HMGA1 protein overexpression in human breast carcinomas: correlation with ErbB2 expression.

We measured, by immunohistochemistry, HMGA1 protein expression in 212 breast tissue specimens: 6 normal samples, 28 hyperplastic lesions (13 with cellular atypia), 11 fibroadenomas, 10 in situ ductal carcinomas, 144 ductal carcinomas, and 13 lobular carcinomas. HMGA1 was not expressed in normal breast tissue; HMGA1 staining was intense in 40% of hyperplastic lesions with cellular atypia and in 60% of ductal carcinomas and weak in fibroadenomas and in hyperplastic lesions without cellular atypia. Because HMGA1 expression was similar among ductal breast carcinomas with different histologic grading, we evaluated the association between HMGA1 expression and that of other markers of breast carcinoma invasion (estrogen and progesterone receptors, Ki-67 antigen, and ErbB2) in 21 cases of grade 3 breast ductal carcinomas and 7 cases of breast lobular carcinomas. We found that HMGA1 expression tended to be associated only with c-erbB-2 expression (Spearman rho: 0.36; P=0.065). Taken together, these results suggest that HMGA1 expression might be a novel indicator for the diagnosis and prognosis of human breast cancer.     

Molecular marker profiles predict locoregional control of head and neck squamous cell carcinoma in a randomized trial of continuous hyperfractionated accelerated radiotherapy.

PURPOSE: Identification of factors that assist prediction of tumor response to radiotherapy may aid in refining treatment strategies and improving outcome. Possible association of molecular marker expression profiles with locoregional control of head and neck squamous cell carcinoma was investigated in a randomized trial of conventional versus continuous hyperfractionated accelerated radiotherapy (CHART). EXPERIMENTAL DESIGN: Tumor material was obtained from 402 patients. Immunohistochemistry was used to assess Ki-67, CD31, p53, Bcl-2, and cyclin D1 expression. A hierarchical clustering algorithm with a Bayesian information criterion was used to group tumors with similar marker expression; resulting expression profiles were then compared in terms of their difference in outcome after CHART and conventionally fractionated radiotherapy. RESULTS: Molecular marker profile was an independent prognostic factor for locoregional control. This was confirmed in multivariate analysis, including clinical variables such as tumor and nodal status, primary site, histological grade, age, and gender (P < 0.001 and P = 0.006 for local and nodal relapse, respectively). In particular, Bcl-2-positive tumors responded significantly better than average in both arms of the trial. Tumors negative for p53- and Bcl-2, with high and randomly patterned Ki-67 expression, responded worse than average with no benefit from CHART. Tumors with similarly negative p53 and Bcl-2, but low Ki-67 staining, with an organized pattern, benefit significantly from CHART schedule. CONCLUSIONS: This study demonstrates the potential of molecular profiles to predict radiotherapy response of head and neck squamous cell carcinoma and for treatment stratification. Distinct expression profiles correlate with three distinct clinical phenotypes, including good locoregional control, poor locoregional control, and an outcome strongly dependent upon fractionation schedule.     

Dual Action of NAMI-A in inhibition of solid tumor metastasis: selective targeting of metastatic cells and binding to collagen.

NAMI-A is a ruthenium complex endowed with a selective effect on lung metastases of solid metastasizing tumors. The aim of this study is to provide evidence that NAMI-A's effect is based on the selective sensitivity of the metastasis cell, as compared with other tumor cells, and to show that lungs represent a privileged site for the antimetastatic effects. The transplantation of Lewis lung carcinoma cells, harvested from the primary tumor of mice treated with 35 mg/kg/day NAMI-A for six consecutive days, a dose active on metastases, shows no change in primary tumor take and growth but a significant reduction in formation of spontaneous lung metastases. Transmission electron microscopy examination of lungs and kidney shows NAMI-A to selectively bind collagen of the lung extracellular matrix and also type IV collagen of the basement membrane of kidney glomeruli. The half lifetime of NAMI-A elimination from the lungs is longer than for liver, kidney, and primary tumor. NAMI-A bound to collagen is active on tumor cells as shown in vitro by an invasion test, using a modified Boyden chamber and Matrigel, and it inhibits the matrix metallo-proteinases MMP-2 and MMP-9 at micromolar concentrations, as shown in vitro by a zimography test. These data show NAMI-A to significantly affect tumor cells with metastatic ability. Binding to collagen allows NAMI-A to exert its selective activity on metastatic cells during dissemination and particularly in the lungs. These data also stress the wide spectrum of daily doses and treatment schedules at which NAMI-A is active against metastases.     

Occupational exposure to polychlorinated biphenyls and cancer risk.

Polychlorinated biphenyls (PCBs) are a class of chemicals characterized by a long-term persistence and diffusion in the environment, and by bioaccumulation through the food chain. The highest exposures occurred in occupational cohorts through inhalation or skin absorption in work environments. These cohorts can therefore provide important information on health risk from exposure to PCBs in the general population. To provide comprehensive evidence on cancer risk from PCB exposure, we have thus reviewed the epidemiological studies on workers occupationally exposed to PCBs. Overall, no excess for all cancer mortality was observed in the six studies providing information (573 cancer deaths versus 630.4 expected, corresponding to a standardized mortality ratio (SMR) of 91). Among neoplasms potentially related to PCB exposure, there were 12 deaths from liver cancer compared with 9.5 expected (SMR=126). No excess was found for cancers of the breast (40 observed versus 47.4 expected, SMR=84) and of the lymphatic and haematopoietic system (51 observed versus 53.2 expected, SMR=96). Therefore, studies on occupational exposure to PCBs do not show any excess in all cancer mortality, or in mortality for specific cancer sites of interest.     

The recent decline in gallbladder cancer mortality in Europe.

Mortality from gallbladder cancer has been traditionally high in Eastern Europe, and lower in northern countries. Trends in 18 European countries, including the European Union (EU) and selected Eastern European countries, have been updated using official death certification data abstracted from the WHO database over the period 1980-1999. In the EU, age-standardized rates declined by about 30% between the late 1980s and 1999 to reach 1.8/100 000 for women, and by about 10% to reach 1.4/100 000 for men. In the Czech Republic and Hungary, rates for women were over 6/100 000 until the early 1990s, and declined by about 25% thereafter. For males, gallbladder cancer mortality showed no consistent trend, with rates over 3/100 000. Thus, a high mortality area from gallbladder cancer is still evident for both sexes in Central and Eastern Europe. The trends in mortality from gallbladder cancer are probably influenced by changes in risk factor exposure, such as diet, nutrition or tobacco, but essentially reflect more widespread and earlier adoption of cholecystectomy in the EU, since gallstones are the major risk factor for gallbladder cancer. The data also indicate the scope for further improvement of the management of gallbladder disease in Eastern Europe.     

Patient-controlled intranasal analgesia: effective alternative to intravenous PCA for postoperative pain relief

PURPOSE: To investigate whether the nasal route for fentanyl administration in patient-controlled analgesia (PCA) provides as effective postoperative analgesia as intravenous PCA. METHODS: Patient-controlled intranasal or intravenous analgesia with fentanyl was investigated in 48 patients (ASA I-III) on the day of surgery (orthopedic, abdominal or thyroid) in a prospective, randomized, double-blind, double-dummy study. Fentanyl was given in a bolus of 25 microg for intranasal and 17.5 microg for i.v. PCA, lockout interval six minutes. The first requested dose was doubled in both groups. Pain intensity (101-point numerical rating scale) and vital parameters were observed at 11 measurement points during the 240 min study. Patients were asked for side effects at every measurement point and for their satisfaction at the end of the study by the same investigator (J.M.). RESULTS: Onset of analgesia, the first reduction in pain intensity on the numerical rating scale, was 21 +/- 11 min (range 15-45 min) in intranasal and 22 +/- 16 min (range 15-90 min) in i.v. PCA. Pain intensity was reduced from 55 +/- 11 to 11 +/- 10 in the intranasal group and from 53 +/- 8 to 11 +/- 6 in the i.v. PCA group. Vital parameters remained stable and side effects were comparable in both groups. The judgement "excellent" or "good" was given by 21 of 23 patients treated intranasally and 24 of 25 patients treated intravenously. CONCLUSION: Intranasal PCA with fentanyl was an effective alternative to i.v. PCA in postoperative patients.     

Cigarette tar yield and risk of upper digestive tract cancers: case-control studies from Italy and Switzerland.

BACKGROUND: Tobacco smoking is one of the main risk factors for oral, pharyngeal and oesophageal cancers in developed countries. Information on the role of the tar yield of cigarettes in upper digestive tract carcinogenesis is sparse and needs to be updated because the tar yield of cigarettes has steadily decreased over the last few decades. PATIENTS AND METHODS: We analysed two case-control studies, from Italy and Switzerland, conducted between 1992 and 1999, involving 749 cases of oral and pharyngeal cancer and 1770 controls, and 395 cases of squamous-cell oesophageal carcinoma and 1066 matched controls. Odds ratios (ORs) were estimated by unconditional multiple logistic regression models, including terms for age, sex, study centre, education and alcohol consumption. RESULTS: Based on the brand of cigarettes smoked for the longest time, the multivariate ORs for current smokers compared with never smokers were 6.1 for <20 mg and 9.8 for >or=20 mg tar for oral and pharyngeal neoplasms, and 4.8 and 5.4 for oesophageal cancer, respectively. For the cigarette brand smoked in the previous six months, the ORs for >or=10 mg compared with <10 mg were 1.9 for cancer of the oral cavity and pharynx and 1.8 for oesophageal cancer, after allowance for number of cigarettes and duration of smoking. CONCLUSIONS: The present study confirms the direct relationship between the tar yield of cigarettes and upper digestive tract neoplasms, and provides innovative information on lower tar cigarettes, which imply reduced risks compared with higher tar ones. However, significant excess risks were observed even in the lower tar category, thus giving unequivocal indications for stopping smoking as a priority for prevention of upper digestive tract neoplasms.     

Insulin resistance is associated with decreased clinical status in cystic fibrosis

Patients with cystic fibrosis (CF) frequently have impaired glucose tolerance and progression to diabetes (DM) with clinical features of both insulin-dependent and non-insulin-dependent diabetes. One feature of non-insulin-dependent DM is decreased insulin sensitivity, also known as insulin resistance. The goal of this study was to determine whether patients with CF exhibit insulin resistance and to determine the potential effect of insulin resistance on clinical status. We also sought to determine whether insulin resistance is associated with a specific CF genotype. We studied 18 patients with CF (8 with normal glucose tolerance, 5 with impaired glucose tolerance, 5 with DM), and 20 lean control subjects matched for age, weight, and sex. All control subjects had normal glucose tolerance. The clinical status for each CF patient was determined according to a modified National Institutes of Health scoring system. Each subject underwent a three-step hyperinsulinemic euglycemic clamp (insulin doses of 10, 40, 120 mU/m ² per minute). Results from the 120 mU/m ² per minute infusion defined maximal glucose disposal rate (defined in milligrams per kilogram body weight per minute) at steady state with peripheral insulin levels 195 ± 20 mU/ml. Subjects with CF demonstrated insulin resistance (control subjects = 13.6 ± 1.1, patients with CF = 10.2 ± 1.6 mg/kg per minute; p = 0.003). When each subgroup was compared separately with control subjects, all subgroups were statistically insulin resistant (glucose disposal rate, patients with CF and normal glucose tolerance = 10.8; those with impaired glucose tolerance = 8.4; those with DM = 10.1 mg/kg per minute), and the patients with CF with impaired glucose tolerance were the most insulin resistant. When plotted versus glucose disposal rate, a striking positive correlation between worsened clinical status and insulin resistance ( r = 0.85) is demonstrated. Furthermore, there is no correlation between insulin resistance and fasting blood glucose, subject age, or percent ideal body weight (all r values not significant). In conclusion, patients with CF exhibit insulin resistance that is associated with worsened clinical status. We believe it is the combination of insulin resistance and decreased insulin secretion that is responsible for the high incidence of CF-related diabetes. (J Pediatr 1997;130:948-56)