Film reading in the East Midlands Breast Screening Programme -- are we missing opportunities for earlier diagnosis?

AIM: To assess whether there are any significant differences in the film-reading histories of interval or screen-detected cancers, and whether this affects stage at diagnosis. MATERIALS AND METHODS: The rates of screen-detected and interval cancers (overall and by radiological categorization) were observed from 268,067 women screened in the East Midlands Breast Screening Programme over 2004-2007 to assess whether there were differences in incidence based on previous film-reading history. Cancers detected at the subsequent screen and film-reading history were analysed to assess whether this affected stage at diagnosis. Analysis undertaken involved cancer detection rates, confidence intervals, and chi-square tests with Monte Carlo simulation. RESULTS: Rates of interval cancers were similar in all groups where at least one reader had indicated recall to assessment (6.1-7.7/1000) and were significantly higher in comparison to women whose previous film-reading outcome was unanimous routine rescreen (2.9/1000; p < 0.001). Four point one percent of interval cancers with no previous recall outcomes were false negatives, which was significantly lower compared to the groups where at least one reader had indicated recall (10.9%; p = 0.005). Cancers detected at the subsequent screen demonstrated no significant difference in prognosis dependent on previous film-reading history (p = 0.503). CONCLUSION: The prognosis of screen-detected cancers was similar and few cancers were false negatives regardless of film-reading history at the previous screen.

Growth hormone in the nervous system: autocrine or paracrine roles in retinal function?

Growth hormone (GH) is primarily produced in the pituitary gland, although GH gene expression also occurs in the central and autonomic nervous systems. GH-immunoreactive proteins are abundant in the brain, spinal cord, and peripheral nerves. The appearance of GH in these tissues occurs prior to the ontogenic differentiation of the pituitary gland and prior to the presence of GH in systemic circulation. Neural GH is also present in neonates, juveniles, and adults and is independent of changes in pituitary GH secretion. Neural GH is therefore likely to have local roles in neural development or neural function, especially as GH receptors (GHRs) are widespread in the nervous system. In recent studies, GH mRNA and GH immunoreactive proteins have been identified in the neural retina of embryonic chicks. GH immunoreactivity is present in the optic cup of chick embryos at embryonic day (ED) 3 of the 21-d incubation period. It is widespread in the neural retina by ED 7 but also present in the nonpigmented retina, choroid, sclera, and cornea. This immunoreactivity is associated with proteins in the neural retina comparable in size with those in the adult pituitary gland, although it is primarily associated with 15-16 kDa moieties rather than with the full-length molecule of approximately 22 kDa. These small GH moieties may reflect proteolytic fragments of "monomer" GH and (or) the presence of different GH gene transcripts, since full-length and truncated GH cDNAs are present in retinal tissue extracts. The GH immunoreactivity in the retina persists throughout embryonic development but is not present in juvenile birds (after 6 weeks of age). This immunoreactivity is also associated with the presence of GH receptor (GHR) immunoreactivity and GHR mRNA in ocular tissues of chick embryos. The retina is thus an extrapituitary site of GH gene expression during early development and is probably an autocrine or paracrine site of GH action. The marked ontogenic pattern of GH immunoreactivity in the retina suggests hitherto unsuspected roles for GH in neurogenesis or ocular development.

Extrapituitary GH in the chicken: underestimation of immunohistochemical staining by Carnoy's fixation.

GH has previously been shown to be present in peripheral extrapituitary tIssues of chick embryos, but the cellular distribution of GH immunoreactivity is still uncertain because of differing immunohistochemical findings. The possibility that this uncertainty reflects differences in fixation of the embryonic tIssues was assessed by comparing GH immunoreactivity in tIssues fixed in 4% (w/v) paraformaldehyde or Carnoy's fluid (60% ethanol (v/v); 30% chloroform (v/v); 10% acetic acid (v/v)). A widespread distribution of GH immunoreactivity was seen in paraformaldehyde-fixed tIssues, although it was particularly intense in the spinal cord, dorsal and ventral root ganglia, notochord, myotome, epidermis, crop, heart, lung and humerus. In marked contrast, GH immunoreactivity in embryonic tIssues fixed with Carnoy's was more discrete and mainly restricted to marginal and mantle layers of the spinal cord, spinal nerves, the ventral root ganglia and the extensor nerve of the anterior limb bud. Since these are neural derivatives, Carnoy's fixation appears to preferentially result in neural GH staining, whereas GH staining in neural and non-neural tIssues is seen after paraformaldehyde fixation. Carnoy's, because it is a precipitive fixative, may only fix large GH moieties, whereas GH in peripheral tIssues includes numerous molecular variants, many of which are of relatively small size. Paraformaldehyde, because it is a cross-linking fixative, preferentially fixes peptides and small proteins, and it may therefore fix more GH moieties than Carnoy's fluid. Carnoy's fixation appears to underestimate GH immunoreactivity in immunohistochemical studies on the cellular distribution of GH-like proteins in embryonic chicks.

Extrapituitary beta TSH and GH in early chick embryos.

Somatotropes and thyrotropes are thought to be derived from the same cellular lineage and the expression of both growth hormone (GH) and thyrotropin (beta TSH) is thought to be dependent upon the same (Pit-1) transcription factor. The presence and comparative distribution of GH- and beta TSH-immunoreactivity in early chick embryos, was therefore investigated, especially as extrapituitary GH-immunoreactive cells are present in some peripheral tissues of early chick embryos prior to the ontogenic differentiation of the pituitary gland. At the end of the first trimester of incubation (embryonic day (ED) 7), GH-immunoreactivity was widespread in the head, particularly in neural tissue. Strong labeling was found in the diencephalon and mesencephalon and in neural ganglia and the trigeminal nerve. beta TSH-immunoreactivity was also present in these tissues, although restricted to the ependymal cells lining the diocoele and mesocoele and absent from mantle layers. It was also present in the cellular layer lining the otic vesicle, which was devoid of GH staining. In contrast, Rathke's pouch, the primordial pituitary gland was without GH- or beta TSH-staining. Control sections incubated with preabsorbed antisera or with pre-immune serum were completely devoid of staining. In the trunk, the epidermal cells were stained for beta TSH, but not for GH. Intense GH-immunoreactivity was present in the ventral and dorsal horns of the spinal cord and was particularly strong in the outer marginal layer. In contrast, beta TSH-immunoreactivity was again restricted to ependymal cells lining the spinal canal, which were devoid of GH-immunoreactivity. Strong GH staining was also present in the dorsal and ventral root ganglia, both of which lacked significant beta TSH staining. In non-neural tissues, both GH and beta TSH staining was present in the crop, although in topographically different cells. beta TSH-immunoreactivity was also present in the cells lining the bronchial ducts and the adluminal linings of the pleural and pericardial cavities. GH-immunoreactivity, in contrast, was absent from the lung but present in the surrounding intracostal muscles and in the Müllerian duct. Both GH- and beta TSH-immunoreactivity was present in liver hepatocytes. These results clearly show, for the first time, the presence of TSH-immunoreactivity in central and peripheral tissues of the ED7 chick embryo, prior to the differentiation of pituitary thyrotropes. They also show that beta TSH- and GH-immunoreactive cells are differentially located within embryonic tissues.

Dealing with the uncertainty of developing a cancer.

Based on a personal experience in a genetic counselling consultation, this article proposes a personal reflection about the different ways in which individuals from high-risk families are living and dealing with the uncertainty of one day developing a cancer. The psychological reactions of the individuals concerned are described before exploring actual issues of genetic testing--such as the reasons for testing--but also technical and familial limits. This paper also presents the limits existing in follow-up and prevention for the carriers of susceptibility genes and insists on the importance of counselling before genetic testing and the necessity of further multidisciplinary research in this field. The original text was presented in French during the Eleventh MASCC International Symposium on Supportive Care in Cancer, at Nice, in February 1999.

Is preoperative cardiac evaluation for abdominal aortic aneurysm repair necessary?

PURPOSE: It is reported that 25% to 50% of patients with abdominal aortic aneurysms (AAA) have severe coronary artery disease (CAD) and should undergo an aggressive cardiac workup before AAA repair. In contrast, it has been our policy that patients referred for AAA repairs undergo no cardiac testing before surgery. METHODS: This report reviews the last 113 consecutive patients who underwent elective AAA repair by the senior author using this policy. Seventy-four patients (group A) had only an electrocardiogram before surgery. The remaining 39 patients (group B) were referred having already had additional testing that included a thallium stress test (n = 20), echocardiogram (n = 18), multiple gated acquisition (MUGA) scan (n = 3), cardiac catheterization (n = 8), or some combination of these. RESULTS: There was no statistical difference between group A and group B with regard to age, sex, tobacco use or history of coronary artery disease, diabetes mellitus, stroke (CVA), hypertension, peripheral vascular disease, or chronic obstructive pulmonary disease. Group B more commonly had a history of myocardial infarction (41% vs 19%, p < 0.03) and congestive heart failure (23% vs 7%, p < 0.03). During surgery there was no significant differences in blood loss, transfusion requirements, or operative times. There were no myocardial infarctions in group A and two (5.1%) in group B, which was not significantly different. Other complications, such as CVA, renal failure, pulmonary failure, pneumonia, wound infection, and hemorrhage, were not significantly different between the two groups. Postoperative hospital stay was not significantly different. There were three deaths in the entire series (2.7%), and only one in group B was cardiac-related in a patient with known end-stage cardiac disease and a symptomatic 8 cm AAA. CONCLUSIONS: These data indicate that most patients with AAA can safely undergo repair with no cardiac workup and that cardiac workup before AAA repair contributes little information that impacts on treatment or final clinical outcome. We conclude that cardiac testing in preparation for AAA repair is not usually necessary and that intraoperative hemodynamic management may be the most important variable in determining outcome.

In vitro generation of human cytolytic T-cells specific for peptides derived from the HER-2/neu protooncogene protein.

The development of T-cell therapy for the treatment of human malignancy has been hindered, in large part, by a lack of identifiable tumor antigens. Studies to identify potential T-cell targets in humans have been difficult because of practical problems limiting the use of in vivo immunization and a lack of reproducible in vitro priming methods. Oncogenic proteins are involved in malignant transformation and maintenance of the transformed phenotype and theoretically are potential targets to T-cell therapy. HER-2/neu protein is a protooncogene product overexpressed in a variety of human malignancies and is associated with malignant transformation and aggressive disease in human breast cancer. Previous studies have shown that some patients with breast cancer have existent helper/inducer T-cell immunity to p185HER-2/neu protein and peptides. The current study represents initial attempts to identify candidate cytotoxic T-lymphocyte (CTL) epitopes. Synthetic peptides were constructed identical to HER-2/neu protein segments with amino acid motifs similar to the published motif for HLA-2.1-binding peptides. Four peptides were synthesized and two were shown to be avid binders to HLA-A2.1. Two of the four peptides could be shown to elicit peptide-specific CTL by primary in vitro immunization in a culture system using peripheral blood lymphocytes from a normal individual homozygous for HLA-A2. p185HER-2/neu protooncogene protein contains immunogenic epitopes capable of generating human CD8+ CTL. The identification of candidate CTL epitopes will allow studies to determine whether some cancer patients have existent CTL immunity to HER-2/neu protein. The demonstrated ability to generate human peptide-specific CTL in vitro allows screening of other oncogenic proteins to identify candidate T-cell epitopes potentially useful for future immunotherapy studies.

Existent T-cell and antibody immunity to HER-2/neu protein in patients with breast cancer.

The HER-2/neu protooncogene is amplified and overexpressed in 20-40% of invasive breast cancers. HER-2/neu protein overexpression is associated with aggressive disease and is an independent predictor of poor prognosis in several subsets of patients. The protein may also be related to cancer formation, with overexpression being detectable in 50-60% of ductal carcinomas in situ. It has been suggested that it might be possible to develop specific T-cell therapy directed against proteins involved in malignant transformation. One question is whether normal proteins that are overexpressed are appropriate targets for therapeutic immune attack. This report demonstrates that some patients with HER-2/neu-positive breast cancers have both existent CD4+ helper/inducer T-cell immunity and antibody-mediated immunity to HER-2/neu protein. Initial studies performed on 20 premenopausal breast cancer patients identified antibodies to HER-2/neu in 11 individuals. Similar antibody responses have been found in some normal individuals. The patient with the greatest antibody response was studied in detail. In addition to a humoral immune response this patient had evidence of a significant proliferative T-cell response to the HER-2/neu protein and peptides. Similar T-cell responses have been detected in additional patients. It has been assumed that patients would be immunologically tolerant to HER-2/neu as a self-protein and that immunity might be difficult to generate. If immunity could be generated, the result might be destructive autoimmunity. The current data support the notion that HER-2/neu-specific immunity might be used in therapy without destroying normal tissue but also raises questions as to the role of existent immunity in immune surveillance and cancer progression.

Defining the surgical personality: a preliminary study.

Noting that noncognitive factors may be more predictive of success in a medical career than is intellectual ability or cognitive performance, we undertook a study to determine whether a surgical personality exists and to delineate the temperament and personality traits that contribute to its definition. The Krug Adult Personality Inventory, the Strelau Temperament Inventory, and Barclay's adjective checklist were administered to 110 physicians, 35 in a "controllable lifestyle" specialty, 28 in primary care, and 47 in surgery or a surgery subspecialty. In addition, participants completed a stress inventory. Results showed that surgeons form a distinct and homogeneous group based on temperament and personality traits. We suggest that noncognitive factors can be of use to medical educators in the selection, counseling, training, and evaluation of medical personnel.