Eva Brandén

Patient's and doctors' delays in the diagnosis of chest tumors

BACKGROUND It is well known that there are delays in diagnosis of lung cancer, both from the patients and from the doctors. We decided to prospectively study this in our area. PATIENTS AND METHODS All patients with known lung cancer (134 cases) seen at the Department of Respiratory Medicine in Gaevle from February 1, 1997, to February 28, 1998, were investigated prospectively. A questionnaire recorded all symptoms, smoking habits, etc. All dates for visits to doctors and investigations were noted. RESULTS The mean delay of the patients, i.e. from the first symptom(s) until the GP was contacted, was 43 days (median 21). From the first contact with the GP until referral to the specialist the mean time was 56 days (median 33). From the first visit to the specialist to diagnosis the mean time was 33 days (median 9), with 68% of the patients diagnosed within a month. The mean time from first symptom(s) until treatment or the decision not to treat (the sum of all delays) was 203 days (median 189), i.e. around 7 months. CONCLUSION The delays are in most instances fairly long. With a planned approach, the delays due to the doctors could probably be shortened.

A prospective study of a total material of lung cancer from a county in Sweden 1997–1999: gender, symptoms, type, stage, and smoking habits

The epidemiology of lung cancer is changing in many parts of the world. In the industrialized countries, there is a trend that the incidence in men is declining, while it is increasing for women. Also, adenocarcinomas are becoming relatively more common, especially among men. The purpose of this study was to investigate whether such trends also occur in Sweden and also to describe other aspects of an unselected lung cancer material today, such as symptoms, stage and smoking habits. In the county of Gaevleborg, Sweden, practically all patients with lung cancer are referred to the lung department, and thus a total material of lung cancer patients with only a minimal selection bias can be studied. All patients with lung cancer in the county from January 1, 1997 to December 31, 1999, were investigated prospectively regarding stage, type of cancer, and symptoms. In all, there were 364 patients, 237 (65.1%) men and 127 (34.9%) women. The mean age for men was 69.8 and for women, 68.1 years. 91.9% of the men and 78.6% of the women were smokers or ex-smokers. In general the men were heavier smokers than were the women (P<0.0001). Adenocarcinoma was the most common subtype found in women and squamous cell carcinoma in men. The excess of adenocarcinoma in women was due to never-smoking women; for smoking and ex-smoking men and women, the proportion of adenocarcinomas was the same. In all, 240 patients (68.0%) were diagnosed at Stage IIIb (27.2%) or IV (40.8%), with no significant differences between the sexes. The most common first symptom was cough. Only 7.0% of patients were asymptomatic. In conclusion, the trend of an increasing proportion of adenocarcinoma in lung cancer is seen also in Sweden. A depressingly high percentage of patients present in late stages and are thus inoperable.

An association between chronic infection with Chlamydia pneumoniae and lung cancer. A prospective 2-year study.

This study assesses a possible relationship between chronic Chlamydia pneumoniae (Cpn) infection and lung cancer (LC). A total of 210 consecutive patients (136 M, 74 F) were diagnosed with LC during a 2‐year period. Blood was obtained from 128 M and 70 F patients for Cpn serology. Repeat blood specimens were taken after 3 months. Throat specimens for Cpn DNA analysis by PCR were taken from 110/136 M and 63/74 F. Seventy‐four cytobrush specimens were taken and also analyzed by polymerase chain reaction (PCR). Fifty (29 M, 21 F) bronchial biopsies and 8 (6 M, 2 F) tumors resected at surgery were analyzed for Cpn by immunohistochemistry (IHC). Males had significantly more often squamous‐cell carcinoma (SCC) than females. Other types of LC were more equally distributed between males and females. The difference between males and females regarding smoking history was significant, and male LC patients had significantly higher levels of IgG and/or IgA antibodies than female LC patients. Male and female LC patients had significantly higher prevalences of high antibody titers than controls. A high prevalence of unusually high titers of specific Cpn antibodies was found in male LC patients. This could indicate that LC may be induced by chronic Cpn infection, since stable high titers of Cpn antibodies, especially IgA, are a hallmark of chronic infections.

Diagnostic and prognostic role of plasma levels of two forms of cytokeratin 18 in patients with non-small-cell lung cancer

PURPOSE Cytokeratin 18 (CK18) can be used as a serum biomarker for carcinoma cell death, whereas caspase-cleaved (ccCK18) fragments reflect tumour apoptosis. We explored the potential diagnostic and prognostic role of circulating CK18 and ccCK18 in patients with non-small-cell lung cancer (NSCLC) in comparison with Cyfra 21.1, a fragment of cytokeratin 19. METHODS Subject cohorts consisted of 200 healthy blood donors (HBD), 113 patients with benign lung diseases (BLD) and 179 NSCLC cases. Plasma levels of ccCK18, total CK18 and Cyfra 21.1 were determined with ELISA assays. RESULTS Plasma levels of ccCK18 and total CK18 were higher in the NSCLC group compared to the HBD and BLD cohorts (p<0.0001). Using a cut-off of 104 U/L for ccCK18 and 302 U/L for total CK18 (95% specificity in the HBD group) the diagnostic accuracy of both CK18 forms to distinguish between NSCLC and BLD cases was 56%, whereas it was 94% for Cyfra 21.1. Multivariate survival analysis showed that total CK18 was a stronger prognostic factor than both ccCK18 and Cyfra 21.1 (HR 0.64 for low versus high total CK18 levels, 95% confidence interval (CI) 0.50-0.82; p=0.0004) in the entire NSCLC cohort and in 78 patients with locally advanced or metastatic disease treated with chemoradiotherapy or first-line chemotherapy (HR 0.70 95% CI 0.52-0.94; p=0.018). CONCLUSIONS Cyfra 21.1 is a useful diagnostic biomarker for NSCLC. Total CK18 shows a promising potential as prognostic marker in NSCLC patients, independently of the therapeutical intervention. In contrast, ccCK18 was not of prognostic value in NSCLC, suggesting that tumour necrosis is of particular importance in this disease.

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.

Profiling cancer testis antigens in non–small-cell lung cancer

Cancer testis antigens (CTAs) are of clinical interest as biomarkers and present valuable targets for immunotherapy. To comprehensively characterize the CTA landscape of non-small-cell lung cancer (NSCLC), we compared RNAseq data from 199 NSCLC tissues to the normal transcriptome of 142 samples from 32 different normal organs. Of 232 CTAs currently annotated in the Caner Testis Database (CTdatabase), 96 were confirmed in NSCLC. To obtain an unbiased CTA profile of NSCLC, we applied stringent criteria on our RNAseq data set and defined 90 genes as CTAs, of which 55 genes were not annotated in the CTdatabase, thus representing potential new CTAs. Cluster analysis revealed that CTA expression is histology dependent and concurrent expression is common. IHC confirmed tissue-specific protein expression of selected new CTAs (TKTL1, TGIF2LX, VCX, and CXORF67). Furthermore, methylation was identified as a regulatory mechanism of CTA expression based on independent data from The Cancer Genome Atlas. The proposed prognostic impact of CTAs in lung cancer was not confirmed, neither in our RNAseq cohort nor in an independent meta-analysis of 1,117 NSCLC cases. In summary, we defined a set of 90 reliable CTAs, including information on protein expression, methylation, and survival association. The detailed RNAseq catalog can guide biomarker studies and efforts to identify targets for immunotherapeutic strategies.

Intermittent azithromycin treatment for respiratory symptoms in patients with chronic chlamydia pneumoniae infection

Chlamydia pneumoniae (Cpn) is a common respiratory pathogen with a biphasic replicative cycle and has a tendency to cause chronic infections. Azithromycin is commonly used for the treatment of Cpn infections, but little is known about the optimal dose and duration of therapy. In this prospective double-blind, randomized study the effects of azithromycin and placebo were compared regarding longstanding airway and/or pharyngeal symptoms in patients with chronic Cpn infection. Further, effects on antibody titres and lung function were assessed. 103 patients were treated with either azithromycin 500 mg daily for 5 d, repeated 3 times with a 23-d interval, or placebo. Patients were examined 4 months and 1 y after completed treatment. Evaluation of symptoms showed general improvement and less hawking in patients treated with azithromycin compared to placebo after 4 months, but there was no sustained difference 1 y after completed treatment. The antibody titres remained stable, and there was no influence on lung function. Adverse events, primarily gastrointestinal, were more frequently reported with azithromycin than placebo. In conclusion, azithromycin was effective for reduction of respiratory symptoms in patients with chronic Cpn infection, but prolonged intermittent treatment with high doses did not eradicate the chronic infection.

Computer tomography-guided core biopsies in a county hospital in Sweden: Complication rate and diagnostic yield

BACKGROUND: Core biopsies are valuable in obtaining sufficient tissue to ensure diagnosis of diseases in the thorax. OBJECTIVE: To evaluate the complication rate and the diagnostic yield in computer tomography (CT)-guided core biopsies performed in a county hospital in Sweden. METHODS: Medical journals, spirometry results, pathology reports and CT scans were reviewed in 463 consecutive cases, where a transthoracic core biopsy was performed between January 2005 and December 2010. Of these 380 (82%) were lung lesions, 48 (10%) were mediastinal lesions and 35 (8%) were pleural lesions. RESULTS: All patients underwent a chest X-ray 4 hours post-biopsy and pneumothorax was seen in 156/463 (34%) patients: 137 after lung biopsy and 17 after mediastinal biopsy. Chest tube insertion was required for 27 (17%) of these patients (6% of all core biopsies). Small intraparenchymal hemorrhages and hemoptysis were observed with subjective difficulty in one case. The diagnostic yield for the 463 patients was 212 (46%) cases of lung cancer, 188 (41%) benign lesions and 39 (8%) pulmonary metastases. CONCLUSIONS: A transthoracic core biopsy ensures diagnosis with a low complication rate and is suitable as an outpatient procedure. An increased risk for pneumothorax was observed when the biopsied lesion was small or when emphysema was in the path of the biopsy needle. Reduced lung function pre-biopsy or emphysema in the path of the biopsy needle increased the need for chest tube treatment of pneumothorax. A CT-guided core biopsy is safe and applicable in a county hospital.

The ‘reservoir’ of undetected bronchial carcinomas in the general population

STUDY OBJECTIVES Autopsy studies have shown that a sizeable portion of lung cancers are never diagnosed and thus not entered into any cancer registry. DESIGN In 1997, we decided to make all available efforts to find all patients with lung cancer who had not been registered previously. SETTING The local hospitals in the county of Gävleborg, Sweden. PATIENTS All patients with lung cancer diagnosed in the county from 1997 to 2000. INTERVENTIONS In meetings with all the general practitioners of the county, these were asked to refer all suspected cases as early as possible, including those with a seemingly dismal prognosis. This initiative was also covered by the newspapers and the local television station. MEASUREMENTS AND RESULTS From 1997 onwards, the incidence of lung cancer in the county was found to be 40-50 per 100,000 inhabitants compared with an incidence of about 30 during the ten preceding years. This difference is significant in time (P<0.0001) and is compared with the incidence of lung cancers in four neighboring counties (P=0.002). CONCLUSIONS There can be a considerable number of patients with lung cancer who are never diagnosed. This can explain differences in survival between various countries and this will also affect the results of screening programs, since the control groups will also include a number of lung cancer cases which will never be recognized.

Lung cancer among native and foreign-born Swedes: histopathology, treatment, and survival

Abstract Background: Lung cancer (LC) is the leading cause of cancer-related death worldwide, including Sweden. Several studies have shown that socioeconomic status affects the risk, treatment, and survival of LC. Due to immigration after Second World War, foreign-born people constitute 12.5% of the Swedish population. We wanted to investigate if there were any differences in LC management, treatment and survival among the foreign-born Swedes (FBS) compared to the native Swedish population (NatS) in Stockholm. Material and methods: A retrospective analysis of all patients diagnosed with non-small cell lung cancer (NSCLC) at the Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Solna from 1 January 2003 to 31 December 2008 was made. In all, 2041 cases of LC were diagnosed, thereof 1803 with NSCLC. Of these, 211 (11.7%) were FBS. Results: The mean age of NatS and FBS patients was 69.9 years, median 70 (range 26–96) and 66.0 years, median 66 (range 38–94), respectively (p < 0.001). In all, 89.8% of NatS and 90.0% of FBS were either smokers or former smokers. Adenocarcinoma was the most common subtype in both groups (NatS 54.7%, FBS 48.3%). In 140 (8.8%) of the NatS and 17 (8.1%) of the FBS the diagnosis was clinical only. There were no significant differences in stage at diagnosis, nor in performance status (PS) or different therapies between the groups. The median overall survival time for the NatS was 272 days and for FBS 328 days, again no significant difference. However, the median overall survival time for female NatS was 318 days and for female FBS 681 days (p = 0.002). Conclusion: FBS patients were significantly younger than NatS at diagnosis, and female FBS lived longer than female NatS, but otherwise there were no significant differences between NatS and FBS patients with LC regarding diagnosis, treatment, and survival.