Increased expression of estrogen-receptor exon-5-deletion variant in relapse tissues of human breast cancer

A substantial percentage (30–70%) of human breast carcinomas that initially respond to endocrine therapy acquire resistance during the treatment. Many patients with tumor progression despite treatment with anti-estrogen tamoxifen show continued expression of estrogen receptors (ER) and/or progesterone receptors (PgR) in the relapse tissue. This indicates that, in these tumors, mechanisms other than loss of ER expression are responsible for treatment failure. We have investigated the occurrence and frequency of the exon-5-deletion variant (d5) of ER in human breast-cancer biopsies and in normal tissues. In all normal and tumor tissues tested, both wild-type (wt) and d5 were detected, indicating that expression of the d5 variant is a naturally occurring polymorphism. However, the primary tumors of patients who relapse within 15 months (n = 13) express higher ratios of d5 than do those of patients with no relapse during the same period (p = 0.4, n = 19), though this difference is statistically not significant. A significant increase in the expression level of d5 was determined in relapse as compared with the respective primary tumor (p = 0.02). These data indicate that increased expression of the ER exon-5-deletion variant in relapse tissues might be due to clonal selection of cells resistant to anti-estrogen treatment. Int. J. Cancer (Pred. Oncol.) 79:44–48, 1998. © 1998 Wiley-Liss, Inc.     

CALCIUM-CHANNEL BLOCKING AGENTS VERAPAMIL AND DILTIAZEM ARE INHIBITORS OF VASOPRESSIN-INDUCED HUMAN PLATELET ACTIVATION

1. This study investigated the influences of calcium-channel blocking agents verapamil and diltiazem on platelet responses induced by arginine vasopressin (AVP) and lysine vasopressin (LVP). 2. The substances inhibited platelet aggregation induced by both low and high AVP concentrations, LVP and adrenaline plus AVP. IC50 values of each drug are lower than those determined for ADP- and collagen-elicited aggregation. Verapamil and diltiazem also decreased AVP-induced thromboxane B2 synthesis. 3. Other series of experiments showed that the addition of ethyleneglycol-bis-(beta-amino-ethyl ether) N, N'-tetra-acetic acid to platelet-rich plasma samples also prevented the platelet response to vasopressin polypeptides. 4. Our data provide evidence that the effects of verapamil and diltiazem on vasopressin-induced platelet responses may be directly related to inhibition of extracellular calcium entry.     

Pooled analysis of prognostic impact of uPA and PAI-1 in breast cancer patients

In this report we present an extension of the pooled analysis of the prognostic impact of urokinase-type plasminogen activator (uPA) and its inhibitor PAI-I in breast cancer patients. We analyzed a different endpoint, metastasis-free survival (MFS). We checked the consistency of the estimates for uPA and PAI-1 for relapse-free survival (RFS) and MFS exploring possible sources of heterogeneity. Nodal status, the most important prognostic factor for breast cancer, introduced heterogeneity in the uPA/PAI-1 survival analyses, reflecting the interaction between nodal status and uPA/PAI-1. The estimates for uPA and PAI-1 were found to be consistent, even when a different transformation of their values was used. The heterogeneity of the separate data sets decreased if the levels of uPA and PAI-1 were ranked, data sets were pooled, and the analyses corrected for the base model that included all traditional prognostic factors, and stratified by data set. We conclude that uPA and PAI-1 are ready to be used in the clinic to help classify breast cancer patients into high and low risk groups.     

Comparison of gene expression profiles in core biopsies and corresponding surgical breast cancer samples

Introduction  

Gene expression profiling has been successfully used to classify breast cancer into clinically distinct subtypes, and to predict the risk of recurrence and treatment response. The aim of this study was to investigate whether the gene expression profile (GEP) detected in a core biopsy (CB) is representative for the entire tumor, since CB is an important tool in breast cancer diagnosis. Moreover, we investigated whether performing CBs prior to the surgical excision could influence the GEP of the respective tumor.     

First-Phase Insulin Secretion Restoration and Differential Response to Glucose Load Depending on the Route of Administration in Type 2 Diabetic Subjects After Bariatric Surgery

OBJECTIVE—The purpose of this study was to elucidate the mechanisms of diabetes reversibility after malabsorptive bariatric surgery.RESEARCH DESIGN AND METHODS—Peripheral insulin sensitivity and β-cell function after either intravenous (IVGTT) or oral glucose tolerance (OGTT) tests and minimal model analysis were assessed in nine obese, type 2 diabetic subjects before and 1 month after biliopancreatic diversion and compared with those in six normal-weight control subjects. Insulin-dependent whole-body glucose disposal was measured by the euglycemic clamp, and glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were also measured.RESULTS—The first phase of insulin secretion after the IVGTT was fully normalized after the operation. The disposition index from OGTT data was increased about 10-fold and became similar to the values found in control subjects, and the disposition index from IVGTT data increased about 3.5-fold, similarly to what happened after the euglycemic clamp. The area under the curve (AUC) for GIP decreased about four times (from 3,000 ± 816 to 577 ± 155 pmol · l⁻¹ · min, P < 0.05). On the contrary, the AUC for GLP1 almost tripled (from 150.4 ± 24.4 to 424.4 ± 64.3 pmol · l⁻¹ · min, P < 0.001). No significant correlation was found between GIP or GLP1 percent changes and modification of the sensitivity indexes independently of the route of glucose administration.CONCLUSIONS—Restoration of the first-phase insulin secretion and normalization of insulin sensitivity in type 2 diabetic subjects after malabsorptive bariatric surgery seem to be related to the reduction of the effect of some intestinal factor(s) resulting from intestinal bypass.In 1987, Pories et al. (1) published a stunning observation that 99% of morbidly obese patients with frank type 2 diabetes or impaired glucose tolerance who had undergone Roux-en-Y gastric bypass (RYGB) became and remained euglycemic after surgery. Most interestingly, these authors reported that the patients were converted to euglycemia within 10 days, even if they had required large doses of insulin.Subsequently, we (2,3) and other authors (4) have found that either restrictive or malabsorptive bariatric surgery is effective in improving/resolving type 2 diabetes. In particular, using the euglycemic hyperinsulinemic clamp we have demonstrated that insulin sensitivity was normalized after malabsorptive bariatric surgery in both obese type 2 diabetic (2) and obese normotolerant subjects.We theorized that the normalization of insulin sensitivity that occurs very early after biliopancreatic diversion (BPD) before a significant weight loss can occur (2) may be dependent on the hormonal changes related to the nutrient diversion from the duodenum, the entire jejunum, and the proximal portion of the ileum. In fact, the enteroendocrine cells are largely found in these tracts of the small intestine.Two main hypotheses have been advanced up to now to explain which part of the small intestine is implicated in the reversibility of diabetes. The first, known as the hindgut hypothesis (5), holds that diabetes control results from accelerated delivery of nutrients in the distal small intestine. The second, the so-called foregut hypothesis, states that the exclusion of duodenum and jejunum from nutrient transit might prevent the secretion of a putative signal that promotes insulin resistance (2,6). The balance between the stimulatory action on insulin secretion exerted by incretins and the anti-incretin effect might allow a finer control of the glucose disposal.To test the hypothesis that an imbalance in the release of intestinal hormone(s) can determine insulin resistance and that after BPD secretion of intestinal hormone(s) is reduced, allowing normalization of insulin sensitivity with subsequent β-cell glucose sensitivity improvement, we assessed peripheral insulin sensitivity and β-cell function after either an intravenous or oral glucose tolerance test in nine obese, type 2 diabetic subjects compared with those in six normal-weight age- and sex-matched control subjects. To further support our results, insulin-dependent whole-body glucose disposal was also measured by the euglycemic clamp.     

Can post-mortem computed tomography be considered an alternative for autopsy in deaths due to haemopericardium? Presentation of a case

Hemopericardium is a common finding at autopsy, but it may represent a challenge for the forensic pathologist when the etiopathologi-cal relationship in causing death is requested. Hemopericardium and cardiac tamponade can be evaluated in living people using radiological techniques, in particular computer tomography （CT）. Only a few studies are reported in literature involving post-mortem （PM） cases, where PMCT imaging has been used in order to investigate acute hemopericardium, and they have shown a good accuracy of this technique. Here we report a case involving a 70-year-old white male found dead on the beach, with a medical history of hepatitis C and chronic hypertension with a poor pharmacological response. A PMCT was performed about 3 h after the discovery of the body. The PMCT examination showed an intrapericardial aortic dissection associated to a periaortic hematoma, a sickle-shaped intramural hematoma, a false lumen, and a hemop-ericardium consisting in fluid and clotted blood. In this case, the PMCT was able to identify the cause of death, even though a traditional autopsy was required to confirm the radiological findings. PMCT is a reliable technique, which in chosen cases, can be performed without the need for a traditional autopsy to be carried out.