Surgical resection versus watchful waiting in low-grade gliomas.

BACKGROUND: Infiltrating low-grade gliomas (LGG; WHO grade 2) typically present with seizures in young adults. LGGs grow continuously and usually transform to higher grade of malignancy, eventually causing progressive disability and premature death. The effect of up-front surgery has been controversial and the impact of molecular biology on the effect of surgery is unknown. We now present long-term results of upfront surgical resection compared with watchful waiting in light of recently established molecular markers. MATERIALS AND METHODS: Population-based parallel cohorts were followed from two Norwegian university hospitals with different surgical treatment strategies and defined geographical catchment regions. In region A watchful waiting was favored while early resection was favored in region B. Thus, the treatment strategy in individual patients depended on their residential address. The inclusion criteria were histopathological diagnosis of supratentorial LGG from 1998 through 2009 in patients 18 years or older. Follow-up ended 1 January 2016. Making regional comparisons, the primary end-point was overall survival. RESULTS: A total of 153 patients (66 from region A, 87 from region B) were included. Early resection was carried out in 19 (29%) patients in region A compared with 75 (86%) patients in region B. Overall survival was 5.8 years (95% CI 4.5-7.2) in region A compared with 14.4 years (95% CI 10.4-18.5) in region B (P < 0.01). The effect of surgical strategy remained after adjustment for molecular markers (P = 0.001). CONCLUSION: In parallel population-based cohorts of LGGs, early surgical resection resulted in a clinical relevant survival benefit. The effect on survival persisted after adjustment for molecular markers.

Prognostic markers for detection of coexistent carcinoma in high-risk endometrial hyperplasia.

OBJECTIVES: Reliable predictive uterus-sparing methods are crucial for treatment decisions among women who wish to preserve fertility and for seriously ill patients for whom surgery is hazardous. Thus, prediction of myoinvasive carcinoma by objective histomorphometry (4C-rule) and subjective diagnosis (endometrial intraepithelial neoplasia, EIN) were investigated in high-risk endometrial biopsies. PATIENTS AND METHODS: A total of 45 patients retrospectively diagnosed with high-risk hyperplasia, of whom ten were found to have concurrent carcinoma, were investigated. The histomorphometric 4C-rule and the EIN classification system were used for outcome prediction. RESULTS: Myoinvasive disease was predicted with a sensitivity of 87% and a specificity of 79% by using 4C-rule assessment. The sensitivity and specificity of the EIN classification to predict coexistent carcinoma or not was 50% and 97%, respectively. CONCLUSION: Six out of the seven reported cases with myoinvasion were correctly diagnosed with the 4C-rule assessment. In contrast, only three out of the seven myoinvasive cases were diagnosed as cancer using the EIN approach.

Success of L-lysine therapy in frequently recurrent herpes simplex infection. Treatment and prophylaxis.

A double-blind, placebo-controlled, multicenter trial of oral L-lysine monohydrochloride for the prevention and treatment of recurrent herpes simplex (HSV) infection was conducted. The treatment group was given L-Lysine monohydrochloride tablets (1,000 mg L-lysine per dose) 3 times a day for 6 months. A total of 27 (6 male and 21 female) subjects on L-lysine and 25 (6 male and 19 female) subjects on placebo completed the trial. The L-lysine treatment group had an average of 2.4 (p less than 0.05) less HSV infections, symptoms were significantly (p less than 0.05) diminished in severity and healing time was significantly reduced (p less than 0.05). L-Lysine appears to be an effective agent for reduction of occurrence, severity and healing time for recurrent HSV infection.

Isolation and characterization of single chain bovine factor V.

A procedure for the isolation of bovine Factor V has been developed. The Factor V is isolated from bovine plasma by a series of steps including barium citrate adsorption, polyethylene glycol precipitation, QAE-cellulose adsorption, hydrophobic chromatography on octyl Sepharose, ammonium sulfate fractionation, preparative electrophoresis on acrylamide gels, and finally, phenyl Sepharose chromatography. During isolation, judicious use of inhibitors including benzamidine hydrochloride, soybean trypsin inhibitor, and diisopropylphosphorofluoridate has been applied to prevent activation of the Factor V TO Factor Va. The activity of the isolated protein increases by a factor of 80 when stimulated by catalytic amounts of thrombin. The specific activity of the material after thrombin activation is 1250 units/mg of protein when evaluated versus a bovine Factor V standard in human factor V-deficient plasma. The isolated protein is a single component when analyzed by a variety of electrophoretic techniques and has been characterized in terms of its gross physical and chemical properties. Bovine Factor V is a single chain glycoprotein which has a molecular weight of 330,000. The single chain nature of the molecule has been established by sedimentation equilibrium studies of the native molecule and on the molecule in 6 M guanidinium chloride with and without disulfide bond reduction. In addition to these mass measurements, the single chain nature of the molecule has been established by hydrodynamic estimation of the random coil volume by sedimentation velocity studies of the reduced carboxyamidomethylated protein in 6 M guanidinium chloride. Native Factor V has a sedimentation coefficient so20,w of 9.19 S, which indicates the molecule is highly asymmetric. The frictional ratio f/fmin for the molecule is estimated to be 2.01, and the axial ratio of the equivalent prolate ellipsoid is 25:1. Thus, present data suggest that Factor V is a rod-like molecule composed of a single chain.

Characteristics of the association between prothrombin fragment 2 and alpha-thrombin.

The esterolytic activity of bovine alpha-thrombin on the synthetic substrate N-alpha-p-tosyl-L-arninine methyl ester (TosArgOMe) is stimulated when the prothrombin activation fragment, prothrombin fragment 2, is added as previously reported by this laboratory (Heldebrant, C. M., and Mann, K. G. (1973), J. Biol. Chem. 248, 3642). A similar stimulation of beta-thrombin is observed upon addition of prothrombin fragment 2. The binding constant of prothrombin fragment 2 to alpha-thrombin has been determined by the method of Gutfreund ((1972), Enzymes, Physical Principles, Wiley, New York, N.Y., pp 67-71). The dissociation constant is 7.7 X 10(-10)M, and there is one molecule of prothrombin fragment 2 bound per molecule of alpha-thrombin. Prethrombin-2 competes for prothrombin fragment 2, so the enhancement of the esterolytic activity of alpha-thrombin by prothrombin fragment 2 was used as a probe to determine the dissociation constant for the binding of prothrombin fragment 2 to prethrombin 2. The dissociation constant for this association is 1.3 X 10(-10)M. The kinetic parameters for the reaction of alpha-thrombin on TosArgOMe were determined in the absence and presence of prothrombin fragment 2 and are as follows: (a) in the absence of prothrombin fragment 2, Km(app) = 1.92 X 10(-4)M, and k3(app) = 35.8 mol of TosArgOMe/mol of alpha-thrombin s(-1); (b) in the presence of prothrombin fragment 2,Km(app = 1.76 X 10(-4)M, and k3(app) = 60.5 mol of TosArgOMe/mol of alpha-thrombin s(-1). Thus, the stimulatory effect of bovine prothrombin fragment 2 on bovine alpha-thrombin is reflected in k3(app) and not in Km(app). In contrast to the stimulatory effect of prothrombin fragment 2 on the thrombin-catalyzed hydrolysis of TosArgOMe, it inhibits the activity of alpha-thrombin toward N-alpha-benzoyl-L-arginine ethyl ester and N-alpha-benzoyl-L-arginine p-nitroanilide. The inhibition of activity toward these substrates by prothrombin fragment 2 is also reflected in k3(app). Activity toward the nonspecific substrate p-nitrophenyl butyrate was completely inhibited by the addition of prothrombin fragment 2. Prothrombin fragment 2 has no effect on the inhibition of alpha-thrombin activity by the active-site serine inhibitors diisopropyl phosphofluoridate, phenylmethanesulfonyl fluoride, or p-nitrophenyl guanidinobenzoate. Inhibition by the active-site-histidine-modifying inhibitor, N-alpha-p-tosyl-L-arginine chloromethyl ketone, was enhanced by the addition of prothrombin fragment 2. Soybean trypsin inhibitor reduces the stimulation by prothrombin fragment 2, but only at high molar ratios. Prothrombin fragment 2 has no effect on the clotting activity of alpha-thrombin, nor inhibition of this activity by heparin, hirudin, or diisopropyl phosphafluoridate. Bovine prothrombin fragment 2 enhances the esterolytic activity of both human and bovine alpha-thrombin, but human prothrombin fragment 2 does not enhance the esterolytic activity of either human or bovine alpha-thrombin.