PREDICT-GTN 1: Can we improve the FIGO scoring system in gestational trophoblastic neoplasia?

Gestational trophoblastic neoplasia (GTN) patients are treated according to the eight-variable International Federation of Gynaecology and Obstetrics (FIGO) scoring system, that aims to predict first-line single-agent chemotherapy resistance. FIGO is imperfect with one-third of low-risk patients developing disease resistance to first-line single-agent chemotherapy. We aimed to generate simplified models that improve upon FIGO. Logistic regression (LR) and multilayer perceptron (MLP) modelling (n = 4191) generated six models (M1-6). M1, all eight FIGO variables (scored data); M2, all eight FIGO variables (scored and raw data); M3, nonimaging variables (scored data); M4, nonimaging variables (scored and raw data); M5, imaging variables (scored data); and M6, pretreatment hCG (raw data) + imaging variables (scored data). Performance was compared to FIGO using true and false positive rates, positive and negative predictive values, diagnostic odds ratio, receiver operating characteristic (ROC) curves, Bland-Altman calibration plots, decision curve analysis and contingency tables. M1-6 were calibrated and outperformed FIGO on true positive rate and positive predictive value. Using LR and MLP, M1, M2 and M4 generated small improvements to the ROC curve and decision curve analysis. M3, M5 and M6 matched FIGO or performed less well. Compared to FIGO, most (excluding LR M4 and MLP M5) had significant discordance in patient classification (McNemar's test P < .05); 55-112 undertreated, 46-206 overtreated. Statistical modelling yielded only small gains over FIGO performance, arising through recategorisation of treatment-resistant patients, with a significant proportion of under/overtreatment as the available data have been used a priori to allocate primary chemotherapy. Streamlining FIGO should now be the focus.     

Correlation of functional parameters derived by equilibrium radionuclide angiocardiography and left ventricular size in patients with old myocardial infarction

A total of 131 patients with old (over 6 months) myocardial infarction (MI) and 18 normal subjects underwent equilibrium radionuclide angiocardiography at rest (rERNA). The following rERNA parameters were assessed: left ventricular ejection fraction (LVEF), peak ejection rate (PER), peak filling rate (PFR), regional wall motion and a left ventricular size index. The patients with old MI were divided into four groups (I to IV) according to increasing left ventricular (LV) size, and the behaviour of the numerical parameters (LVEF, PER, PFR) was evaluated in each group. LVEF proved to be the most sensitive numerical parameter of overall LV performance. PFR decreased significantly from group I to group III but not from group III to group IV, suggesting that for extreme degrees of left ventricular enlargement some compensatory mechanism acts to prevent a too large fall in LV compliance. The effects of the site of the previous MI on LV performance were also evaluated. Both LV size and performance were least affected by postero-inferior MI. The LVEF was, however, a better predictor of LV size than the site of the MI.     

Hypotheses on basis mechanisms arising from recent research

Clinical Rheumatology -     

Adverse reactions to Zn1-24 ACTH therapy associated with specific cellular immunity.

Lymphocyte transformation to 1-24ACTH, as assessed by the incorporation of tritiated thymidine, has been demonstrated to be associated with severe adverse reactions occurring in patients receiving a Zn-linked 1-24ACTH preparation (Tetra cosactrin depot, 'Synacthen'). Antibodies measured with an isotope-binding assay occurred commonly in all patients receiving therapy and did not correlate with adverse reactions. Lymphocyte transformation with the 1-24ACTH polypeptide, a part of the naturally occurring ACTH molecule, has not been previously recorded. The significance of antibodies and cell-mediated immunity to this polypeptide hormone is discussed.     

The omptin family of enterobacterial surface proteases/adhesins: from housekeeping in Escherichia coli to systemic spread of Yersinia pestis

The omptins are a family of enterobacterial surface proteases/adhesins that share high sequence identity and a conserved beta-barrel fold in the outer membrane. The omptins are multifunctional, and the individual omptins exhibit differing virulence-associated functions. The Pla plasminogen activator of Yersinia pestis contributes by several mechanisms to bacterial invasiveness and the systemic, uncontrolled proteolysis in plague. Pla proteolytically activates the human proenzyme plasminogen and inactivates the antiprotease alpha2-antiplasmin, and its binding to laminin localizes the uncontrolled plasmin activity onto basement membranes. These properties enhance bacterial migration through tissue barriers. Pla also degrades circulating complement proteins and functions in bacterial invasion into human epithelial cells. PgtE of Salmonella enterica and OmpT of Escherichia coli have been shown to degrade cationic antimicrobial peptides from epithelial cells or macrophages. PgtE and SopA of Shigella flexneri appear important in the intracellular phases of salmonellosis and shigellosis, whereas functions of OmpT have mainly been associated with protein degradation in E. coli cells. The differing virulence roles and functions have been attributed to minor sequence variations at the surface-exposed regions important for substrate recognition, to the dependence of omptin functions on lipopolysaccharide, and to the different regulation of omptin expression.     

Analysis of a positive feedback mechanism in the anti-Sm autoantibody response of MRL/MPJ-lpr/lpr mice

The mechanism of induction of anti-Sm antibodies by passive transfer of anti-Sm mAb in MRL/lpr mice was investigated. No idiotypic relationship was detected between the inducing monoclonal antibody KSm2 and either the induced circulating anti-Sm antibodies or the products of anti-Sm-producing hybridomas derived from spleen cell fusion of treated mice. Treatment of mice with ribonucleoprotein Sm antigen, alone or as an immune complex, induced anti-Sm and anti-ribonucleoprotein antibodies similarly to treatment with KSm2. This suggests that autoantigen contributes to the development of the anti-Sm response in MRL mice.     

Identification of Two Laminin-Binding Fimbriae, the Type 1 Fimbria of Salmonella enterica Serovar Typhimurium and the G Fimbria of Escherichia coli, as Plasminogen Receptors

Escherichia coli strains carrying recombinant plasmids encoding either the type 1 fimbria of Salmonella enterica serovar Typhimurium or the G fimbria of E. coli exhibited binding of human ¹²⁵I-Glu-plasminogen and enhanced the tissue-type plasminogen activator-catalyzed conversion of plasminogen to plasmin. Purified type 1 or G fimbriae similarly bound plasminogen and enhanced its activation. The binding of plasminogen did not involve the characteristic carbohydrate-binding property of the fimbriae but was inhibited at low concentrations by the lysine analog -aminocaproic acid. Because these fimbrial types bind to laminin of basement membranes (M. Kukkonen et al., Mol. Microbiol. 7:229–237, 1993; S. Saarela et al., Infect. Immun. 64:2857–2860, 1996), the results demonstrate a structural unity in the creation and targeting of bacterium-bound proteolytic plasmin activity to basement membranes.     

Spontaneous recovery of the decreased expression in vitro of interleukin 2 receptors in rheumatoid arthritis.

Peripheral blood mononuclear cells (PBM) from 11 patients with rheumatoid arthritis (RA) stimulated with 0.13 and 0.25 microgram/ml phytohaemagglutinin (PHA) for 3 days showed a depressed expression of interleukin 2 receptor (IL-2R) when compared with 14 normal controls (P less than 0.01). At these two doses of PHA a depressed lymphocyte proliferative response was also observed (P less than 0.01). However the kinetics of the response of the RA group differed from those of the control group. Whereas by day 6 IL-2R expression and lymphocyte proliferation in the control group was decreased compared with day 3, responses of the RA cells were increased. Following stimulation with the higher dose of PHA (1 microgram/ml) the kinetics of lymphocyte proliferation and IL-2R expression were equivalent in control and RA cultures. These results demonstrate that the impaired IL-2R expression and lymphocyte proliferation observed with sub-optimally stimulated PBM from RA patients is spontaneously reversed during prolonged culture and is consistent with the hypothesis that there is a lack of available IL-2 in the early stages of culture.