Prognostic index to identify patients who may not benefit from whole brain radiotherapy for multiple brain metastases from lung cancer

Palliative whole brain radiotherapy (WBRT) is often recommended in the management of multiple brain metastases. Allowing for WBRT waiting time, duration of the WBRT course and time to clinical response, it may take 6 weeks from the point of initial assessment for a benefit from WBRT to manifest. Patients who die within 6 weeks (‘early death’) may not benefit from WBRT and may instead experience a decline in quality of life. This study aimed to develop a prognostic index (PI) that identifies the subset of patients with lung cancer with multiple brain metastases who may not benefit from WBRT because of ‘early death’. The medical records of patients with lung cancer who had WBRT recommended for multiple brain metastases over a 10-year period were retrospectively reviewed. Patients were classified as either having died within 6 weeks or having lived beyond 6 weeks. Potential prognostic indicators were evaluated for correlation with ‘early death’. A PI was constructed by modelling the survival classification to determine the contribution of these factors towards shortened survival. Of the 275 patients recommended WBRT, 64 (23.22%) died within 6 weeks. The main prognostic factor predicting early death was Eastern Cooperative Oncology Group (ECOG) status >2. Patients with a high PI score (>13) were at higher risk of ‘early death’. Twenty-three per cent of patients died prior to benefit from WBRT. ECOG status was the most predictive for ‘early death’. Other factors may also contribute towards a poor outcome. With further refinement and validation, the PI could be a valuable clinical decision tool.     

Surgical treatment of spinal chordomas

The clinical features and results of 34 patients with chordomas treated over a seven-year period were analyzed. Surgical treatment consisted of wide local excision (n = 6), marginal resection (n = 5), intralesional resection (n = 20), and biopsy (n = 3). Eighteen patients received postoperative radiotherapy. The local recurrence rate was 65%, with 30% of patients developing distant metastases. With the introduction of computed tomography, smaller tumors are currently being diagnosed; as a result, 35% of the patients in this series are disease free, compared with 10% described previously.     

Neuroendocrine differentiation and clinical behaviour in non-small cell lung tumours.

The present study examines the relationship between neuroendocrine (NE) differentiation and the clinical behaviour of non-small cell lung cancer (NSCLC). Retrospective (n = 315) and prospective (n = 44) cohorts of non-small cell tumours were obtained from surgically treated cases of lung cancer, comprising 218 squamous cell carcinomas, 65 adenocarcinomas, 51 adenosquamous carcinomas, and 25 large cell undifferentiated carcinomas. Paraffin wax embedded and fresh frozen tissue sections were stained for the NE markers neurone specific enolase, creatine kinase-BB, bombesin, neurotensin, chromogranin A, synaptophysin and UJ-13A. The expression of two or more markers was observed in 30% of cases, and was taken to identify NE-NSCLC. A statistically significant correlation between nodal status and NE differentiation (P = 0.05), and disease stage and NE differentiation (P = 0.04) was observed. However, there was no correlation between NE differentiation and survival. These findings suggest that NE-NSCLC, analogous to SCLC is more highly metastatic than non-NE-NSCLC.     

Paraffin wax-embedded material as a source of DNA for the detection of somatic genetic changes

Loss of genetic material, corresponding to chromosomal deletions, has been detected in a wide range of tumours and may indicate the position of a tumour suppressor gene. In order to identify the position of such a gene more precisely, many tumour samples must be studied until a minimum consensus deletion is characterized. This process is particularly necessary for lung tumours in which the deletion in chromosome 3, seen with such high frequencies in all histological subtypes, is almost always large. We have recently described the use of the polymerase chain reaction (PCR) for restriction fragment length polymorphism (RFLP) analysis of DNA isolated from small bronchial biopsies of lung tumours. In this study we adapted this technique to allow genotyping of DNA isolated from paraffin wax-embedded material (PWEM) microdissected from glass slides. We have investigated 12 lung tumours at polymorphic loci on chromosome 3 and showed allelic loss in all samples. In adapting PCR–RFLP analysis for DNA isolated from PWEM, we have concentrated on those approaches which might be adaptable to routine clinical practice. Somatic genetic changes are now being identified in many tumour types, and this information is expected to be of diagnostic and prognostic significance.     

Differential interaction of anti-lymphocyte serum with sub-populations of lymph node cells

Interaction of normal and Salmonella typhi `H'-sensitized rat lymph node cells with two different types of anti-lymphocyte serum (ALS) has been studied. One type of ALS, named as ALS(N), was prepared by immunizing rabbits with normal non-sensitized lymph node cells while the other, ALS(I), was produced by injecting rabbits with sensitized cells.

The histogram of electrophoretic mobilities (EPM) of ALS(N)-treated normal cells resolves into two Gaussian components corresponding to Class `A' and Class `B' cells respectively. ALS(N) brings about a significant reduction in the mean EPM of both these components indicating that ALS(N) binds to both the functional cell types with equal avidity. Analysis of the histogram of EPM of ALS(N)-treated sensitized cells reveals that ALS(N) leaves the mean EPM of antibody-producing Class `C' cells unchanged. ALS(I), on the other hand, is effective in binding to Class `C' cells in addition to the other cell types. These investigations thus demonstrate that ALS(N) has a differential action on the antigen-sensitive cells as compared to the antibody-producing cells. Further, this lack of interaction with Class `C' cells appears to be a result of a radically different surface-antigenic configuration of these cells.

     

Genes for HMG-CoA reductase and serotonin 1a receptor are on mouse chromosome 13

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase is the key regulatory enzyme for cholesterol biosynthesis. The human gene (HMGCR)has been assigned to the q13.3–q14 region of chromosome 5 (HSA5). We have now mapped the mouse gene Hmgcrto mouse chromosome 13 by Southern analysis of somatic cell hybrids. We also report the mapping to mouse chromosome 13 of the murine homolog of the gene for an intronless ₂-adrenergic-like receptor, which is also located on human chromosome 5 region q11.2–q13 and has recently been identified as the serotonin la receptor. Our results confirm the existence of an evolutionarily conserved syntenic group of genes on the proximal long arm of HSA5 and on MMU13 that also includes the loci for arylsulfatase B, hexosaminidase B and dihydrofolate reductase.     

Pharmacokinetics of Nisoldipine Coat--Core Formulation in Subjects with Liver Cirrhosis

The pharmacokinetics of a controlled-release formulation (coat--core) of the calcium channel blocker nisoldipine was investigated in eight subjects with biopsy-proved liver cirrhosis and eight healthy subjects. In Stage I, subjects received a single 10-mg dose to determine if this dose would be safely tolerated in the subjects with cirrhosis. Because all subjects in both groups tolerated the dose without difficulty, all were continued to Stage II. In Stage II, subjects received a once-daily dose of 10-mg coat-core tablets for 7 days. Serial plasma samples were assayed for nisoldipine in both stages. The C(max) and AUC of nisoldipine were approximately fourfold to fivefold higher (p < 0.01) in subjects with cirrhosis as compared to healthy subjects; however, there was overlap in the range of pharmacokinetic parameters between the two groups. The accumulation factor following multiple dosing was similar in both groups. Results suggest that nisoldipine dose should be optimized by monitoring of a pharmacodynamic end point, such as effect on blood pressure. It is likely that dose requirements for patients with liver disease will be lower.     

Cytotoxic T lymphocytes directed against donor HLA class I antigens on airway epithelial cells are present in bronchoalveolar lavage fluid from lung transplant recipients during acute rejection

BACKGROUND: The lung epithelium is among the first donor tissues encountered by the lung allograft recipient's immune system. The purpose of this study was to determine whether lung epithelium was recognized by T lymphocytes that are isolated from bronchoalveolar lavage fluid of lung allograft recipients during periods of acute rejection. METHODS: Lymphocytes isolated from 45 bronchoalveolar lavage samples (from 41 lung transplant recipients) served as effector cells in standard cell-mediated cytolytic assays with several cell lines as targets: BEAS-2B (an immortalized airway epithelial cell line); B-lymphoblastoid cell lines; and K562 (a natural killer-sensitive cell line). Cytotoxic T-lymphocyte activity of bronchoalveolar lavage lymphocytes was correlated with pathologic status. RESULTS: During acute rejection alone (ie, without concomitant cytomegalovirus infection), mean lysis of the airway epithelial target was significantly greater, compared with during no rejection, when these targets expressed donor-specific HLA class I antigens (P =.007). Lysis of donor class I-matched B-lymphoblastoid cell line targets during rejection was not significantly different from lysis during no-rejection periods (P =.18). Mean lysis of K562, a natural killer cell target, did not differ between acute rejection (without concomitant cytomegalovirus infection) and no rejection (P =.30). During cytomegalovirus infection (without concomitant acute rejection), there was no difference in mean lysis of airway epithelial cells, B-lymphoblastoid cell lines, or K562 targets compared with during no cytomegalovirus infection, whereas during acute rejection, compared with cytomegalovirus infection without rejection, there was a significant increase in mean lysis of the airway epithelial target when it expressed donor-specific HLA antigens (P =.01). CONCLUSIONS: Donor HLA class I-specific cytotoxic T-lymphocyte activity directed at airway epithelial cells was demonstrated in bronchoalveolar lavage lymphocytes from lung transplant recipients. Lysis of these targets was significantly higher during episodes of acute rejection.