Short-term administration of the glucagon receptor antagonist LY2409021 lowers blood glucose in healthy people and in those with type 2 diabetes.

AIM: To describe the clinical effects of single and multiple doses of a potent, selective, orally administered, small-molecule antagonist of the human glucagon receptor, LY2409021, in healthy subjects and in patients with type 2 diabetes. METHODS: LY2409021 was administered in dose-escalation studies to healthy subjects (n = 23) and patients with type 2 diabetes (n = 9) as single doses (Study 1) and daily to patients with type 2 diabetes (n = 47) for 28 days (Study 2). Safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) assessments were made after single doses and in patients receiving once-daily doses of LY2409021 (5, 30, 60 or 90 mg) for 28 days. RESULTS: LY2409021 was well tolerated at all dose levels in both studies. Fasting and postprandial glucose were reduced and glucagon levels increased after single and multiple dosing, with reductions in fasting serum glucose of up to ∼1.25 mmol/l on day 28. Serum aminotransferases increased in a dose-dependent manner with multiple dosing and reversed after cessation of dosing. Significant glucose-lowering was observed with LY2409021 at dose levels associated with only minor aminotransferase increases. CONCLUSION: Blockade of glucagon signalling in patients with type 2 diabetes is well tolerated and results in substantial reduction of fasting and postprandial glucose with minimal hypoglycaemia, but with reversible increases in aminotransferases. Inhibition of glucagon signalling by LY2409021 is a promising potential treatment for patients with type 2 diabetes and should be evaluated in longer clinical trials to better evaluate benefits and risks.

Nuclear morphometry in columnar cell lesions of the breast: is it useful?

AIMS: To evaluate the nuclear morphometric features of breast columnar cell lesions (CCLs) observed on mammotome core biopsies, to determine if there are significant measurable differences between those with atypia and those without. Correlation with follow-up open excision specimens was made. METHODS: Mammotome core biopsies performed on patients that contained CCLs were derived from the departmental case files. Histological material was reviewed and foci of CCLs demarcated for nuclear morphometric assessment, which was accomplished using an imaging system. Nuclear parameters studied were nuclear area and perimeter, circularity factor and feret's diameter. Statistical analysis used the GraphPad Prism software, with p<0.05 indicating significance. RESULTS: On examination of core biopsies of 40 patients with CCLs, 8 lesions were benign, 4 showed atypical lobular hyperplasia, 8 showed CCLs with nuclear atypia, 19 disclosed atypical ductal hyperplasia (ADH) and 1 showed ductal carcinoma in situ (DCIS). The nuclear area, perimeter and feret's diameter of CCLs with atypia were significantly greater than those without (p = 0.04, 0.03 and 0.019, respectively), whereas no difference was observed in the circularity factor. Follow-up open excision biopsy specimens in 24 patients showed upgrading to DCIS in 40% of cases diagnosed initially with ADH on core biopsy compared with 20% of CCLs with atypia. CONCLUSIONS: Nuclear morphometry in CCLs confirms nuclear size as the key parameter in the assessment of nuclear atypia. Whether it can be potentially used as an adjunctive tool depends on the establishment of appropriate cut-offs.

Oxygen consumption and resting energy expenditure during phototherapy in full term and preterm newborn infants.

OBJECTIVES: To determine the effect of phototherapy on the oxygen consumption and resting energy expenditure of term and preterm newborn infants. METHODS: A total of 202 infants (gestation 30-42 weeks; body weight 1270-4100 g) requiring phototherapy for the treatment of neonatal hyperbilirubinaemia were enrolled in a randomised crossover study. In random sequence, the oxygen consumption and resting energy expenditure were measured twice in each infant by indirect calorimetry, once at the end of six hours of continuous phototherapy and once after a control period of at least six hours without phototherapy. Anterior abdominal wall temperature was servocontrolled at 36.5 degrees C throughout the study. RESULTS: At the end of six hours of continuous phototherapy, oxygen consumption (mean (SD): 6.21 (1.35) v 6.26 (1.51) ml/kg, p = 0.555) and resting energy expenditure (178.11 (37.62) v 180.37 (43.14) kJ/kg/24 h, p = 0.382) did not differ significantly from those measured after the control period. There were also no significant differences in heart rate, respiratory rate, or rectal temperature. Subgroup analysis of those of gestation < 37 weeks or < 34 weeks also showed no effect of phototherapy on either oxygen consumption or resting energy expenditure. CONCLUSION: Phototherapy has no effect on the metabolic rate of thermally stable term or preterm infants.

Isolation and sequence of cDNA clones encoding rat phosphatidylinositol transfer protein.

Phosphatidylinositol (PtdIns) transfer protein is a cytosolic protein that catalyzes the transfer of PtdIns between membranes. It is expressed in organisms from yeast to man, and activity has been found in all animal tissues examined. Using antibodies prepared against bovine brain PtdIns transfer protein, lambda gt11 rat brain cDNA libraries were screened and several clones isolated. DNA sequence analysis showed that the cDNAs encoded a polypeptide of 271 amino acids with a mass of 31,911 Da. Comparison of the deduced amino acid sequence with N-terminal sequence data obtained for the intact purified bovine brain protein and rat lung phospholipid transfer protein verified that the cDNAs were PtdIns transfer protein clones. The predicted protein shows no significant sequence similarity to other known (phospholipid)-binding proteins. DNA blot hybridization suggests that the rat genome may contain more than one gene encoding PtdIns transfer protein. RNA blot hybridization reveals that the PtdIns transfer protein gene is expressed at low levels in a wide variety of rat tissues; all tissues examined showed a major mRNA component of 1.9 kilobases and a minor component of 3.4 kilobases. The isolation of clones encoding rat PtdIns transfer protein will greatly facilitate studies of the structure and function of PtdIns transfer proteins and their role in lipid metabolism.

Hepatocellular carcinoma: importance of histologic classification as a prognostic factor.

The characteristics and clinical courses of 15 patients with fibrolamellar carcinoma have been compared to 62 patients with hepatocellular carcinoma treated over the same time period. Marked differences were found in patient, tumor, and treatment characteristics. Survival rates in these two groups of patients have been compared by univariate analysis of the subsets of those patient, tumor, and treatment characteristics. The longer survival of the group of patients with fibrolamellar carcinoma could not be accounted for by the prevalence or absence of any of these characteristics. Comparison of subsets of patients with documented noncirrhotic livers or those having complete resection of their tumors revealed a significantly prolonged survival in patients with the fibrolamellar variant. The 5 year survival rate of the patients with fibrolamellar carcinoma who had complete tumor resection was 45 percent, with a median survival time of 50 months. The 5 year survival of patients with hepatocellular carcinoma who had complete tumor resection was 0 percent, with a median survival time of 22 months.

Surgery as an alternative to chemotherapy for hepatic metastases from colorectal cancer.

The mean survival for patients with untreated hepatic metastases from primary colorectal carcinoma has been reported to range from 4 to 9 months. The authors describe seven patients with liver metastases following curative resection. They had partial hepatectomy as treatment for metastatic disease confined to the liver. Survival from the time of partial hepatectomy to April 1983 for the five patients who died with progressive disease was 20, 32, 39, 40 and 44 months and was 45 and 61 months for the two patients still alive and disease-free. All seven patients treated surgically survived longer than they would have if they had received treatment for symptoms, with or without chemotherapy for hepatic metastases. The increased duration of survival suggests that partial hepatectomy, in appropriately selected patients, is a worthwhile alternative to chemotherapy.

Gastrointestinal complications in patients with acute and chronic leukemia.

Between July 1, 1972 and June 30, 1977, 541 leukemic patients were admitted to the University Hospital in Edmonton. Eight of 11 patients who underwent emergency operation for complications of leukemia or antileukemic therapy died within 30 days of operation. Six cases are reviewed to illustrate the four basic types of gastrointestinal lesions and complications of leukemia: hemorrhagic and agranulocytic necrosis, leukemic infiltrates and fungal lesions. A fifth type which is a mixture of the four basic types was also noted. As a result of their experience and a review of the literature the authors believe that an aggressive approach, consisting of close monitoring and early laparotomy combined with vigorous supportive therapy, should be used when dealing with suspected gastrointestinal complications in leukemic patients.

Value of serial CEA determinations in a surgical adjuvant trial of colorectal and gastric carcinoma.

At the Cross Cancer Institute in Edmonton, a concurrently controlled, randomized, prospective surgical adjuvant trial involving Dukes' B2 and C colorectal carcinoma and gastric carcinoma (T1-4, No-2, Mo) has been activated for the last two years. To date, a total of 150 patients have been entered into the three arms of the trial (namely control, immunotherapy, and chemoimmunotherapy). Of these, 127 cases are colorectal carcinoma and 28 are gastric cancer. As part of the protocol, serial CEA determinations are obtained in all patients on a regular three-monthly basis. So far, 28 patients have confirmed recurrence (colorectal 20, gastric 8) demonstrated clinically or radiologically. Out of these 28 patients, 25 (89.2%) had CEA greater than 2.5 ng/ml months before actual demonstration of recurrence. However, if one uses a cutoff of 5.0 ng/ml as significant, that is, one standard deviation from the usual accepted value, then 21 out of 28 (75%) had persistent, elevated CEA's months before the recurrence manifested itself clinically or radiologically. The CEA profiles of three representative cases from each arm of the adjuvant trial are included. It is suggested that serial CEA determinations will be an invaluable adjunctive test in following patients in an adjuvant trial setting.