance of magnetic resonance (MR) imaging. The MR images were acquired primarily to exclude a brain lesion responsible for vestibular signs. No brain lesion was detected, but obvious signs of chronic changes in the left bulla and external ear canal were confirmed. Thickening of the epithelium and soft tissue surrounding the external ear canal and a laminated appearance of high and low T2 intensities in the tympanic bulla's mucosa were present. The hypointense lines were suspected to be fibrous tissue, indicating chronic changes. This report suggests that MR imaging may serve as a useful imaging tool for otitis media and that it supplies information not obtained with radiography or computed tomography.
This study compared the sensitivity of ECG and cardiac troponins to predict cardiac histopatholog... more This study compared the sensitivity of ECG and cardiac troponins to predict cardiac histopathological changes, clinical severity, and survival in canine babesiosis. One control group (n = 9) and 4 groups of dogs with mild uncomplicated babesiosis (n = 8), severe uncomplicated babesiosis (n = 9), complicated babesiosis (n = 8), and babesiosis and concurrent immune-mediated he-molytic anemia (IMHA) (n = 9) were studied. A 1-minute lead II ECG was recorded, and cardiac troponin I (cTnl) and T (cTnT) concentrations in plasma were measured. cTnl concentrations were significantly higher in the complicated (mean, 9.9; SE, ±5.76) and concurrent IMHA (mean, 6.53; SE, ±4.32) groups and in the 3 dogs that died of the disease (mean, 22.17; SE, ±12.85) than in the control dogs (concentration below detection limit of test, —0.3 ng/mL). The 3 nonsurvivors had the most severe cardiac histopathological changes, but no arrhythmia and minimal other ECG changes. Dogs with babesiosis developed a variety of ECG abnormalities, but the abnormalities were not associated with disease severity, outcome, or plasma cardiac troponin concentrations. The exception was the presence of ventricular premature complexes (VPCs), which were associated with high cardiac troponin concentrations. This study showed an association between cTnl concentration and histological changes, clinical severity, and survival and no correlation between ECG abnormalities and histological changes or biochemical evidence of myocardial damage as reflected by cTnl concentrations. From this study, it was concluded that the analysis of plasma cTnl is a feasible and sensitive test and is superior to cTnT in diagnosing cardiac involvement in dogs with babesiosis.
The main purpose of this study was to describe electrocardiographic (ECG) changes in canine babes... more The main purpose of this study was to describe electrocardiographic (ECG) changes in canine babesiosis, and to relate these to clinical severity, outcome and cardiac pathology.
This study compared the sensitivity of ECG and cardiac troponins to predict cardiac histopatholog... more This study compared the sensitivity of ECG and cardiac troponins to predict cardiac histopathological changes, clinical severity, and survival in canine babesiosis. One control group (n = 9) and 4 groups of dogs with mild uncomplicated babesiosis (n = 8), severe uncomplicated babesiosis (n = 9), complicated babesiosis (n = 8), and babesiosis and concurrent immune-mediated hemolytic anemia (IMHA) (n = 9) were studied. A 1-minute lead II ECG was recorded, and cardiac troponin I (cTnI) and T (cTnT) concentrations in plasma were measured. cTnI concentrations were significantly higher in the complicated (mean, 9.9; SE, +/-5.76) and concurrent IMHA (mean, 6.53; SE, +/-4.32) groups and in the 3 dogs that died of the disease (mean, 22.17; SE, +/-12.85) than in the control dogs (concentration below detection limit of test, -0.3 ng/mL). The 3 nonsurvivors had the most severe cardiac histopathological changes, but no arrhythmia and minimal other ECG changes. Dogs with babesiosis developed a variety of ECG abnormalities, but the abnormalities were not associated with disease severity, outcome, or plasma cardiac troponin concentrations. The exception was the presence of ventricular premature complexes (VPCs), which were associated with high cardiac troponin concentrations. This study showed an association between cTnI concentration and histological changes, clinical severity, and survival and no correlation between ECG abnormalities and histological changes or biochemical evidence of myocardial damage as reflected by cTnI concentrations. From this study, it was concluded that the analysis of plasma cTnI is a feasible and sensitive test and is superior to cTnT in diagnosing cardiac involvement in dogs with babesiosis.
DP-155 is a lipid prodrug of indomethacin that comprises the latter conjugated to lecithin at pos... more DP-155 is a lipid prodrug of indomethacin that comprises the latter conjugated to lecithin at position sn-2 via a 5-carbon length linker. It is cleaved by phospholipase A2 (PLA)2 to a greater extent than similar compounds with linkers of 2, 3, and 4 carbons. Indomethacin is the principal metabolite of DP-155 in rat serum and, after DP-155 oral administration, the half-life of the metabolite was 22 and 93 h in serum and brain, respectively, compared to 10 and 24 h following indomethacin administration. The brain to serum ratio was 3.5 times higher for DP-155 than for indomethacin. In vitro studies demonstrated that DP-155 is a selective cyclooxygenase (COX)-2 inhibitor. After it is cleaved, its indomethacin derivative nonselectively inhibits both COX-1 and -2. DP-155 showed a better toxicity profile probably due to the sustained, low serum levels and reduced maximal concentration of its indomethacin metabolite. DP-155 did not produce gastric toxicity at the highest acute dose tested (0.28 mmol/kg), while indomethacin caused gastric ulcers at a dose 33-fold lower. Furthermore, after repeated oral dosing, gastrointestinal and renal toxicity was lower (10- and 5-fold, respectively) and delayed with DP-155 compared to indomethacin. In addition to reduced toxicity, DP-155 had similar ameliorative effects to indomethacin in antipyretic and analgesia models. Moreover, DP-155 and indomethacin were equally efficacious in reducing levels of amyloid ß (Aß)42 in transgenic Alzheimer's disease mouse (Tg2576) brains as well as reducing Aß42 intracellular uptake, neurodegeneration, and inflammation in an in vitro AD model. The relatively high brain levels of indomethacin after DP-155 administration explain the equal efficacy of DP-155 despite its low systemic blood concentrations. Compared to indomethacin, the favored safety profile and equal efficacy of DP-155 establish the compound as a potential candidate for chronic use to treat AD-related pathology and for analgesia.
Purpose: To investigate a novel mechanism for oral controlled release of drugs involving a contin... more Purpose: To investigate a novel mechanism for oral controlled release of drugs involving a continuous degradation of a phospholipid prodrug along the intestine. An indomethacin-lecithin conjugate with the drug attached to the sn-2 position of the phospholipid through a 5-carbon linker (DP-155) was used as a model molecule. Methods: The pharmacokinetics of DP-155 and free indomethacin liberated from the prodrug following intravenous, oral or intra-colon administration was investigated in rats, and evaluated in comparison to free indomethacin administration. Degradation by phospholipase A 2 (PLA 2 ) enzymes was assessed in-vitro. The impact of the linker length was evaluated in comparison to an indomethacin-phospholipid conjugate with a shorter linker (2-carbons). Results: Following oral or intra-colon DP-155 administration, free indomethacin was liberated along the intestine and absorbed into the systemic circulation, resulting in a controlled release profile of indomethacin in the plasma. The shorter linker caused a 20-fold decrease in the subsequent indomethacin absorption. DP-155 in-vitro degradation by PLA 2 was over 60%, while shorter linkers were profoundly less degradable. Conclusions: DP-155 caused a continuous input of free indomethacin into the plasma following degradation by PLA 2 in the gut lumen. Since the rate of drug release is not formulation dependent, the prodrug can be compounded even in a liquid dosage form. The phospholipid-drug conjugate is thus a potential novel mechanism for oral controlled release of drugs.
This study aims to outline the histological progression of the Spirocerca lupi nodule from infect... more This study aims to outline the histological progression of the Spirocerca lupi nodule from infection to neoplastic transformation. Sixty-two spirocercosis-induced nodules, 42 nonneoplastic and 20 neoplastic, were stained with HE. Ten non-overlapping high power fields per nodule were examined and non-neoplastic and neoplastic nodules were compared. Inflammation was scored 0-3 and revealed a score of 1.91 AE 0.52 in the non-neoplastic and 0.97 AE 0.5 in the neoplastic cases (p < 0.01). In most non-neoplastic cases the inflammatory infiltrate was lymphoplasmacytic and in the neoplastic cases neutrophils predominated. Necrosis was scored 0-3 and revealed a score of 0.88 AE 0.41 in the non-neoplastic and 1.47 AE 0.5 in the neoplastic cases (p < 0.01). The average number of mitoses over 10 high power fields per nodule was 1.31 AE 1.55 in the non-neoplastic compared to 42.85 AE 30.79 in the neoplastic cases (p < 0.01). The average number of multinucleated giant cells over 10 high power fields per nodule was 0.9 AE 1.45 in the non-neoplastic compared to 13.9 AE 14.66 in the neoplastic cases (p < 0.01). In the non-neoplastic cases, collagen, immature fibroblasts and fibroblast activation (excessively plump euchromatic nuclei with single or multiple prominent nucleoli) were scored 0-3 and a combined score, fibroblasts + activation score À collagen was calculated. The non-neoplastic cases were divided into a combined score of 1 (n = 15) or >1 (n = 27). The 2 groups had similar scores for inflammation and necrosis, but were significantly different (p < 0.01) in mitotic index (0.26 AE 0.46 vs. 1.89 AE 1.65) and number of multinucleated cells (0 vs. 1.4 AE 1.6). These results indicate 2 stages in the non-neoplastic nodules: early inflammation, characterized by fibrocytes and abundant collagen, and a pre-neoplastic stage, characterized by activated fibroblasts and reduced collagen. ß
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