Gunnar Hillerdal

Phase III Trial of Gemcitabine Plus Carboplatin Versus Single-Agent Gemcitabine in the Treatment of Locally Advanced or Metastatic Non-Small-Cell Lung Cancer: The Swedish Lung Cancer Study Group

PURPOSE This phase III study compared overall survival in patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) when treated with single-agent gemcitabine versus gemcitabine/carboplatin. Secondary objectives were to compare response, time to progression, toxicity, and quality of life. PATIENTS AND METHODS Chemotherapy-naive patients received either gemcitabine alone (1,250 mg/m2 on days 1 and 8; gemcitabine arm) or with carboplatin (area under the curve 5 on day 1; GC arm) every 21 days. RESULTS Demographics and disease characteristics of 334 randomly assigned patients were comparable on both arms. An intent-to-treat analysis showed significantly better overall survival (log-rank P = .0205) and 2-year survival (15% v 5%; P = .009) favoring the GC arm. Per Cox multivariate analysis, only two covariates, treatment arm (GC v G) and baseline performance status (0 or 1 v 2), independently influenced survival. Per-protocol analyses showed significantly longer median time to progression (5.7 v 3.9 months; P = .0001) and significantly higher objective response rate (29.6 v 11.3%; P < .0001) in the GC arm. Grade 3 to 4 leucopenia and thrombocytopenia were significantly more pronounced in the GC arm (P for both variables < .001) but importantly without associated increases in fever, infection, bleeding, or hospitalizations. There was no discernible difference in global quality-of-life patterns between treatment arms. CONCLUSION In advanced NSCLC, gemcitabine/carboplatin therapy resulted in significant survival benefit compared with single-agent gemcitabine without undue increase in toxicity.

Environmental asbestos exposure and malignant pleural mesothelioma.

Asbestos-related benign and malignant pleural diseases are endemic in some rural parts of central Turkey because of environmental exposure to asbestos fibres. We report here epidemiological data on 113 patients with diffuse malignant pleural mesothelioma (DMPM) diagnosed in our clinic in Eskişehir, located in central Turkey. Of the 113 patients, 59 were men and 54 women (male:female ratio = 1). Ninety-seven patients (86%) had non-occupational asbestos exposure; all were living in villages. Their mean age was 56 years. As the patients had been exposed to asbestos from birth, the latency period was equivalent to the age of the patients. Twenty-eight patients (29%) had lived in villages their entire lives. The other 69 (71%) had been born in a village but migrated to the city or had given up white-soil usage for various reasons. The mean exposure time was 55 years for those with a long exposure period and 25 years for those with a short exposure period, but there was no significant difference between the age of the disease appearance for both groups (55 and 56 years, respectively). Thus, the latency time of mesothelioma due to environmental exposure to asbestos was longer than that due to occupational exposure, but independent of the length of exposure. Soil samples from 67 villages were analysed, comprising a population of 10,120 villagers. Tremolite and some other types of asbestos were found. In conclusion, DMPM in our region is due to mainly to environmental exposure to asbestos. The risk is substantial as a large proportion of the villagers are exposed. After smoking, asbestos exposure is one of the most serious health hazards in our rural population.

Treatment of malignant pleural mesothelioma with carboplatin, liposomized doxorubicin, and gemcitabine: a phase II study.

Background: Malignant pleural mesothelioma has a poor prognosis and there is limited effect of treatment. The Nordic Mesothelioma groups decided in the year 2000 to investigate a combination of liposomized doxorubicin, carboplatin, and gemcitabine for this disease in a phase II study. Methods: From January 2001, to December 2003, 173 evaluable patients with biopsy-verified malignant mesothelioma were included. Two patients were lost to follow-up, but all the others were followed for at least 4 years or until death. Results: Toxicity was fairly low. There were 56 responses (32.4%), of which 2 were complete; the median time to progression was 8.6 months, and the median overall survival was 13 months. Some patients had their responses 4 to 6 months after last treatment. For 116 patients with epitheloid subtype, median survival was 17 months. A subgroup of these patients with good performance status, early stage, and age 70 years or less, showed a median survival of 22 months. Conclusion: The treatment yields good results with a high number of responses and long survival, and a low toxicity. The long survival of the epitheloid subgroup with good prognostic factors is as good as or even better than some studies on “radical” surgery or multimodal treatment, underlining the need of randomized studies to evaluate such treatment options.

Chlamydia pneumoniae may be associated with lung cancer. Preliminary report on a seroepidemiological study.

Material from 117 consecutive patients with lung cancer was investigated with respect to serological markers for chronic Chlamydia pneumoniae infection. Specific C. pneumoniae IgA antibodies were found significantly more often in patients with lung cancer than in control groups with coronary heart disease and in healthy controls, even after adjustment for smoking. The results suggest that chronic C. pnmmoniae infection is common in patients with lung cancer.

Endemic malignant mesothelioma: exposure to erionite is more important than genetic factors.

ABSTRACT The village of Karain, Turkey, has the worlds highest prevalence rate of malignant mesothelioma (MM). Environmental exposure to erionite is thought to cause the disease. However, it has also been suggested that the disease is mainly genetic. Residents in Karain village were traced from 1990to 2006. Mineral samples were obtained from stones used in construction of their houses and any fibers present were identified. All women who had moved to the village as brides were traced and their cause of death determined. MM was the cause of death in 52 of 322 villagers, representing 50.5% of all deaths. Only 2 of 8 types of stones used in construction contained erionite, and these stones had been used almost exclusively in the mid-sections of the village, where MM was common. In houses not containing erionite, no cases of MM were observed. Sixty-four women came as brides to Karain from villages where erionite or asbestos is not found. Of the 16 women who have died, 11 (69%) died from MM. The extreme risk of MM in Karain is due to indoor exposure to erionite. The effect of genetic factors on mesothelioma development cannot be evaluated in this study, but is likely to be minor.

Prognostic value of malignant cells in pleural lavage at thoracotomy for bronchial carcinoma

Despite seemingly radical surgery many patients operated on for bronchial carcinoma will die from their disease. Some patients might benefit from postoperative treatment and a prognostic factor that could identify those with an increased risk for tumor relapse would be of great clinical importance. One possible such factor is the occurrence of malignant cells in pleural lavage performed at operation. To test this hypothesis 224 consecutive patients who had been operated on due to verified or strongly suspected bronchial carcinoma, preoperatively staged as stage I or II, were investigated. After opening the thorax and before manipulation or palpation of the lungs, 300 ml of physiological saline solution was installed into the pleura. After excluding patients who were not radically operated, there remained 138 patients with histologically confirmed lung cancer (carcinoids excluded) and 12.3% showed tumour cells in the washings. Two of 18 patients with metastatic lung disease ( 11%) and one of ten patients with carcinoid tumor also showed malignant cells in the lavage. The patients with lung cancer have been followed for 3 years or until death. After three years 60.2% of those without malignant cells in the pleural lavage were still alive, while this figure was 41.2% in the other group. The difference was not statistically significant. Other factors, such as spread to local lymph nodes, size of tumor, etc. were related to the occurrence of malignant cells in the pleura, and these factors were also better prognostic ones. We conclude that the clinical use of pleural lavage cytology is limited.

Hyaluronan and N-ERC/Mesothelin as Key Biomarkers in a Specific Two-Step Model to Predict Pleural Malignant Mesothelioma

Purpose Diagnosis of malignant mesothelioma is challenging. The first available diagnostic material is often an effusion and biochemical analysis of soluble markers may provide additional diagnostic information. This study aimed to establish a predictive model using biomarkers from pleural effusions, to allow early and accurate diagnosis. Patients and Methods Effusions were collected prospectively from 190 consecutive patients at a regional referral centre. Hyaluronan, N-ERC/mesothelin, C-ERC/mesothelin, osteopontin, syndecan-1, syndecan-2, and thioredoxin were measured using ELISA and HPLC. A predictive model was generated and validated using a second prospective set of 375 effusions collected consecutively at a different referral centre. Results Biochemical markers significantly associated with mesothelioma were hyaluronan (odds ratio, 95% CI: 8.82, 4.82–20.39), N-ERC/mesothelin (4.81, 3.19–7.93), CERC/mesothelin (3.58, 2.43–5.59) and syndecan-1 (1.34, 1.03–1.77). A two-step model using hyaluronan and N-ERC/mesothelin, and combining a threshold decision rule with logistic regression, yielded good discrimination with an area under the ROC curve of 0.99 (95% CI: 0.97–1.00) in the model generation dataset and 0.83 (0.74–0.91) in the validation dataset, respectively. Conclusions A two-step model using hyaluronan and N-ERC/mesothelin predicts mesothelioma with high specificity. This method can be performed on the first available effusion and could be a useful adjunct to the morphological diagnosis of mesothelioma.

One- to Four-Year Follow-Up of Endobronchial Lung Volume Reduction in Alpha-1-Antitrypsin Deficiency Patients : A Case Series

Background: Lung volume reduction surgery can improve lung function and working capacity in severe heterogeneous emphysema. Endobronchial lung volume reduction (ELVR) performed by one-way valves inserted via a flexible bronchoscope can result in a moderate but significant improvement in lung function and exercise tolerance, eliminating the surgical risks. Objectives: Most studies of this method have excluded patients with α1-antitrypsin (AAT) deficiency, but small series of cases with positive short-term outcome have been reported. The sustainability of results has been questioned and we here present our experience in AAT-deficient patients treated with ELVR followed up for up to 4 years. Methods: From August 2008 to January 2012, 15 patients were treated with ELVR. Inclusion criteria were homozygotic AAT deficiency, age <80 years, residual volume of 140% or more, forced expiratory volume in 1 s (FEV1) 15-45% of predicted, severe heterogeneous emphysema, symptoms severely restricting daily life, informed consent and absence of other serious diseases. Results: One patient coughed up valves after 2 months, 1 developed pneumothorax and had valve displacement and subsequent removal, and 1 improved from an FEV1 of 0.62 to 0.84 liters, but after 4 months developed repeated and severe pneumonia and the valves had to be removed. Thus, 12 patients remained and were followed up for at least 1 year. In these patients, FEV1 increased (mean: 54%), the quality of life was much improved, and 2 patients could be taken off oxygen therapy. During the 4-year follow-up, patients demonstrated no significant deterioration in lung function. Conclusion: In carefully selected AAT deficiency patients with severe emphysema, ELVR can be safely performed with encouraging long-lasting results.

Yellow nail syndrome: treatment with octreotide

Introduction:  The yellow nail syndrome (YNS) is the triad of ‘yellow’ nails, peripheral oedema and pleural effusions. For diagnosis, which is clinical, at least two of these findings are necessary. Also typical is a long‐standing chronic cough often caused by low‐grade bronchiectases. The pleural effusions often require pleurodesis. The pathogenesis is probably a dysfunction of the lymphatic system ( 1, 2 ). Octreotide regulates the release of growth hormone and thyrotropin, and also has effects on the gastro‐intestinal tract, where it inhibits glandular secretion, neurotransmission, smooth‐muscle contraction and absorption of nutrients. Adverse effects are nausea, abdominal cramps, diarrhoea, malabsorption of fat and flatulence ( 3 ). Because of the inhibition of absorption of fats and other nutrients, octreotide has been useful in chylothorax from many different causes ( 4 ). The pleural effusion in YNS is usually an exudate, but in rare cases a frank chylothorax. One such case with successful octreotide treatment has been described in the literature ( 5 ).

Prospective Clinical and Radiologic Study of Zeolite-Exposed Turkish Immigrants in Sweden

Ninety-four persons from the village of Karain, Turkey, now residing in Stockholm, were investigated clinically and radiologically. In this village, environmental exposure to erionite, a fibrous zeolite, occurs, and there is an extremely high risk of mesothelioma among the villagers. Since an earlier investigation of the cohort in 1980, another 4 young persons have fallen ill with malignant mesothelioma in this group, where the incidence thus approaches 1%/year and is the most common cause of death. Solitary pleural plaques were found in 6%, thickening of the interlobar pleura in 4% and other radiologic signs of affection of the pleura in 2%. Thickening of the interlobar fissures were observed in 1 patient as the first sign of mesothelioma which has remained asymptomatic until 1 year later. The comparatively low incidence of pleural lesions in the cohort is probably due to the low mean age (36 years). Further follow-up could give clues to the pathogenesis of malignant mesothelioma.