Value of CT in the preoperative assessment of lung cancer: a survey of thoracic surgeons

Practicing thoracic surgeons were randomly surveyed to evaluate how computed tomography (CT) has influenced the preoperative evaluation of bronchogenic carcinoma. Thirty-six percent of the 529 respondents routinely requested CT and 62% did so selectively. Approximately 40% indicated that CT provided useful information in most cases. Nearly all surgeons (98.7%) do not rely on the identification of enlarged lymph nodes with CT to spare the patient surgical staging; however, 77.5% are influenced by CT results in their staging procedures. Fifty-seven percent reported that a negative CT study eliminates surgical staging entirely unless the patient has a "coin lesion," in which case 75% are willing to proceed directly to thoracotomy. For surgeons who use CT selectively, an abnormal mediastinal contour on the radiograph was the most frequent radiologic abnormality to prompt CT (85%). Thirty-seven percent are influenced by tumor histology in their decision to request CT. There was little difference in the pattern of CT use between university and community hospital surgeons.     

The factor VIII complex: structure and function

Normal human plasma contains a complex of two proteins that are important in hemostasis and coagulation. The factor VIII procoagulant protein (antihemophilic factor) and the factor VIII-related protein (von Willebrand factor) are under separate genetic control, have distinct biochemical and immunologic properties, and have unique and essential physiologic functions. While the nature of their interaction and the details of the biochemical structures remain to be determined, the information now available permits a preliminary understanding of the molecular defects in hemophilia and von Willebrand's diseases.     

Evidence for a multipotential stem cell disease in some childhood Philadelphia chromosome-positive acute lymphoblastic leukemia

Children with Philadelphia chromosome (Ph+) acute lymphoblastic leukemia (ALL) have a poorer prognosis than do most pediatric patients with ALL. Because of this poor prognosis and the presence of the Ph chromosome, we have asked whether or not Ph + ALL involves a multipotential stem cell. We cultured hematopoietic progenitors from two children with Ph+ ALL and examined individual BFU-E and CFU-GM colonies for the Ph chromosome. We studied cells from two patients after 18 to 34 months of first complete clinical remission; direct cytogenetic analyses showed 26% and 13% Ph+ metaphases in these patients' marrow cells. BFU-E colonies were obtained from light density marrow cells cultured in methylcellulose supplemented with erythropoietin and CFU-GM colonies from agar or methylcellulose cultures stimulated with leukocyte feeder layers. Fifty-seven G-banded metaphases were recovered from 33 colonies. Ten metaphases from seven colonies were Ph+. Ph+ metaphases were found in three of 12 and three of five BFU-E colonies from the two patients. One of 16 CFU-GM colonies from one patient had the Ph+ chromosome; analyzable metaphases were not obtained from CFU-GM of the other patient. No colonies contained both Ph+ and Ph- cells. These results indicate that Ph+ ALL with persistence of Ph+ cells in remission involves a multipotential stem cell for erythroid and granulocyte/macrophage as well as lymphoid lineages. Multipotential stem cell involvement in the pathogenesis of some childhood Ph+ ALL suggests similarities to Ph+ chronic myelocytic leukemia and may contribute to the poor prognosis of these patients.     

Comparative biochemical and cytogenetic studies of childhood acute lymphoblastic leukemia with the Philadelphia chromosome and other 22q 11 variants

We studied the relationship of direct karyotypes, determined at diagnosis and remission, to Abelson-related tyrosine kinase activity and the cytogenetic features of erythroid and myeloid colonies derived from remission marrow of six children with acute lymphoblastic leukemia (ALL). These patients had either the characteristic Philadelphia chromosome (Ph1) [t(9;22)(q34;q11)] or cytogenetically similar variants with a 22q11 breakpoint but no detectable cytogenetic involvement of 9q34. The findings suggested two distinct subtypes of ALL: one defined by t(9;22)(q34;q11) and expression of P185BCR-ABL tyrosine kinase and one with variant karyotypes and no P185BCR-ABL expression. The former comprises cases with Ph1 + marrow cells and Ph1 + erythroid and (or) myeloid colonies in remission marrow and others in which the t(9;22) is undetectable in remission marrow cells. In the latter subgroup, the disease may reflect more extreme mosaicism with a similar stem cell that is cytogenetically undetectable. Variant karyotypes included a del(22)(q11) in one patient and a t(6;22;15;9) (q21;q11;q?22;q21) in another; in both instances, the malignant blast cells lacked P185BCR- ABL expression. Thus ALL with t(9;22)(q34;q11) should be distinguished from ALL with other involvement of the 22q11 breakpoint by molecular studies including protein expression. The diversity of karyotypic findings in cases with involvement of 22q11 suggests at least two mechanisms of leukemogenesis in patients with ALL defined by this breakpoint.     

Some factor VIII inhibitor antibodies recognize a common epitope corresponding to C2 domain amino acids 2248 through 2312, which overlap a phospholipid-binding site

The finding that human factor VIII (fVIII) inhibitor antibodies with C2 domain epitopes interfere with the binding of fVIII to phosphatidylserine (PS) suggested that this is the mechanism by which they inactivate fVIII. We constructed a recombinant C2 domain polypeptide and demonstrated that it bound to all six human inhibitors with fVIII light chain specificity. Thus, some antibodies within the polyclonal anti-light chain population require only amino acids within C2 for binding. Recombinant C2 also partially or completely neutralized the inhibitor titer of these plasmas, demonstrating that anti-C2 antibodies inhibit fVIII activity. Immunoblotting of a series of C2 deletion polypeptides, expressed in Escherichia coli, with inhibitor plasmas showed that the epitopes for human inhibitors consist of a common core of amino acid residues 2248 through 2312 with differing extensions for individual inhibitors. The epitope of inhibitory monoclonal antibody (MoAb) ESH8 was localized to residues 2248 through 2285. Three human antibodies and anti-C2 MoAb NMC-VIII/5 bound to a synthetic peptide consisting of amino acids 2303 through 2332, a PS- binding site, but MoAb ESH8 did not. These antibodies also inhibited the binding of fVIII to synthetic phospholipid membranes of PS and phosphatidylcholine, confirming that the blocked epitopes contribute to membrane binding as well as binding to PS. In contrast, MoAb ESH8 did not inhibit binding. As the maximal function of activated fVIII in the intrinsic factor Xase complex requires its binding to a phospholipid membrane, we propose that fVIII inhibition by anti-C2 antibodies is related to the overlap of their epitopes with the PS-binding site. MoAb ESH8 did not inhibit fVIII binding to PS-containing membranes, suggesting the existence of a second mechanism of fVIII inhibition by anti-C2 antibodies.     

Tumor-specific, cytotoxic T-lymphocyte response after idiotype vaccination for B-cell, non-Hodgkin's lymphoma

Patients with non-Hodgkin's B-cell lymphoma who received an antitumor vaccine of idiotypic ig protein showed humoral and proliferative immune responses. Because immunity to some antigens, including tumor antigens and human pathogenic viruses, may be better correlated with the cytolytic cellular immune response, we evaluated 16 non-Hodgkin's lymphoma patients immunized with autologous idiotypic ig molecules for changes in tumor-specific cytotoxic T-lymphocyte precursor (CTLp) frequency using limiting dilution analysis. Eleven patients had a significant increase in tumor-specific CTLp. Eight of these 11 patients remain without evidence of disease or with stable minimal disease. In contrast, all five patients who did not have a significant change in tumor-specific CTLp have developed progressive disease. Patient vaccination with tumor associated protein antigens can increase tumor- specific CTLp frequencies. The correlation of increased tumor specific CTLp with freedom from progression is significant at P = .002. This study indicates that measurement of CTLp frequencies are relevant to the clinical evaluation of human tumor vaccines and suggests that cell- mediated cytolytic immune responses may be an important determinant of vaccine efficacy.     

In vivo magnetic resonance spectroscopy of gynaecological tumours at 3.0 Tesla

Background  Magnetic resonance spectroscopy (MRS) uses the same hardware as MR imaging and allows us to analyse the biochemistry of tissues in vivo . Published data for gynaecological lesions are limited and are largely based on MRS carried out at the lower magnetic field strength of 1.5 Tesla (T).
Objective  The purpose of this study was to determine whether in vivo proton MRS could be performed at the higher magnetic field strength of 3 T to characterise the spectra of a variety of benign and malignant gynaecological lesions.
Design  Prospective, non-randomised study.
Setting  MRI department within a tertiary referral centre for gynaecological cancers.
Sample  All women with a pelvic mass under going 3T MRI.
Methods  We carried out MRS on nonrandomised women undergoing routine 3 T MRI within our MRI department during investigation for gynaecological lesions from February 2006 to April 2008. Only those women for whom histopathological data were available were included.
Main outcome measures  The presence of choline detected by in vivo 3T MRS.
Results  Eighty-seven women underwent MRS, 57 of whom had newly diagnosed neoplasms. MRS data for 39 of these new women (18 were excluded because of technical errors or missing data) were used to detect the presence of choline, an indicator of basement membrane turnover. Overall, choline was present in 13 of the 14 ovarian cancers, 8 of the 11 cervical tumours and all 4 of the uterine cancers. There was no statistical significant difference between choline levels in various lesion types ( P = 0.735) or between benign and malignant disease ( P = 0.550).
Conclusions  In vivo MRS can be performed at 3 T to provide biochemical information on pelvic lesions. The way in which this information can be utilised is less clear but may be incorporated into monitoring tissue response in cancer treatments.     

Bronchopulmonary dysplasia and very low birthweight: Lung function at 11 years of age

Objective : To determine the relationship between lung function at 11 years of age and bronchopulmonary dysplasia (BPD) in very low birthweight (VLBW) children.
Methodology : This study comprised 154 consecutive surviving VLBW children, divided into three groups with respect to their neonatal respiratory morbidity: group I developed BPD; group II required assisted ventilation but did not develop BPD; and group III required no assisted ventilation. Lung function tests were measured on 120/154 (77.9%) children at 11 years of age. The relationship between various lung function variables and neonatal lung disease was analysed by multiple linear regression.
Results : Several lung function variables reflecting airflow were significantly diminished in the BPD group ( n = 15), and residual volume was significantly higher. Despite poorer lung function overall, few children in the BPD group had lung function abnormalities in the clinically significant range ( n = 2 [13.3%] with a forced expired volume in 1 s <75% predicted; n = 2 [13.3%] with a forced vital capacity <75% predicted; n = 1 [6.7%] with a residual volume/total lung capacity >35%). There were no significant differences in lung function variables between group II ( n = 41) and group III ( n = 64). Changes in lung function tests between 8 and 11 years did not vary significantly between the three groups.
Conclusions : VLBW children with BPD in the newborn period have poorer lung function at 11 years of age than other surviving VLBW children without BPD, although few have lung function abnormalities in the clinically significant range.     

Genotypes of glutathione transferase M1 and P1 and their significance for lung DNA adduct levels and cancer risk

The A-G polymorphism at codon 104 in the glutathione S-transferase P1 (GSTP1) gene was examined in 138 male lung cancer patients and 297 healthy controls. The patients had significantly higher frequency of the GG genotype (15.9%) and a lower frequency of AA (38.4%) than the controls (9.1% and 51.5%, respectively). The level of hydrophobic DNA- adducts were determined in lung tissue from 70 current smokers. Patients with the GG genotype had a significantly higher adduct level than patients with AA (15.5 +/- 10.2 vs 7.9 +/- 5.1 per 10(8) nucleotides, P = 0.006). We also analyzed the deletion polymorphism in the GSTM1 gene in 135 male patients and 342 controls. The patients were stratified according to histology, smoking dose, age, adduct level and mutational types found in the tumors (Ki-ras and p53 genes). The results consistently indicated that the GSTM1 null genotype was associated with a slightly increased lung cancer risk. When the combined GST M1 and P1 genotypes were examined, patients with the combination null and AG or GG had significantly higher adduct levels than all other genotype combinations (P = 0.011). The distribution of combined genotypes was also significantly different in cases and controls, mainly due to increased frequency of the combination GSTM1 null and GSTP1 AG or GG among patients.