p53 Accumulation Is a Prognostic Factor in Intestinal-Type Gastric Carcinoma but Not in the Diffuse Type

Background: The prognostic value of p53 nuclear accumulation in gastric cancer is still unclear, as shown by the discordant results still reported in the literature. In this study, we evaluated the correlation between p53 accumulation and long-term survival of patients resected for intestinal and diffuse-type gastric cancer.Methods: Eighty-three patients with carcinoma of the intestinal type and 53 patients with carcinoma of the diffuse type were included in the study. Immunohistochemical staining of the paraffin sections was performed by using monoclonal antibody DO1; cases were considered positive when nuclear immunostaining was observed in 10% or more of the tumor cells. Prognostic significance of different variables was investigated by univariate and multivariate analysis.Results: p53 positivity was found in 51.8% of intestinal-type and 50.9% of diffuse-type cases. No significant correlation between the rate of p53 overexpression and age, sex, tumor location, tumor size, depth of invasion, lymph node involvement, distant metastases, and surgical radicality was found in the two groups of patients. A statistically significant difference in survival rate was observed between p53-negative and p53-positive cases in the intestinal type (P < .05), confirmed by multivariate analysis (P < .005; relative risk = 3.09). On the contrary, no correlation with survival was found in diffuse-type cases according to p53 overexpression.Conclusions: These results suggest that the immunohistochemical detection of p53 accumulation is a useful indicator of poor prognosis in the intestinal but not in the diffuse type of gastric cancer, and are indicative of distinct molecular pathways and pattern of progression in the two histotypes.     

Differentiation of fetal pig endocrine cells after allografting into the thymus gland

BACKGROUND: The thymus of large animals, such as the pig, is thought to be an appropriate site for transplanting adult islets, which contain numerous beta cells, for the purpose of reversing diabetes. Whether fetal islet-like cell clusters (ICCs), which contain few beta cells, will develop at this site, so that adequate amounts of insulin can be produced, is unknown. METHODS: Between 15,000 and 40,000 ICCs were injected into the thymus gland of six juvenile immunosuppressed pigs, and the animals were killed up to 30 days later. The graft was then examined histologically and comparisons made with untransplanted ICCs and those grafted into the omentum of immunosuppressed pigs. RESULTS: At transplantation, the percentage of cells in the ICCs containing insulin, glucagon, somatostatin, or pancreatic polypeptide was 9+/-1%, 13+/-2%, 9+/-1%, and 3+/-1% respectively. Within 9-30 days of transplantation into the thymus, the percentage of all endocrine cells increased, insulin to 41+/-3%, glucagon to 43+/-6%, somatostatin to 26+/-4%, and pancreatic polypeptide to 9+/-3%. There was co-localization of more than one hormone in some cells. Omental grafts contained a similar percentage of insulin and glucagon-containing cells, but significantly fewer somatostatin and pancreatic polypeptide-containing cells. CONCLUSIONS: Endocrine cells from the fetal pig pancreas will differentiate when transplanted into the thymus gland of the pig, making this a suitable site for grafting ICCs to test their ability to normalize blood glucose levels of diabetic recipients.     

Orally active isoxazoline glycoprotein IIb/IIIa antagonists with extended duration of action

Modification of the alpha-carbamate substituent of isoxazoline GPIIb/IIIa (alphaIIb beta3) antagonist DMP 754 (7) led to a series of alpha-sulfonamide and alpha-sulfamide diaminopropionate isoxazolinylacetamides which were found to be potent inhibitors of in vitro platelet aggregation. Aryl- and heteroaryl-alpha-sulfonamide groups, in conjunction with (5R)-isoxazoline (2S)-diaminopropionate stereochemistry, were found to impart a pronounced duration of antiplatelet effect in dogs, potentially due to high affinity for unactivated platelets. Isoxazolylsulfonamide 34b (DMP 802), a highly selective GPIIb/IIIa antagonist, demonstrated a prolonged duration of action after iv and po dosing and high affinity for resting and activated platelets. The prolonged antiplatelet profile of DMP 802 in dogs and the high affinity of DMP 802 for human platelets may be predictive of clinical utility as a once-daily antiplatelet agent.     

Physiological perspectives of therapy in bronchial hyperreactivity

Purpose

This paper reviews the literature on the aetiology and therapy of bronchial hyperreactivity to describe the underlying pathophysiology, identify patients at risk and update knowledge on new and existing therapies.

Source

Information was obtained from monograms on New Drugs for Asthma, Respiratory Medicine: recent advances, Agents and Actions Supplements, Pulmonary Pharmacology, Anesth Analg, the European Journal of Respiration and a Medline literature search.

Principal findings

Reduced airway calibre, increased bronchial contractility, altered permeability of the bronchial mucosa, humoral and cellular mediators, and dysfunctional neural regulation are critical factors for bronchial hyperreactivity, a characteristic feature of hyperreactive airways which results in bronchoconstriction after exposure to varied stimuli. Preoperative anaesthetic considerations in these patients include FEV₁ and PEFR testing to assess the severity and for optimal control of the condition. Bronchospasm causing hypoxaemia is the major intraoperative problem anticipated in these patients. Current therapeutic management of bronchoconstriction focusses on the β₂ agonists, theophylline and steroids. Besides relaxing the airway smooth muscle these agents are all capable of altering bronchial inflammatory responses. Future developments of therapy are directed towards the inflammatory components of the disease.

Conclusion

This review has presented background information on physiological mechanisms of smooth muscle contractility, pathophysiological alterations of bronchial contractility and the pharmacological basis of therapy in bronchoconstrictive disease. Information is presented to enable the prompt arrest and reversal of airway constriction, and to maintain prophylactic treatment during the perioperative period. Intraopera’tive bronchospasm is managed by adequate oxygenation and reversal of bronchoconstriction     

"Masked" Ph1 chromosome abnormalities in CML: a report of two unique cases

Two patients with chronic myeloid leukemia (CML) showed previously undescribed variants of a "masked" Ph1 abnormality. The first patient had the karyotype 46,XY, + 21, -9, -22, +mar9,mar18 at presentation in the chronic phase. The dicentric marker 9 was interpreted as representing the usual translocation of 22q11 to 9q34, followed by translocation of the Ph1 chromosome (the deleted 22) to 9p and probable translocation of 9p to the distal long arm of the marker. The patient developed clones containing 2 and 3 copies of the "Ph1-containing" marker 9 concomitant with the metamorphosis of his disease to a more aggressive phase. The second case presented with the karyotype 46,XY,- 9,-22,+two D-group markers. A complex rearrangement of chromosomes 9 and 22 is postulated, with interstitial insertion of either 9p or distal 9q into chromosome 22q11. This patient is still in the chronic phase of his disease 9 mo after presentation. The common denominator in these unusual "masked" cases is the 22q11 breakpoint. The paucity of published reports of duplication of 9q + without concurrent duplication of the Ph1 chromosome, supported by the findings in our first case, leads us to conclude that the amplification of genes on the Ph1 chromosome are more important for the evolution of the abnormal stem cell in CML than the chromosome 9 derivative.     

The vasa vasorum and angioplasty

Interruption of flow in the vasa vasorum may lead to medial necrosis and aneurysm formation. The purpose of this study was to determine whether angioplasty produces significant alterations in the morphology or blood flow of the vasa vasorum of the dilated artery. The morphology of the canine vasa vasorum was studied before and after angioplasty; in a separate experiment vessel wall blood flow (VWBF) in canine carotid arteries was measured after angioplasty to determine whether physiologic regulation of the blood flow was disrupted by arterial dilation. No morphologic changes could be demonstrated in the vasa vasorum of the dilated artery; however, VWBF was increased by 1194 +/- 215% (mean +/- standard error, p less than 0.01) between 90 and 120 minutes after angioplasty. VWBF in the adjacent nondilated arterial segment was also increased (720 +/- 177% between 10-30 minutes, p less than 0.01) but returned toward normal after 60 minutes. Adenosine caused a "paradoxical" decrease in VWBF (p less than 0.05) of the dilated arterial segment while causing increased VWBF (p less than 0.05) in the thoracic aorta. Angioplasty appears to produce persistent hyperemia in the dilated arterial wall. A paradoxical response to adenosine suggests that vasa vasorum in the dilated arterial segment are maximally vasodilated. This may be due to mechanical disruption of vasomotor tone or to release of vasoactive substances.     

Detrimental effect of neoadjuvant chemotherapy in patients with stage-iiib carcinoma of the cervix - results of a randomized trial

With the objective of testing the value of neoadjuvant chemotherapy in patients with stage III B carcinoma of the cervix, we began in 1984 a randomized, phase III trial comparing BOMP chemotherapy followed by pelvic radiotherapy versus pelvic radiotherapy alone. Patients were stratified by age, extension of parametrial involvement, and lymphangiographic findings. Despite a higher complete response rate, the overall 5-year survival was significantly inferior in the combined therapy group (39% vs 23%, P=0.02). Toxicity was more pronounced in the chemoradiation arm and 4 patients developed fatal pulmonary complications. Patterns of failure were similar in both groups. The use of primary chemotherapy in advanced carcinoma of the cervix was detrimental to the patients and its use outside a protocol setting is discouraged.