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P E O'Brien

Publications and source records attributed to P E O'Brien.

At least 55 records · Page 3Linked to original sources
PubMed1995

Microvascular structure of benign and malignant tumors of the colon in humans.

Studies of experimental tumors in rodents indicate that there are morphological abnormalities of the tumor microcirculation compared to normal tissues. The aim of this study was to examine the structure of the microvasculature in benign and malignant colonic tumors in humans using microvascular casting techniques. There were 15 adenocarcinomas, four benign sporadic adenomas, and three specimens from patients with familial adenomatous polyposis (FAP). A cast of the microvessels of these tumors was prepared by intraarterial administration of acrylic resin (Mercox) and the cast examined by scanning electron microscopy. Quantitative measures of the microvasculature were obtained from histological sections using stereological techniques in four carcinomas, two sporadic adenomas, and 12 adenomas from patients with FAP. Vascular casts of benign colonic adenomas showed that the microvasculature had a similar organization to normal colon. However, capillaries and venules were elongated and had increased diameters compared to normal. In adenomas greater than 3 mm in diameter, there was an increased density of microvessels in the spaces between tumor cells. Vascular casts of colonic carcinomas were characterized by a disorganized structure and increased density of microvessels. The organization of microvessels within carcinomas had a similar overall pattern to normal colon. However, the increased number and density of microvessels resulted in formation of nodular clusters of capillaries, formation of "sheets" of frequently anastomosing capillaries, or almost complete packing of the interstitial spaces of the tumor by capillaries in places. Most capillaries had a long and tortuous course and numerous capillary sprouts were identified. Tumor microvessels had greater mean diameters than normal. Extravasation of resin from microvessels in carcinomas was frequently seen. The vascular volume of carcinomas (23.1% +/- 12.2), sporadic adenomas (16.3% +/- 3.4), and adenomas > 3 mm diameter in patients with FAP (17.7% +/- 3.0) were significantly greater than in normal colon (11.0% +/- 4.2). This study indicates that there is an increased vascular density in benign and malignant tumors of the colon compared to normal colon. The presence of profusely anastomotic microvessels and frequent capillary sprouts is evidence of active neovascularization and suggests control of tumor growth could be achieved by modifiers of angiogenesis.

Adenocarcinoma↗
PubMed1995

NSAID-induced delay in gastric ulcer healing is not associated with decreased epithelial cell proliferation in rats.

Nonsteriodal antiinflammatory drugs initiate gastric ulceration and delay gastric ulcer healing. This study aimed to investigate the role of epithelial cell proliferation in delayed ulcer healing and to identify the most reproducible technique for measuring cell proliferation. Rats with acetic acid-induced gastric ulcers were treated for two weeks with indomethacin (1 mg/kg), aspirin (200 mg/kg), or vehicle control. Ulcers were assessed by macroscopic measurement of ulcer area, quantitative histological measurement of mucosal regeneration, and 5-bromo-2'-deoxyuridine immunohistochemistry to assess epithelial cell proliferation. Indomethacin and aspirin significantly delayed ulcer healing and inhibited mucosal regeneration. Three techniques for assessing cell proliferation were compared, and a scoring system, designed to take into account the entire tissue, was shown to be the most reproducible technique. Indomethacin significantly enhanced cell proliferation in the fundic area of ulcer and aspirin had no effect on cell proliferation. We conclude that aspirin and indomethacin delay ulcer healing by an inhibition of mucosal regeneration, but they do not inhibit epithelial cell proliferation.

Animals↗
PubMed1995

Acetaminophen-induced microvascular injury in the rat liver: protection with misoprostol.

Studies into the mechanism of acetaminophen (APAP)-induced hepatotoxicity have focused mainly at the hepatocellular level. This study aimed to investigate the effect of acetaminophen on the hepatic microvasculature using a vascular casting technique. Acetaminophen was administered at a dose of 650 mg/kg body weight (intraperitoneally) to fasted male Long Evans rats. Microvascular casting was performed at various points after drug administration. Liver casts from control rats showed good patency with normal hepatic microvasculature. Thirty-six hours after overdose with acetaminophen, liver casts showed rounded centrilobular cavities of various sizes, representing regions in which cast-filled sinusoids were absent with relatively normal microvasculature within periportal regions. Evidence of microvascular injury occurred as early as 5 hours after acetaminophen overdose. This injury consisted of changes to centrilobular sinusoids including areas of incomplete filling and dilated centrilobular sinusoids. Misoprostol (a prostaglandin E1 analog) treatment (6 x 25 micrograms/kg) given before and after acetaminophen administration markedly reduced the extent of microvascular injury with only small focal unfilled areas in the casts and a generally intact microvasculature. In conclusion, this study shows that overdosage with APAP resulted in an extensive, characteristic pattern of hepatic microvascular injury in the centrilobular region. The results also suggest that microvascular injury is an early event in the pathogenesis of acetaminophen hepatotoxicity. Misoprostol was found to protect against injury occurring at the microvascular level.

Acetaminophen↗
PubMed1994

Effects of misoprostol on delayed ulcer healing induced by aspirin.

Clinical studies have suggested that treatment with the prostaglandin E1 analog, misoprostol, leads to significant healing of ulcers in patients taking regular nonsteroidal antiinflammatory therapy. This study aimed to investigate mechanisms involved in this healing using a rat model. Gastric ulcers were induced by application of acetic acid using a standard technique. Rats were treated with 200 mg/kg aspirin, 100 micrograms/kg misoprostol, a combination of both treatments, or methylcellulose vehicle for up to two weeks, starting two days after ulcer induction. Ulcers were assessed by macroscopic measurements of area and by quantitative histological measurements. Aspirin delayed ulcer healing compared with controls, while misoprostol significantly reversed this effect. Quantitative histology revealed that misoprostol cotreatment significantly increased mucosal regeneration compared with aspirin treatment alone. However, misoprostol did not reverse the effects of aspirin on an index of wound contraction. We conclude that treatment with misoprostol significantly reverses the delayed healing effect of aspirin, and this may occur via an effect on epithelial regeneration.

Acetates↗
PubMed1994

Microvascular changes in liver after ischemia-reperfusion injury. Protection with misoprostol.

Morphological changes in the hepatic microvasculature were studied in experimentally induced ischemia-reperfusion injury in the rat using a vascular casting technique. Partial hepatic ischemia was induced for 90 min followed by 24 hr reperfusion. Microvascular casting was performed after 24 hr reperfusion by either intraarterial or intravenous infusion of acrylic resin (Mercox). After corrosion of the tissue, the cast was examined by scanning electron microscopy. Casts of normal livers showed good patency with no evidence of unfilled areas. The mean diameter of sinusoids was 14 +/- 3 microns with those in zone 1 slightly smaller than those in zone 3. Liver casts from rats subjected to ischemia and reperfusion resulted in gross disruption of normal architecture. The common characteristics seen in both prograde and retrograde casts were clusters of closed sinusoids around zones 2 and 3 of the liver acini, which resulted in cavities of various sizes. Varicosities were observed in some areas. The mean diameter of sinusoids in areas of patent microvascular structure (10 +/- 2 microns) was significantly smaller compared to those in normal livers (P < 0.001). Misoprostol given at 1 min before reperfusion markedly reduced the microvascular injury. The hepatic microvascular was generally intact with mild focal unfilled areas. The majority of the sinusoids were of normal size and no clusters of blind ending sinusoids were detected. The present study shows that hepatic ischemia-reperfusion results in extensive microvascular injury in the liver. The protective effects of misoprostol against this injury may occur at the vascular level.

Animals↗
PubMed1994

Protection against gastric ischemia-reperfusion injury by nitric oxide generators.

Nitric oxide appears to play an important role in maintaining gastric mucosal integrity. This study aimed to investigate whether a nitric oxide donor (sodium nitroprusside) or stimulation of endogenous nitric oxide synthesis (with acetylcholine) protects against gastric ischemia-reperfusion injury. Rats were subjected to 30 min of ischemia followed by 15 min of reperfusion. Injury was assessed by quantitative histology. Intravenous sodium nitroprusside (50-75 micrograms/kg) or acetylcholine (10-25 micrograms/kg), immediately before reperfusion, significantly reduced the percentage of mucosal injury compared with controls. Inhibition of nitric oxide synthesis by topical application of 12.5 mg/kg NG-methyl-L-arginine before acetylcholine treatment, abolished the effects of acetylcholine. The protective effects of acetylcholine and sodium nitroprusside did not appear to be related to local vasodilation since neither drug improved gastric blood flow and infusion of a non-nitric oxide vasodilator (papaverine, 1 mg/kg), had no protective effect on reperfusion injury. Sodium nitroprusside (50 micrograms/kg) and acetylcholine (25 micrograms/kg) significantly reduced polymorphonuclear leukocyte infiltration and extravasation into the mucosa compared with controls. NG-Methyl-L-arginine pretreatment before acetylcholine abolished these effects. We conclude that nitric oxide generators significantly reduce mucosal injury following ischemia-reperfusion and that this may occur via a reduction in polymorphonuclear leukocyte infiltration into the mucosa.

Acetylcholine↗
PubMed1994

Misoprostol protection against acetaminophen-induced hepatotoxicity in the rat.

The hepatoprotective effects of misoprostol on acetaminophen (APAP)-induced toxicity were studied in the rat. Liver injury was evaluated at 36 hr after APAP administration by measuring serum ornithine carbamoyltransferase (OCT) and alanine aminotransferase (ALT) levels, by using tetranitroblue tetrazolium (TNBT) staining and by histological analysis. After APAP administration, peak serum levels of the drug were detected at 15 min. Liver GSH was depleted from control levels of 448 +/- 48 micrograms/g to 82 +/- 2 micrograms/g (P < 0.01) within 3 hr. Serum ALT levels increased significantly after 16 hr and H&E staining revealed significant hepatic necrosis after 12 hr. Rats treated with misoprostol before and after APAP administration showed reduced OCT and ALT levels at 36 hr of overdose (454 +/- 446 IU/liter and 2571 +/- 2944 IU/liter, respectively) compared to those without misoprostol treatment (1348 +/- 480 IU/liter and 6077 +/- 3025 IU/liter, respectively, P < 0.01). TNBT staining showed a reduced area of damage from 28.6 +/- 22.3% to 7.3 +/- 8.9% (P < 0.01), and H&E staining also showed less extensive hepatic necrosis in rats treated with misoprostol before and after the overdose. In a time sequence study, misoprostol treatment starting within 10 hr of overdose showed the same protective effect as when it was given before and after APAP ingestion. No protection was detected when the treatment was started during the development of hepatic injury. However, misoprostol given when injury was established seemed to be protective. Our results show that misoprostol protects the liver against APAP-induced injury if given within 10 hr of overdose.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗
PubMed1994

Polymorphonuclear leukocyte infiltration into gastric mucosa after ischemia-reperfusion.

Polymorphonuclear leukocytes (PMN) have been implicated in the pathogenesis of ischemia-reperfusion injury. The objective of this study was to investigate PMN infiltration and distribution within the gastric mucosa of rats subjected to 30 min gastric ischemia followed by reperfusion. Sections of mucosa were stained for PMN using an immunoperoxidase technique, and injury was assessed by quantitative histology. In control animals, there were 4 +/- 2 PMN/mm2 in the superficial and 9 +/- 4 PMN/mm2 in the deep mucosa. This increased significantly to 67 +/- 9 PMN/mm2 (P < 0.05) and 160 +/- 53 PMN/mm2 (P < 0.01) respectively at 15 min of reperfusion. The percentage of these PMN which were extravasated was 83 +/- 4% in the superficial mucosa and 82 +/- 4% in the deep mucosa (P < 0.001 compared with control levels of 0% in superficial and 10% in deep mucosa). Significant PMN infiltration occurred before full expression of mucosal injury and treatment of rats with anti-PMN antisera blocked reperfusion injury (treated 10.7 +/- 1.4% mucosa damaged, controls 33.5 +/- 2.4%; P < 0.001). Treatment with allopurinol (100 mg/kg) significantly reduced the number of infiltrating PMN (superficial 7 +/- 1/mm2, deep 16 +/- 2/mm2; P < 0.01) and the percentage of extravasating PMN (superficial 40 +/- 10%, deep 30 +/- 15%; P < 0.01) while also significantly reducing tissue injury (21.9 +/- 1.9% mucosa damaged, P < 0.01 compared with controls). We conclude that the immunoperoxidase staining provides a simple means of identifying PMN in histological sections. Furthermore, our results support a role for PMN in gastric ischemia-reperfusion injury.

Animals↗
PubMed1994

Effect of nonsteroidal anti-inflammatory drugs on LFA-1 and ICAM-1 expression in gastric mucosa.

Leukocyte adhesion to the endothelium appears to play an important role in gastric injury. This study aimed to develop immunohistochemical staining techniques to investigate the distribution and sequence of expression of both leukocyte [lymphocyte function associated antigen 1 (LFA-1)] and endothelial [intracellular adhesion molecule 1 (ICAM-1)] adhesion molecules in the mucosa after treatment with nonsteroidal anti-inflammatory drugs (NSAIDs). In control rats there were 803 +/- 72 LFA-1-stained cells/mm2 in the deep mucosa, 134 +/- 32 cells/mm2 in the superficial mucosa, and 6.4 +/- 1.2 ICAM-1-stained blood vessels/mm2 in the total mucosa. The number of ICAM-1-stained blood vessels in the mucosa increased significantly after 30 min of treatment with intragastric aspirin (30 mM; 25.2 +/- 7.2/mm2, P < 0.01) and indomethacin (20 mg/kg; 20.7 +/- 4.4/mm2, P < 0.01) before any appreciable mucosal damage was evident. This increase was reversed by treatment with misoprostol (100 micrograms/kg) in both aspirin- (7.6 +/- 1.7/mm2, P < 0.01) and indomethacin-treated animals (10.7 +/- 2.6/mm2, P < 0.05). There was no significant increase in LFA-1-positive cells until 60 min of NSAID treatment. We conclude that the adhesion molecules LFA-1 and ICAM-1 are expressed in the normal gastric mucosa and that the number of ICAM-1-stained blood vessels increase rapidly after NSAID treatment. This increase in ICAM-1 expression may be associated with an inhibition of prostaglandin synthesis by NSAIDs. These results provide further support for the role of early vascular changes in NSAID gastropathy.

Animals↗
PubMed1993

A multicenter trial for resuscitation of injured patients with 7.5% sodium chloride. The effect of added dextran 70. The Multicenter Group for the Study of Hypertonic Saline in Trauma Patients.

OBJECTIVE: To evaluate the use of 250 mL of a 7.5% sodium chloride solution, both with and without added dextran 70, for the prehospital resuscitation of hypotensive trauma patients. DESIGN: Double-blind randomized trial. SETTING: Six trauma systems served by helicopter transport. PATIENTS: Injured patients with systolic blood pressures less than 90 mm Hg at any time in the field or during helicopter transport. INTERVENTIONS: Infusion of study solution, in the field or during transport, followed by conventional isotonic solutions as needed. Solutions studied in four cohorts were as follows: (1) lactated Ringer's; (2) 7.5% sodium chloride (hypertonic saline); (3) 7.5% sodium chloride combined with 6% dextran 70; and (4) 7.5% sodium chloride combined with 12% dextran 70. MAIN OUTCOME MEASURES: Blood pressure response; survival to time of hospital discharge among the treatment groups; and survival compared with that predicted by norms from the Major Trauma Outcome Study (MTOS). RESULTS: The mean (+/- SD) change in systolic blood pressure on arrival in the emergency department was significantly higher in the hypertonic saline solution group than that in the lactated Ringer's solution group (34 +/- 46 vs 11 +/- 49 mm Hg, P < .03). Overall survival in the four treatment groups was 49%, 60%, 56%, and 45% (not statistically significant). Survival in the hypertonic saline solution group, however, was significantly higher than that predicted by the MTOS norms (60% vs 48%, P < .001). Survival to hospital discharge in patients with baseline Glasgow Coma Scale scores of 8 or less was correlated with treatment group (P < .05 by logistic regression and P < .01 by Cox proportional-hazards analysis; with survival in the hypertonic saline solution group [34%] vs lactated Ringer's solution group [12%]). CONCLUSIONS: Prehospital infusion of 250 mL of 7.5% sodium chloride is associated with an increase in blood pressure and an increase in survival to hospital discharge compared with survival predicted by the MTOS norms. Patients with low baseline Glasgow Coma Scale scores seem to benefit the most from 7.5% sodium chloride resuscitation. Hypertonic saline solution without added dextran 70 is as effective as the more expensive solutions that contain dextran 70.

Adolescent↗
PubMed1992

Codependency: a disorder separate from chemical dependency.

This study examined the relationship between codependency (an excessive preoccupation with the lives, feelings, and problems of others), chemical dependency of a significant other, and depression. The Significant Others' Drug Use Survey (SODS) determined whether the subject was in a relationship with a significant other at risk of being chemically dependent. Beck's Depression Inventory (BDI) was used to assess depression. Two hypotheses were tested: first, that codependency exists independently of chemical dependency and, second, that codependent people tend to be more depressed than non-codependents. Results supported the first hypothesis, but not the second. A significant correlation between depression and having a significant other likely to be chemically dependent was observed. The usefulness of the concept of codependency is discussed with proposals for subsequent research.

Adult↗
PubMed1992

Sequence of gastric mucosal injury following ischemia and reperfusion. Role of reactive oxygen metabolites.

The mechanisms of gastric mucosal injury following a period of ischemia remain unclear. The aim of this study was to determine the relative contributions of ischemia, reperfusion, and reactive oxygen metabolites to mucosal injury induced by temporary occlusion of the celiac artery. Rats were subjected to 30 min of gastric ischemia in the presence of 100 mM HCl. Reperfusion periods ranged from 1 min to 24 hr. Drug treatments included allopurinol (100 mg/kg) or a combination of superoxide dismutase (15,000 units/kg), catalase (90,000 units/kg), and desferrioxamine (50 mg/kg). Mucosal injury was assessed by quantitative histology and the extent of macroscopic hemorrhage. Approximately one third of the total injury to the volume of the mucosa (11.8 +/- 9.1%) was due to ischemia alone. Another third was blocked by allopurinol or superoxide dismutase, catalase, and desferrioxamine (22.1 +/- 6.9%, P less than 0.001; and 25.9 +/- 4.6%, P less than 0.01), respectively, compared with control (32.5 +/- 5.1%). In contrast, extensive surface mucosal injury (62.2 +/- 27.6%) occurred primarily during ischemia and was not affected by antioxidants. Macroscopic hemorrhage was halved by treatment with allopurinol (17.5 +/- 12.6%, P less than 0.01) or superoxide dismutase, catalase, and desferrioxamine (15.9 +/- 14.5%, P less than 0.01). We conclude that temporary celiac occlusion results in gastric mucosal damage that consists of both ischemic and reperfusion components. The majority of surface mucosal injury occurred during ischemia, whereas injury to the volume of the mucosa and the vasculature occurred equally during reperfusion and was associated with reactive oxygen metabolites.

Allopurinol↗
PubMed1992

Misoprostol hepatoprotection against ischemia-reperfusion-induced liver injury in the rat.

The hepatoprotective effects of misoprostol, a PGE1 analog, against ischemia-reperfusion liver injury were studied using a rat partial liver ischemia model. Serum ornithine carbamoyltransferase (OCT) and alanine aminotransferase (ALT) levels were determined as biochemical indices of injury. Hepatic cell necrosis was assessed histologically using tetranitroblue tetrazolium (TNBT) and hematoxylin and eosin (H&E) staining. With placebo treatment, 90 min of partial hepatic ischemia followed by 24 hr of reperfusion resulted in increased levels of serum OCT (760 +/- 521 IU/liter) and ALT (4327 +/- 1982 IU/liter), while extensive hepatic necrosis was evident by TNBT and H&E staining. Treatment with two doses of 25 micrograms misoprostol/kg body weight at 1 min before ischemia and 1 min before reperfusion significantly reduced the serum levels of OCT and ALT (207 +/- 189 IU/liter, P less than 0.01 and 2075 +/- 1217 IU/liter, P less than 0.01, respectively) and hepatic necrosis. When a single dose of misoprostol was administered 1 min before reperfusion, similar protective effects were observed. However, when the treatment of misoprostol was delayed to 1 min after reperfusion, significantly less hepatoprotection was seen. Misoprostol exerted no hepatoprotection at all when it was administered at 5 min or later after reperfusion. These results demonstrate that misoprostol partially protects the liver against ischemia-reperfusion injury in the rat. The observation that the protective effect of misoprostol occurs only within the first minute of reperfusion suggests that its mechanism of action involves an early event in reperfusion injury, such as modifying the effects of reactive oxygen metabolites.

Animals↗
PubMed1991

Sulindac inhibits the rate of growth and appearance of colon tumors in the rat.

Sulindac (cis-5-fluoro-2-methyl-1-[p-(methylsulfinyl) benzylidene] indene-3-acetic acid), an inhibitor of prostaglandin synthesis, has been reported to cause regression of colon polyps in patients with familial polyposis coli and Gardner's syndrome. We examined the effect of sulindac on the growth of primary colon carcinomas in rats. Colon tumors were induced in 18 rats by repeated subcutaneous administration of dimethylhydrazine. The site and diameter of each tumor were measured via laparotomy and colonoscopy. Rats were randomized to receive either sulindac (10 mg/kg) twice daily or vehicle (0.5% methylcellulose). After 4 weeks of treatment, the site and size of tumors in the colon were again recorded. In eight rats receiving sulindac, no new tumors were identified, while in 10 control rats, 13 additional tumors were found after treatment. There was a significantly greater increase in size of the tumors in the control group (56.4 mm for 26 tumors) compared with the rats receiving sulindac (9.3 mm for 14 tumors). We report that sulindac inhibits the rate of development and the rate of growth of colon tumors in the rat.

Adenocarcinoma↗
PubMed1991

Inability of cytoprotection to occur during a period of gastric ischemia.

Prostaglandin E2 (PGE2), colloidal bismuth subcitrate (CBS), and sucralfate (SUC) are known to protect the gastric mucosa from ethanol injury. The proposed central role for the microcirculation in gastric mucosal defense and as a site for the expression of the protective effects of these agents was investigated in the rat stomach. Animals were pretreated with either PGE2, CBS, or SUC. Control rats were given normal saline. After allowing 15 min for expression of the pretreatment, ethanol was administered as a 10%, 25%, 50%, or 100% solution to groups of rats with normally perfused stomach and to other groups of rats in whom the stomach was made ischemic by cross-clamping the supracoeliac aorta immediately prior to the instillation of ethanol. The extent of gastric mucosal damage was measured using quantitative histological techniques and expressed as a percentage of surface area and volume of mucosa damaged. In the presence of ischemia, the extent of damage by ethanol was markedly increased, with total destruction of the mucosa by the 50% and 100% solutions. With 25% ethanol, the volume of mucosal damage was increased from 0.5% in the normally perfused stomach to 53.5% with ischemia. When 10% ethanol was instilled into the ischemic stomach, only 0.8% of the volume of the mucosa was damaged, which was not different from the volume of mucosa damaged after the ischemic stomach was exposed to normal saline alone (1.0%). Pretreatment with PGE2, CBS, or SUC did not significantly change the extent of damage seen with exposure of the ischemic stomach to 25% or 50% ethanol.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Microvascular architecture of experimental colon tumors in the rat.

Tumor cell proliferation is dependent upon concurrent growth of a supporting vasculature. This study aims to characterize the structural features of the microvasculature within a primary tumor model. There were 22 colon tumors induced in 16 rats by repeated administration of dimethylhydrazine. A cast of the microvessels was prepared by intraarterial administration of acrylic resin (Mercox). After corrosion of the tissue, the cast was examined by scanning electron microscopy. Tumors 2.6 to 12.0 mm in diameter were examined. Within polypoid carcinomas up to 5.7 mm in diameter, there were two distinct vascular zones, a luminal vascular zone continuous with the vasculature of normal mucosa and a central zone continuous with the normal submucosa and muscularis propria vessels. Within both vascular zones, the organization of microvessels had the same general pattern as in normal mucosa. However, in tumors with diameters greater than 5.7 mm, the vasculature was seen to be disorganized and of a greater density than normal. In the smallest tumors, few morphological changes were seen in the individual microvessels when compared to normal. However, with tumor growth, there was elongation and increased diameters of the microvessels within the tumor. Microvessels within the luminal zone of the tumors which could definitely be traced to veins had diameters of 50 to 100 microns (compared to 12 to 30 microns for normal venules). Individual microvessels varied in diameter along their course forming saccular dilations in places. Networks of frequently anastomosing microvessels were formed. Extravasation of resin occurred from some microvessels. Elongated vessels of uniform diameter which travel distances up to 2 mm without branching were seen and were probably arterioles. These appearances indicate that there are two distinct stages of development of the vasculature within primary tumors, an early phase where the tumor is supplied by the preexisting host microvessels, followed by a phase of proliferation of new vessels with abnormal morphological characteristics.

Adenocarcinoma↗