Minimal portal vein stenosis is a promising preconditioning in living donor liver transplantation in porcine model.

BACKGROUND & AIMS: The main hindrance in promoting living donor liver transplantation remains the morbi-mortality risk for the donor. Considering the opposed remodeling influence of portal and hepatic artery flows, our working hypothesis was to identify a lobar portal vein stenosis capable of inducing a contralateral liver mass compensatory enlargement, without the downstream ipsilateral atrophic response. METHODS: Twenty-four pigs entered this study. Six of them were used to establish hemodynamic changes following a progressive left portal vein (LPV) stenosis, in blood flow, pressure and vessel diameter of the LPV, main portal vein and hepatic artery. Sixteen pigs were divided into 4 groups: sham operated animals, 20% LPV stenosis, 50% LPV stenosis, and 100% LPV stenosis. Daily liver biopsies were collected until post-operative day 5 to investigate liver regeneration and atrophy (Ki67, STAT3, LC3, and activated caspase 3) according to the degree of LPV stenosis. Finally, changes in liver volumetry after 20% LPVS were investigated. RESULTS: A 20% LPV stenosis led to dilatation of the hepatic artery and a subsequent four-fold increase in hepatic arterial flow. Concomitantly, liver regeneration was triggered in the non-ligated lobe and the cell proliferation peak, 5 days after surgery, was comparable to that obtained after total LPV ligation. Moreover, 20% LPV stenosis preconditioning did not induce left liver atrophy contrary to 50 and 100% LPV stenosis. CONCLUSIONS: A 20% LPV stenosis seems to be the adequate preconditioning to get the remnant liver of living donor ready to take on graft harvesting without atrophy of the future graft.

[Pathological features of radiofrequency ablation (RFA) renal scar CT-imaging in a swine model]. / Cicatrice de radiofréquence rénale : corrélations anatomopathologiques-tomodensitométriques chez le porc. Applications pratiques pour le suivi en imagerie.

PURPOSE: To analyze the changes in vicinal kidney parenchyma after percutaneous RFA. MATERIALS AND METHODS: [corrected] Twenty-four CT-guided RFA procedures were performed on six pigs using 2 cm LeVeen coaxial needles. We studied volume, morphology, cavitation and enhancement of the ablation zones (AZ) before and after the procedure on contrast-injected CT-scans. The kidneys were removed four weeks later and studied in the path lab. RESULTS: All the procedures were successfully completed. Four weeks later, the CT-scans showed AZ that were either clearly circumscribed or with unclear borders, heterogenous areas associating necrosis and infarct tissue and mesenchyma showing a process of apoptosis around the edges. A treatment considered as incomplete on the CT-scan (presenting as an enhancement) was always associated with necrosis on the histology slides, although the necrotic areas behaved in various different ways on the CT-scan after injection of contrast medium: an enhancement of more than 10 HU did not mean that no necrotic tissue was present. CONCLUSION: RFA causes heterogenous tissue changes, associating necrotic and ischemic zones and an apoptotic reaction. The mechanisms of these changes and their therapeutic significance should be studied. CT-scans performed immediately after RFA procedure and one month later are not predictive of the efficacy of the treatment because an enhancement of the AZ does not mean that it is not necrotic. The value of a CT-scan performed one month after the procedure is debatable, because the tissue remodeling that occurs in the kidneys is not definitive at this time-point.

The haemodynamics of the distal arterial Y-shaped autograft bypass-flap in a porcine experimental model.

BACKGROUND: The haemodynamic effects of revascularisation with combined bypass and free-muscle flap remain controversial. In a porcine experimental model, we investigated the transplantation-induced changes in the haemodynamics of a Y-shaped combined arterial autograft bypass-muscle flap (AABF). METHODS: Anatomy of AABF was identified in eight dissections in four porcine cadavers. In five animals, AABF served as a superficial femoral artery (SFA) defect replacement. Modelled, triggered pulsatile pressure (P) and flow (Q) waves delivered mean haemodynamics and PQ hysteresis loops before and after transplantation at days 0 and 10. RESULTS: Anatomically, AABF combined subscapular and circumflex-scapular arteries, and thoracodorsal artery as latissimus dorsi flap pedicle. Surgical feasibility and AABF patency were confirmed in each case. At day 0, the proximal flow was increased in the grafted Y-shaped AABF, which also adopted the specific SFA pulsatile haemodynamics. Regulatory mechanisms of AABF vasomotricity were preserved and AABF-flow-dependence amplified the flow in the distal segment, which otherwise preserved its own flow dependence. At 10 days, the AABF flow was unchanged in the distal segment, and remained elevated in the proximal and pedicle segments. CONCLUSIONS: Combined AABF, as a single one-piece arterial autograft, was shown highly adaptive to the receiving arteries. The transplantation-induced changes in AABF pulsatile flow profile and vascular reactivity improve the overall graft flow, and strongly advocate for beneficial effects on the blood propelling capacity of the grafted circulation.

Onyx Migration Into the Anterior Spinal Artery During Lumbar Artery Embolisation: an Adverse Event.

INTRODUCTION: The impact of sequential lumbar and intercostal artery occlusion on the risk of spinal cord ischaemia was evaluated; however, an adverse event (paraplegia) was encountered, which resulted in study interruption. Investigations were carried out to understand the reasons for the paraplegia. REPORT: To develop a porcine model of spinal cord ischaemic preconditioning prior to extensive thoraco-abdominal aneurysm endovascular aortic repair, the lumbar arteries were selectively embolised with Onyx 5 days prior to an extended thoracic aortic stent graft. Six pigs were used in this preliminary work. Four cases of paraplegia secondary to accidental migration of Onyx to the anterior spinal artery from the lumbar arteries are reported. Histological analysis confirmed severe spinal ischaemic injury and the presence of Onyx particles in the anterior spinal artery. DISCUSSION: Onyx is used for lumbar artery embolisation in type II endoleak treatment after endovascular aortic repair, and while migration in lumbar arteries is frequent, the risk of spinal cord ischaemia has never been described. The current study demonstrates the risk of paraplegia following Onyx migration to the anterior spinal artery from the lumbar artery in an experimental model. Thus, Onyx treatment for type II endoleaks from lumbar arteries should be used cautiously.

Prostaglandin in human breast cancer: Evidence suggesting that an elevated prostaglandin production is a marker of high metastatic potential for neoplastic cells.

Prostaglandin (PG) production by human breast cancers was investigated in 91 lesions selected so that the distribution of histologic type was similar to that of the general population of mammary carcinomas. With regard to the shape characteristics of the tumors, PG production was higher in lesions classified T1 and T2 than in lesions classified T3 and T4 (T-classification is based on extent of tumor as graded by the International Union Against Cancer), higher in tumors exhibiting a high cellularity than in lesions with a low tumor cell density and higher in tumors in which the cells were still adherent to each other. A high PG production was associated with the presence of neoplastic cells in tumor lymphatic and blood vessels and in axillary lymph nodes. PG production by node metastases was always higher than that by the primary tumor sites. The analysis of the stroma reaction and the presence of edema and necrosis suggest that an active PG synthesis occurred in lesions in which the tumor cell-surrounding stroma presented characteristics of low resistance to invasive growth of cancer cells. With regard to histologic differentiation and histoprognostic grade of lesions, PG production was elevated in carcinomas that retained a minute part of the acinoductal differentiation and in tumors with a moderate or high degree of cancer. A lesion containing a steroid receptor (SR) tended to produce less PG than did an SR-negative tumor. PG production increased slightly according to ages and times of menopause of the patients. PG production occurred early in the natural course of breast cancer and was elevated in tumors at a time when active tumor invasion proceeded. By contrast, PG production decreased later in the course of tumor development. These results indicated that elevated PG production can be used as a marker of high metastatic potential for neoplastic cells in breast cancer.

Preclinical study on an animal model of a new non-adhesive cyanoacrylate (Purefill®) for arterial embolization.

PURPOSE: The goal of this study was to assess the distal dispersion, the adhesion strength to catheter, the vascular toxicity and the ability in excluding embolized vessels using Purefill® (α-hexil-cyanoacrylate) as embolic material, which is a new high purity cyanoacrylate and compare these results with those obtained with N-butyl-2-cyanoacrylate (Histoacryl®) and a mixture of N-butyl-2-cyanoacrylate and methacryloxysulfolane. MATERIAL AND METHODS: In six pigs, the right rete mirabile (RM) and right renal arteries were embolized with α-hexil-cyanoacrylate, and the left rete mirabile and left renal artery were embolized with N-butyl-2-cyanoacrylate and N-butyl-2-cyanoacrylate+Methacryloxysulfolane for comparison. One minute after glue injection through the microcatheter, displacements of the kidney and the pharyngeal artery were measured on angiographic images, before exercising any traction and during catheter pulling, when the forces were maximal. Displacement was measured in terms of distance (mm) with respect to renal pedicles and in terms of angle (°) with respect to the rete. After acute embolization (4 pigs) or three-month follow-up (2 pigs), the kidneys and the RM were removed and further analysed using computed tomography and histopathological examination. RESULTS: Similar short and long-term embolic efficacies were observed with the three glues. The mean displacement distances of renal pedicles were 2.6mm for α-hexil-cyanoacrylate, 22.6mm for N-butyl-2-cyanoacrylate and 19.8mm for N-butyl-2-cyanoacrylate+Methacryloxysulfolane (P=0.021). The mean angles of displacement of the ascending pharyngeal arteries were for 12.2° for α-hexil-cyanoacrylate, 23.5° for N-butyl-2-cyanoacrylate and 30° for N-butyl-2-cyanoacrylate+Methacryloxysulfolane (P=0.070). Histopathologically, findings were similar for the three glues, immediately and 90 days after embolization. CONCLUSION: α-hexil-cyanoacrylate has occlusive efficacy in the short and long term similar to those of N-butyl-2-cyanoacrylate and N-butyl-2-cyanoacrylate+Methacryloxysulfolane. In addition, histopathological changes are similar with the three glues immediately or 90 days after embolization. Conversely, α-hexil-cyanoacrylate results in a reduced angle and distance of displacement compared to the other two glues, assumably reflecting a limited adhesive strength.

Effects of folate supplementation in hyperhomocysteinemic pigs.

OBJECTIVES: The aim of this study was to evaluate the therapeutic effects of folic acid in the pig model of hyperhomocysteinemia. BACKGROUND: We have previously shown that pigs fed a methionine-rich diet develop hyperhomocysteinemia, arterial lesions and thrombotic events. Elevated homocysteine level is an independent risk factor for atherosclerosis that can be markedly lowered with daily folic acid administration. However, it is not known whether this treatment can prevent arterial lesions. METHODS: Three groups of pigs were studied: 8 control subjects received a standard diet; 8 received a methionine-rich diet for four months; 8 received a methionine-rich diet for 1 month and then the methionine-rich diet + 5 mg/day folic acid for 3 months. At month 4 after hemodynamic investigation, all the pigs were sacrificed. RESULTS: Control animals developed few usual vascular streaks. All the pigs fed a methionine-rich diet without folic acid treatment developed hyperhomocysteinemia (10.3+/-1.3 micromol/liter at basal state, 18.2+/-2.5 micromol/liter at one month and 14.6+/-3.8 micromol/liter at four months), hemodynamic abnormalities and diffuse arterial lesions with smooth muscle cell hyperplasia, endothelial alterations and elastic lamina dislocation. In this group, one pig died of venous thromboembolism and one of myocardial infarction. The pigs fed a methionine-rich diet + folic acid displayed similar arterial lesions and two had thrombotic events (one myocardial infarction and one pulmonary embolism), despite normalization of homocysteine levels (10.9+/-1.3 micromol/liter at basal state, 19.5+/-2.5 micromol/liter at one month and 11.4+/-3.8 micromol/liter at four months). CONCLUSIONS: In the pig model of hyperhomocysteinemia, 5 mg/day folic acid did not prevent arterial lesions or thrombotic events.

Homocysteine induces synthesis of a serine elastase in arterial smooth muscle cells from multi-organ donors.

OBJECTIVES: In heart transplant recipients with diffuse coronary arteriopathy, we have previously demonstrated the prevalence of elevated homocysteinemia, also known as an independent risk factor for myocardial infarction and stroke. In hyperhomocysteinemic mini-pigs we also observed early detectable pathologic changes in the elastic laminae. We hypothesized that homocysteine causes premature breakdown in the arterial elastic fibers by activation of the elastolytic activities. METHODS: We examined the effect of homocysteine on elastase-like production by smooth muscle cells from sub-inguinal arteries of multi-organ donors (23.4 +/- 3.4 yr, n = 8). The freshly isolated cells were incubated for 0-72 h with homocysteine (0-250 microM), in the presence or absence of specific protease inhibitors. RESULTS: Homocysteine was devoid of a direct effect, but after 18 h incubation the elastase-like activities increased by 5-6-fold in the extracellular medium. The enzymes were characterized as serine proteases. Incubation of cells with a nucleic acid synthesis inhibitor (actinomycin D) or a protein synthesis inhibitor (cycloheximide) suppressed the enzyme induction. CONCLUSIONS: This is the first report of serine protease induction by homocysteine in vascular smooth muscle cells. The process may require protein synthesis and account for the early alterations of the arterial elastic structures in heart transplant recipients, and in other hyperhomocysteinemic patients, as well.

Medial elastic structure alterations in atherosclerotic arteries in minipigs: plaque proximity and arterial site specificity.

Using a model of atherosclerosis in minipigs, we analyzed changes in elastic structure within the medial sections of the abdominal aorta and left interventricular coronary artery both in the vicinity of and distal to atheromatous plaques. Twenty-four animals, divided into three groups, were fed either a control diet or a hypercholesterolemic and hyperhomocysteinic atherogenic diet, alone or in association with an antihypertensor, namely isosorbide dinitrate (Risordan). The atherogenic diet, administered for a period of four months, induced in the minipig advanced noncalcified atherosclerotic lesions that were histologically similar to those found in humans. A morphodensitometric analysis of the medial elastic structures was carried out on images obtained from specifically stained transverse arterial sections examined under a light microscope. The volume density of the elastic structures was diminished in the arterial media of the atherosclerotic animals due to opening and widening of the fenestrae in the elastic laminate and increased communication between the interlamellar spaces. Whereas this elastolytic process was uniform and independent of the proximity of atheromatous plaques in the left interventricular coronary artery, it was intensified in the vicinity of the plaques in the abdominal aorta. Overall elastolytic activity was increased in the walls of atheromatous artery in both arterial sites, and metalloproteinases were implied in this increase of activity. We previously reported that treatment with isosorbide dinitrate significantly reduced the moderate systolic hypertension and the increase in transparietal stress observed in the abdominal aorta of atheromatous animals. We report here that isosorbide dinitrate prevented the atherogenic-diet-induced deterioration of the elastic structure in these arteries; complete inhibition of changes to the elastic laminae was evident in areas remote from plaque formation, but only partial inhibition in the vicinity of such plaques. It did not, however, prevent structural damage in the left interventricular coronary artery or modify the increase in parietal elastolytic activity in either of the two arteries. This suggests that damage to the elastic structure in atheromatous arteries is dependent not only on overall elastolytic activity but also on localized factors, possibly related to parietal stresses, affected by the presence of atheromatous plaques.

Hyperhomocysteinemia induces elastolysis in minipig arteries: structural consequences, arterial site specificity and effect of captopril-hydrochlorothiazide.

Hyperhomocysteinemia is a risk factor for arterial diseases, and the deterioration of the arterial elastic structures is one of the possible mechanisms underlying this epidemiological association. The aim of this paper is to quantitatively characterize such structural alterations and to explore their causes in a previous model of dietary induced mild hyperhomocysteinemia in minipigs. After four months, both a morphodensitometrical analysis of the elastic structure and a biochemical analysis of elastin and elastase activities were performed on the infrarenal abdominal aorta (IRAA) and the proximal left interventricular coronary artery (LIVCA) of control (C), hyperhomocysteinemic (H) and captopril-hydrochlorothiazide (Cp-Htz, 25 + 12.5 mg/d)-treated (H+/-Cp) minipigs (n = 8/group). Hyperhomocysteinemia was found to induce an increase in parietal elastolytic metalloproteinase activities. It resulted in opening and enlargement of fenestrae through the medial elastic laminae and in a decrease in medial elastin content (p < 10(-3)), expressed as well as volume density (%) as weight concentration (microg elastin/mg dry tissue). The thickness of the media and its basic lamellar organization was unchanged. The reduction in volume density was more dramatic in LIVCA (H: 4.7 +/- 0.9 vs C: 8.8 +/- 2.4), where it was evenly distributed within the media, than in IRAA (H: 6.7 +/- 1.1 vs C: 9.3 +/- 1.2), where the deep medial layers were less affected. Cp-Htz partly prevented the hyperhomocysteinemia-induced reduction of the medial elastin content in LIVCA (5.7 +/- 1.2) and IRAA (7.9 +/- 1.4). This effect, occurring in the subintimal layers of the media in both arteries but not in the deeper layers, resulted in a less beneficial effect in LIVCA than in IRAA. This result parallels the moderate beneficial therapeutic effect of ACE inhibitors against coronary atherosclerosis in humans. This paper reports for the first time a quantitative analysis of the arterial site-dependent deterioration of the elastic structure caused by mild hyperhomocysteinemia and the involvement of metalloproteinases in this process. These results confirm that the plaque-independent damage to elastic structure previously described in hyperhomocysteinemic-atherosclerotic minipigs was mainly due to homocysteine. This highlights that the metalloproteinase-related elastolysis and the subsequent structural deterioration is one of the major events underlying the epidemiological association between mild hyperhomocysteinemia and arterial diseases.

Abnormal taurocholate ileal transepithelial transport in atherosclerotic mini-pigs and effects of ACE inhibitors.

In atherosclerotic mini-pigs, we attempted to determine (i) whether high-fat atherogenic diet disturbs the taurocholate transepithelial transport and incorporation in the ileal epithelium mounted in Ussing chambers, and (ii) whether these processes are sensitive to angiotensin converting enzyme (ACE) inhibitors which slow the development of vascular atherosclerosis. In atherosclerotic mini-pigs, the mucosal to serosal transepithelial fluxes were markedly lower (72% inhibition) and free diffusion was more altered than active processes. Taurocholate incorporation into enterocyte (75% inhibition) paralleled the flux reduction. The transport disturbance observed here might be explained by changes in bile salt permeability in relation to alterations of the membrane properties. Taurocholate absorption was lowered by atherogenic diet, whereas bile salts were not trapped in the enterocyte, therefore atherosclerosis-induced alterations preferentially affected the passage through the brush-border. In the ACE inhibitor treated atherosclerotic mini-pigs, perindopril and enalapril similarly inhibited serum ACE activities. Perindopril further corrected taurocholate fluxes by 50% and fully restored taurocholate incorporation. Since enalapril did not restore the atherosclerosis-induced alterations, the involvement of intestinal ACE in bile acid recycling and of an ACE inhibitor class effect on these mechanisms both remain to be ascertained.

Association of mild hyperhomocysteinemia with cardiac graft vascular disease.

In non-transplant patients mild hyperhomocysteinemia is an independent risk factor for vascular disease. The aim of this study was to determine whether hyperhomocysteinemia is associated with graft vascular disease. Fasting total plasma homocysteine was assessed in 18 patients with graft vasculopathy and 18 transplanted patients without graft vasculopathy matched for age, sex and the time since transplant. All were on cyclosporin. Graft vasculopathy was defined at coronary angiography as stenoses > or = 25%, or aneurysms. We found that hyperhomocysteinemia ( > or = 15 micromol/l) is common among transplanted heart recipients and significantly more frequent in the patients with graft vasculopathy (17/18 versus 11/18). Accordingly, the mean homocysteinemia was significantly higher in the group with graft vasculopathy (23.6+/-7.8 versus 16.9+/-7.1 micromol/l, P=0.01). The elevation of homocysteine plasma levels in the heart transplant recipients has probably multiple causes. The main cause seems to be renal failure. Additional causes could be azathioprine treatment or genetic polymorphisms. These results suggest that besides the immunological factors, homocysteine can play an additional role in the pathogenesis of graft vascular disease.

Effects of angiotensin-converting enzyme inhibition with perindopril on hemodynamics, arterial structure, and wall rheology in the hindquarters of atherosclerotic mini-pigs.

The effects of ACE inhibition with perindopril on the atherosclerosis-induced impairment of arterial flow were investigated via histopathologic studies, hemodynamics, and vascular rheology of hindlimb arteries in 7 adult Pitman-Moore mini-pigs (7 months of age) fed for 4 months with an atherogenic diet and perindopril (at the daily oral dose of 4 mg, which induced a continuous 70% inhibition of serum ACE activity), versus 7 atherogenic and 7 control animals. Major fibroproliferative fatty lesions with medial intimalization were observed in the abdominal aorta. Atherosclerosis impaired the function of both capacitance and resistance hindlimb arteries. In atherogenic mini-pigs, blood pressure (BP) increased significantly due to increased hindlimb peripheral resistance (HPR) and aortic input impedance, although aortic blood flow was not affected. Altered aortic wall rheology revealed that the stiffness of the aorta was markedly increased due to increased wall tension and reduced viscoelasticity, the viscous component being reduced in the arterial wall. Perindopril significantly opposed these alterations by reducing BP, HPR and input impedance and by returning parietal stiffness to control values by increasing aortic compliance. Angiotensin converting enzyme (ACE) inhibition significantly prevented the development of atherosclerosis in the abdominal aorta by decreasing the cross-sectional area of lesions and the presence of lipid-laden cells, as well as by preventing alteration and fragmentation of elastic laminae. In conclusion, ACE inhibition with perindopril showed a significant preventive action on atherosclerosis-induced deleterious effects on vascular wall function and structure in mini-pig arteries.

Molsidomine prevents post-ischaemic ventricular fibrillation in dogs.

Forty anaesthetized dogs were subjected to left circumflex coronary artery ligation followed by reperfusion. Molsidomine was randomly administered to 20 dogs (50 micrograms kg-1 as an i.v. bolus - 15 min prior to coronary occlusion - followed by an infusion of 0.05 micrograms kg-1 min-1. Standard electrocardiographic leads 2 and 3 were continuously recorded to measure ST segment and delta R% changes and to document both the number of ventricular premature beats and the onset of ventricular fibrillation; aortic pressure and cardiac output were measured; thromboxane B2 plasma levels, platelet aggregation produced by ADP, and molsidomine plasma levels were determined before and at 10, 30 and 75 min after the start of the drug protocol. Molsidomine protected the treated animals from early (10 min) post-ischaemic ventricular fibrillation (0 of 20 vs 6 of 20, P = 0.0202), reduced the incidence of overall post-occlusion ventricular fibrillation (3 of 20 vs 10 of 20, P = 0.0407) and improved the total survival rate (P = 0.0067). In molsidomine treated dogs: mean aortic pressure and the rate-pressure product were lowered 10 min after the start of the drug; immediate post-occlusion (3 min) ST segment changes (0.82 +/- 0.52 vs 1.52 +/- 0.78 mV, P less than 0.025) and delta R% changes (37 +/- 50 vs 90 +/- 84%, P less than 0.025) were less marked; the number of ventricular premature beats was lowered and finally, a progressive decline of platelet aggregation produced by ADP was achieved after 75 min of drug infusion. These results were obtained in the presence of mean plasma levels of molsidomine ranging from 20 to 28 ng ml-1. The time-action curve of the antifibrillatory effect of molsidomine parallels those at the level of post-ischaemic electrocardiographic changes.

Effect of prostaglandins on steroidogenesis by bovine adrenal cortex mitochondria.

Prostaglandins (PGA1, PGE2, PGF2 alpha) were found to increase cholesterol side-chain clevage activity in isolated bovine adrenal cortex mitochondria, provided calcium was present in the incubation medium. Optimal stimulation was observed at low PG concentrations (10-7 to 10-9 M), with malate or malate-NADPH supported side-chain cleavage. Under the same conditions, two endoperoxide analogs and several fatty acids were ineffective. The PG action was not observed with a mitochondrial acetone powder preparation. These observations suggest that primary PG may act by interfering with calcium distribution at the mitochondrial level, leading to the activation of cholesterol side-chain cleavage. Thus, an intracellular action of endogenous PG may be considered in the regulation of adrenal cortex steroidogenic functions.

Prostaglandins and steroidogenesis in isolated bovine adrenal cells. Effects of ACTH, prostaglandin-synthesis inhibitors, prostaglandins and prostaglandin analogs.

In bovine adrenal cortex cells, dispersed without preferential loss of cells, we investigated (1) whether endogenous prostaglandins (PGs) are involved in ACTH-induced adrenal steroidogenesis, and (2) the steroidogenic effects of PGs and PG analogs. Free cells produced considerable amounts of PGE2, whereas only minute quantities of PGF2 alpha and PGA1 were synthesized. PGE2 synthesis, however, was not significantly increased when ACTH elicited a steroidogenic response in free cells. High concentrations of PG-synthesis inhibitors such as indomethacin affected both PG synthesis and steroidogenesis, whereas intermediate concentrations (10(-6) M) inhibited production of both PGE2 and aldosterone even after cAMP and cortisol response to ACTH had returned to normal values. It is concluded that endogenous PGE2 is not a link in the acute mechanism of action of trophic hormones in which cAMP is involved. Of the prostanoid structures, PGs of the E series were the most potent stimulating agents of cortisol production, although less active than ACTH. On the other hand, PGA1 induced an ACTH-like aldosterone synthesis. PGE2 was less active, and other prostanoid structures were without effect on aldosterone production. It is suggested that in pathological circumstances, PGA1 regulates aldosterone production and PGE2 increases both aldosterone and cortisol production.

Benign breast disease: studies of prostaglandin E2, steroids, and thermographic effects of inhibitors of prostaglandin biosynthesis.

Plasma levels of estradiol (E2), prostaglandin (PG)E2, and progesterone (P) were measured in both phases of the menstrual cycle in 22 women with benign mastopathies and in 5 normal women. In both phases of the cycle, PGE2 blood levels were significantly higher in patients with benign mastopathies than in normal women. In contrast, the plasma levels of both steroids were lower in patients than in controls. An estrogen-directed synthesis of PGE2 is proposed. In 10 patients, breast thermogenic response to inhibitors of PG biosynthesis (aspirin and indomethacin) revealed a cooling effect in 4 cases, a partly positive response in 3 cases, and no response in 3 cases. The 7 cases with positive responses also had a deficiency of variable magnitude of both steroids without an unbalanced P/E2 ratio. In contrast, patients with a negative thermographic response manifested very low levels of progesterone and a low P/E2 ratio. The significance of patients' unresponsiveness to inhibitors of PGE2 biosynthesis is discussed, as well as the implications with regard to breast cancer.

Histological differentiation in human breast cancer is related to steroid receptors and stromal elastosis.

In 503 cases of human breast cancer, the stroma reaction of elastosis was investigated with respect to histological differentiation, pathological and biochemical prognostic factors, and steroid receptor (SR) content. Unlike perivascular elastosis, gland-related (ductal + interstitial) elastosis was not related to age, menopausal status, and number of pregnancies of each patient, and could thus be considered a histological feature characteristic of mammary cells. Elastosis was encountered most frequently in histologically differentiated lesions and in lesions of histoprognostic grades I and II (low degree of malignancy). Elastosis-positive lesions thus seem to constitute a good prognosis. Elastosis was related to the presence of estrogen and progestin receptors (ER and PR), and in menopausal patients it was observed mostly when both ER and PR were present concurrently, i.e., under conditions reflecting the hormone-dependence of neoplastic cells better than the presence of ER alone. Taken together, these results suggest that the presence of hormone-dependent cells in breast carcinomas can be demonstrated by both biochemical and morphological features. Since each of these factors has its own prognostic value, prognosis could probably be by the assessed more accurately if all these parameters were examined at the same time.

PIP: In 503 cases of human breast cancer, the stroma reaction of elastosis was investigated with respect to histological differentiation, pathological and biochemical prognostic factors, and (SR) steroid receptor content. Unlike perivascular elastosis, gland-related (ductal + interstistial) elastosis was not related to the age, menopausal status, and number of pregnancies of each patient, and could thus be considered a histological feature characteristic of mammary cells. Elastosis was encountered most frequently in histologically differentiated lesions and in lesions of histoprognostic grades 1 and 2 (low degree of malignancy). Elastosis-positive lesions thus seem to constitute a good prognosis. Elastosis was related to the presence of (ER and PR), estrogen and progestin receptors and in menopausal patients it was observed mostly when both ER and PR were present concurrently, i.e., under conditions reflecting the hormone-dependence of neoplastic cells better than the presence of ER alone. Taken together, these results suggest that the presence of hormone-dependent cells in breast carcinomas can be demonstrated by both biochemical and morphological features. Since each of these factors has its own prognostic value, prognosis could probably be by the assessed more accurately if all these parameters were examined at the same time.

Multiple steroid receptors in human breast cancer. III. Relationships between steroid receptors and the state of differentiation and the activity of carcinomas throughout the pathologic features.

Histopathologic features (tumor cell density, histological type, and histoprognostic grade) were analyzed in 314 breast cancers investigated for estrogen (E) and progestin (P) receptors (R). The presence of PR is associated with the presence of ER. A relationship was found between the acinoductal differentiation of the lesions and the presence of SR: the more differentiated the carcinoma, the higher the frequency of ER. HPG III carcinomas have the lowest frequency of positive ER and HPG I tumors the opposite: the likelihood of the presence of SRs is inversely correlated with HPG. No statistically significant relationship existed between tumor cell density (TCD) and the presence of ER or ER content. Similar findings were observed for the stromal reaction. The results are discussed with respect to the biological significance of SR and histopathologic features: SR presence could be correlated with (1) a differentiated state of the tumors and (2) a slow rate of cellular replication.