Lauri Tammilehto

Inoperable non-small cell lung cancer: Radiation with or without chemotherapy

We report a randomized multicentre study of split-course radiotherapy (RT), with or without combination chemotherapy (CT), in 238 patients with inoperable non-small cell lung cancer (NSCLC), previously untreated, confined to one hemithorax and the mediastinal nodes. In both treatment groups RT consisted of 55 Gy in 20 F given over 7 weeks with a 3-week rest interval. CT consisted of the 3-drug regimen CAP: C = cyclophosphamide 400 mg/m2, A = adriamycin 40 mg/m2, P = cisplatin 40 mg/m2; 2 cycles of CAP given before RT, one during the rest interval and six after RT. Seventy per cent in the RT arm and 67% in the RT-CT arm had epidermoid carcinoma. No significant difference was apparent between the RT and the RT-CT arms with respect to objective response rates (CR + PR) (44 and 49%, respectively), median duration of response (278 and 320 days), local failure (31 and 20%), distant progression (23 and 20%) or median survival (311 and 322 days). The survival figures showed an almost significant (P = 0.05) therapeutic advantage of the combined regimen with stage IIIM0 disease. Progressive disease was the cause of death in 92% and 88%. We conclude that chemotherapy did not contribute significantly to either local control or survival as compared to radiotherapy alone.

Overlap Syndrome of Asthma and COPD Predicts Low Quality of Life

Background. In clinical practice, patients whose airway disease shares features of both asthma and chronic obstructive pulmonary disease (COPD) remain poorly recognized. Material and methods. The study population consisted of 1546 patients with a diagnosis of asthma or COPD or both. Based on patient-reported outcomes and retrospective medical record data, the study population was divided into three groups: (1) asthma only, (2) COPD only, and (3) both asthma and COPD (overlap syndrome group). We evaluated patient characteristics associated with health-related quality of life (HRQoL). Results. In many respects, the overlap group fell between the asthma and COPD groups. In the overlap group, however, HRQoL was the poorest of all. In the logistic regression model, with the asthma group as the reference, both the overlap and the COPD group showed higher risk for low HRQoL [odd ratio (OR): 1.9; 95% confidence interval (CI): 1.2–3.2; and OR: 1.8, 95% CI: 1.0–3.2; respectively]. In addition, female gender, obesity, duration of disease, disability pension, and coexisting cardiovascular disease were associated with low HRQoL across the study population. Conclusions. Patients with overlapping asthma and COPD differed from those patients with asthma or COPD only. Overlap syndrome was associated with low HRQoL.

Chromosomal abnormalities and their correlations with asbestos exposure and survival in patients with mesothelioma

Cytogenetic findings of our 30 previously reported and eight new patients with malignant pleural mesothelioma were summarised and correlated with asbestos fibre burden in lung tissue and survival. Successful cytogenetic analyses were performed on cells obtained from the tumours and/or pleural effusions of 34 of the 38 patients. Clonal chromosomal abnormalities were detected in 25 patients, 19 of them studied before treatment. Nine patients, seven of them studied before treatment, had normal karyotypes and/or non-clonal chromosomal abnormalities. Most of the karyotypic findings in the patients with clonal abnormalities were complex and heterogeneous, and no chromosome aberration specific to mesothelioma could be demonstrated. The following numerical abnormalities in decreasing order of frequency were preferentially present in karyotypic changes: -22, +7, -1, -3, -9, +11 and -14 (-/+ denoting partial or total loss or gain). Translocations and deletions involving a breakpoint at 1p11-p22 were the most frequent structural aberrations. Statistically significant correlations were found between high content of asbestos fibres in lung tissue and partial or total losses of chromosomes 1 and 4, and a breakpoint at 1p11-p22 (P = 0.0001, P = 0.003, P = 0.009, respectively). The number of copies of chromosome 7 short arms was inversely correlated with survival (P = 0.02). In this study no diagnostic cytogenetic markers of mesothelioma were found, instead the copy number of chromosome 7 short arms turned out to be a possible prognostic factor in malignant mesothelioma.

Recurrent DNA copy number changes in 1q, 4q, 6q, 9p, 13q, 14q and 22q detected by comparative genomic hybridization in malignant mesothelioma.

Comparative genomic hybridization (CGH) analyses were performed on 27 human pleural mesothelioma tumour specimens, consisting of 18 frozen tumours and nine paraffin-embedded tumours, to screen for gains and losses of DNA sequences. Copy number changes were detected in 15 of the 27 specimens with a range from one to eight per specimen. On average, more losses than gains of genetic material were observed. The loss of DNA sequences occurred most commonly in the short arm of chromosome 9 (p21-pter), in 60% of the abnormal specimens. Other losses among the abnormal specimens were frequently detected in the long arms of chromosomes 4 (q31.1-qter, 20%), 6 (q22-q24, 33%), 13 (33%),14 (q24-qter, 33%) and 22 (q13, 20%). A gain in DNA sequences was found in the long arm of chromosome 1 (cen-qter) in 33% of the abnormal specimens. Our analysis is the first genome-wide screening for gains and losses of DNA sequences using comparative genomic hybridization in malignant pleural mesothelioma tumours. The recurrent DNA sequence changes detected in this study suggest that the corresponding chromosomal areas most probably contain genes important for the initiation and progression of mesothelioma.

Self reported respiratory symptoms and diseases among hairdressers.

OBJECTIVES: Hairdressers are exposed to many irritative and allergenic substances capable of causing occupational respiratory symptoms and diseases. The self reported prevalence of respiratory symptoms and diseases was studied, and the risks among hairdressers compared with saleswomen was estimated. METHODS: A cross sectional prevalence study of respiratory symptoms and diseases was carried out among hairdressers and supermarket saleswomen, with a computer assisted telephone interview method (CATI). The study population comprised all the female hairdressers and supermarket saleswomen aged 15-54 years in the Helsinki metropolitan area, Finland. Disproportionate random samples of female hairdressers and sales-women were drawn from the trade union membership registers. The interviews were carried out between February and April 1994. A response rate of 80.5% (355/440) was obtained for hairdressers and 82.2% (583/709) for saleswomen. Atopy, smoking, chronic illnesses, type of work, working hours, working conditions, personal and professional use of hair products, and the use of personal protective devices were assessed. The outcome variables were self reported symptoms of the upper and lower respiratory tract. These were used to define chronic bronchitis, and asthma, laryngitis, and allergic rhinitis diagnosed by a physician. RESULTS: There was a considerable difference in the prevalence of chronic bronchitis; 6.8% in hairdressers versus 1.9% in saleswomen. The odds ratio (OR) adjusted for age, smoking, and atopy for chronic bronchitis indicated an increased risk of chronic bronchitis (OR 4.8, 95% confidence interval (95% CI) 2.2 to 10.1). No association was found between work as a hairdresser and asthma, laryngitis, and allergic rhinitis. Also the prevalence of rhinitis, rhinitis with eye symptoms, cough with phlegm, dyspnoea, and dyspnoea accompanied by cough was increased among hairdressers. The corresponding adjusted risk ORs were 1.7 (95% CI 1.3 to 2.3) for rhinitis, 1.9 (95% CI 1.4 to 2.6) for rhinitis with eye symptoms, 1.4 (CI 1.1 to 1.9) for cough with phlegm, 1.5 (95% CI 1.0 to 2.2) for dyspnoea, and 1.6 (95% CI 1.0 to 2.7) for dyspnoea with cough. CONCLUSIONS: Our results indicate an increased prevalence of upper and lower respiratory symptoms among hairdressers. Allergenic and irritative chemicals in hairdressing are likely candidates explaining the difference found between the hairdressers and controls. Work related reasons should be considered when a hairdresser presents with airway symptoms. Preventive actions are needed to improve the working conditions and personal protection.

Multimodality treatment programs for malignant pleural mesothelioma using high-dose hemithorax irradiation

The characteristic of malignant pleural mesothelioma is a tumor that grows by plate-like extension over the pleura, and invades adjacent tissues and organs. Radical surgical removal of the tumor is generally not possible, and most treatment regimens involve combined chemotherapy and radiotherapy, as well as debulking surgery. We have prospectively evaluated five locally-aggressive multi-modality treatment programs, using different hemithorax irradiation schedules and chemotherapy regimens. One hundred patients with confirmed malignant pleural mesothelioma entered the study between 1977 and 1989. The treatment programs, which can consecutively, were: I, 20 Gy (10 x 2 Gy) to the hemithorax + CYVADIC (cyclophosphamide 500 mg/m2 d 1, vincristine 1 mg/m2 d 1 and 5, adriamycin 40 mg/m2 d 1 and dacarbazine 200 mg/m2 d 1 and 5, several cycles before and after irradiation); II, 55 Gy (25 x 2.2 Gy) to the hemithorax + 15 Gy (6 x 2.5 Gy) to the tumor + CYVADIC (2 cycles before, 1 cycle during, and 2 cycles after irradiation); III, Mitoxantrone (14 mg/m2 q 28 d, < or = 6 cycles) followed by 70 Gy (56 x 1.25 Gy, twice a day); IV, 4-Epirubicin (110-130 mg/m2 q 28 d, < or = 6 cycles) followed by 35 Gy (28 x 1.25 Gy twice a day) to the hemithorax + 36 Gy (9 x 4 Gy every 2 days) to the tumor; V, Etoposide (150 mg/m2 1, 3, 5 q 28 d) followed by 38.5 Gy (11 x 3.5 Gy) to the hemithorax. A new system for evaluating tumor response in pleural mesothelioma was applied. None of the combined treatment programs prevented local invasive growth or the spread of mesothelioma outside the hemithorax. The median survival time was slightly increased from 8 to 12 months for those patients who completed the protocol treatments, but progressive disease was the invariable outcome. Radiation pneumonitis and fibrosis were severe and compatible with results of total loss of lung function on the irradiated side. We conclude that data relating to therapeutic responses and treatment programs in malignant mesothelioma should be better correlated internationally, if the problems associated with the evaluation of treatment and the management of patients with mesothelioma are to be improved.

Gains and losses of DNA sequences in malignant mesothelioma by comparative genomic hybridization.

The molecular basis of malignant mesothelioma is poorly known. We examined genetic changes in 11 mesothelioma specimens by comparative genomic hybridization (CGH). Five DNA specimens originated from uncultured tumor tissues and six from cell lines established from the same patients. Findings from the classical karyotypic characterization of both primary tumors and cell lines have been reported previously. In the CGH analyses the most common genetic alterations in the 11 mesothelioma specimens were losses of chromosomal regions in 1p, 8p, 14q, and 22q and gains of 5p, 6p, 8q, 15q, 17q, and 20. The cell lines had on average a much higher total number of genetic changes than the uncultured tumor specimens. Clonal relationship between the cell lines and the uncultured tissue specimens could not usually be demonstrated even though they originated from the same patient. The observed differences may partly be due to high frequency of chromosomal rearrangements, which CGH cannot detect, partly due to contamination of tumor specimens with normal tissue, and partly due to genetic evolution in tumor cell lines.

Malignant mesothelioma: prognostic factors in a prospective study of 98 patients

We have prospectively studied 98 patients with histologically confirmed mesothelioma in order to increase our knowledge of the biology of mesothelioma and to assess clinical characteristics, asbestos exposure and S-phase fraction as prognostic factors. Multivariate analysis of the clinical characteristics of the patients (77 men and 21 women) showed that good performance status (WHO ≤ 1), diagnostic delay of more than 6 months, epithelial histology, female gender and clinical stages I or IIA were favourable prognostic factors. Asbestos exposure was estasblished by individual interview (7098 patients) or by lung tissue fibre analysis (2898 patients). Low lung tissue fibre concentration (< 1 × 106 f/g) was a good prognostic factor only in univariate analysis. DNA flow cytometry studies showed diploid predominance in 39 of the 63 tumours analysed; and that a low S-phase fraction was an independent and favourable prognostic factor. In addition to identifying these clinical prognostic factors, our results suggest that the S-phase fraction has independent prognostic significance and that the prognostic importance of asbestos exposure needs to be confirmed.

High-dose methotrexate in combination with interferons in the treatment of malignant pleural mesothelioma.

SummaryTwenty six patients with pleural mesothelioma of UICC stage I–IV excluding M1 disease (46% of whom had stage I disease and 38% stage III disease) were treated intravenously with high dose MTX (3 g) and calcium folinate rescue three times at intervals of 2 weeks and three times at intervals of 3 weeks. Natural interferon (IFN)-α (3 MIU days 2–10) and recombinant IFN-γ 1b (50 μg m–2 on days 2, 6 and 10) were injected subcutaneously after each MTX dose. At the end of MTX treatment the IFNs were continued as maintenance therapy until disease progression. Seven partial responses were observed among 24 patients evaluable for response (response rate 29%, 95% confidence interval 13–51%). Median duration of response was 10 months (range 3–24 months). Median survival was 17 months and 1-year and 2-year survival rates 62% and 31% respectively. The toxicity of the chemo-immunotherapy was acceptable. Treatment was stopped in one patient who developed grade IV neurological toxicity. MTX dose reductions were rare (two patients with grade 1–2 renal toxicity). The combination of high dose MTX and IFN-α and IFN-γ is active against malignant pleural mesothelioma and well-tolerated. The survival rates are encouraging.

Diploid Predominance and Prognostic Significance of S-phase Cells in Malignant Mesothelioma

70 histologically verified, malignant mesotheliomas were analysed by flow cytometry for DNA content and S-phase fraction (SPF) of tumour cells. 60% (42/70) were DNA diploid. 18 of the 28 aneuploid tumours were near-diploid with DNA indices of 1.3 or less. SPF could be calculated in 51 cases. SPF was significantly higher in aneuploid (median 16.0%) than in diploid tumours (median 5.6%). DNA ploidy was not a prognostic determinant; survival was the same for both aneuploid and diploid tumours. SPF, however, was significantly correlated (P = 0.039) with prognosis. Patients who had tumours with a low SPF survived almost twice as long as those with a high SPF. Thus malignant mesothelioma has a peculiar DNA ploidy pattern compared with many other solid tumours, with a predominance of diploid or near-diploid type cells. As in many other tumours, SPF may be used as a clinically relevant prognostic indicator.