J. M. M. Van Den Bosch

Update in pulmonary carcinoid tumors: a review article.

Pulmonary carcinoid tumors are neuroendocrine malignant tumors that make up 1% to 2% of all lung tumors. According to histopathologic criteria, carcinoids can be divided into typical (TC) and atypical (AC) carcinoids. Carcinoids can be placed in a spectrum of neuroendocrine tumors, ranging from low-grade malignant TC to intermediate AC to high-grade large-cell neuroendocrine carcinoma and small-cell lung carcinoma. Familial pulmonary carcinoids are rare. The most common symptoms are hemoptysis, cough, recurrent pulmonary infection, fever, chest discomfort and chest pain, unilateral wheezing, and shortness of breath. Paraneoplastic syndromes are rare and include carcinoid syndrome, Cushing’s syndrome, and ectopic growth hormone–releasing hormone secretion. The diagnosis is usually established by flexible bronchoscopy and biopsy, although occasionally this can result in severe hemorrhage. Immunoscintigraphy by somatostatin analogs can also be useful in diagnosis. The treatment of choice is surgical resection, and prognosis is relatively good in TC, although it is worse in AC. The role of radiotherapy and chemotherapy as part of multimodality treatment or palliation is still debated.

Statin treatment and reduced risk of pneumonia in patients with diabetes.

Background: Recent prognostic studies have shown that previous treatment with statins is associated with a better outcome in patients admitted to hospital with pneumonia. Because of an increased risk of pneumonia in patients with diabetes, we assessed the effects of statin use on the occurrence of pneumonia in adult diabetic patients. Methods: All patients with a diagnosis of diabetes (types 1 and 2) enlisted in the UK General Practice Research Database between 1 June 1987 and 21 January 2001 were included. A case-control study was performed with cases defined as patients with a first recorded diagnosis of pneumonia. For each case up to four controls were matched by age, sex, practice, and index date. Patients were classified as current users when the index date was between the start and end date of statin treatment. Conditional multiple logistic regression analysis was used to estimate the strength of the association between statin treatment and the occurrence of pneumonia. Results: Statins were used in 1.1% of 4719 cases and in 2.1% of 15 322 matched controls (crude odds ratio (OR) 0.51, 95% CI 0.37 to 0.68). After adjusting for potential confounders, treatment with statins was associated with a significant reduction in the risk of pneumonia (adjusted OR 0.49, 95% CI 0.35 to 0.69). The association was consistent among relevant subgroups (cardiovascular diseases, pulmonary diseases) and independent of the use of other prescription drugs. Conclusions: The use of statins is associated with a considerable reduction in the risk of pneumonia in diabetic patients. In addition to lowering the risk of cardiovascular disease, statins may be useful in preventing respiratory infections.

Mesenchymoma of the lung (so called hamartoma): a review of 154 parenchymal and endobronchial cases.

In a series of 154 patients (116 male and 38 female) with so called pulmonary hamartoma the peak incidence was in the sixth decade, with only three patients less than 20 years of age. Sequential radiographs showed that in 55 patients the tumour first appeared in adult life and that in 53 it progressively increased in size. The age incidence and progressive growth leads to the conclusion that the tumour is a benign neoplasm rather than a hamartoma, consisting of various connective tissues intersected by clefts lined by respiratory epithelium. The epithelial elements are regarded as entrapped non-neoplastic inclusions and the tumour as a purely mesenchymal neoplasm: the name mesenchymoma therefore seems the most appropriate. There were two recurrences after simple enucleation, 10 and 12 years later. A total of 142 tumours were parenchymal, and only 12 were endobronchial. All lobes were affected but there was a slight preponderance in the left upper lobe. Four patients had two (synchronous) mesenchymomas. There was an associated bronchial carcinoma in 11 patients, synchronous in six and metachronous in five.

Corticosteroid treatment in sarcoidosis

At present there is no curative treatment for sarcoidosis. Immunosuppressive and/or immunomodulatory drugs can, however, be used for controlling the disease. Corticosteroids remain the mainstay of therapy. They function by suppressing the pro-inflammatory cytokines and chemokines that are involved in cell-mediated immune responses and granuloma formation. Only in a select group of patients is it justifiable to use these drugs, after careful evaluation of the pros and cons. Importantly, disease severity, e.g. threatened organ functions, and not disease activity itself should be the deciding factor in this process. In the case of parenchymal involvement, there is substantial evidence that corticosteroids can improve respiratory symptoms and chest radiography and lung function parameters over 6–24 months. Other generally acknowledged (empirical) criteria for systemic treatment include neurological, cardiac and sight-threatening ocular involvement and hypercalcaemia. Remarkably, despite >50 yrs of use, there is no proof of long-term (survival) benefit from corticosteroid treatment. In addition, there are still no data regarding the optimal dose and duration of corticosteroid or other immunosuppressive therapy. One of the weightiest questions remaining is whether or not these drugs can prevent scarring in patients with a fibrogenic phenotype. As new agents, including infliximab and thalidomide, enter the stage and new diagnostic tools are now available, there is clearly a momentum to design multicentric randomised controlled trials with long enough follow-up (>5 yrs) to answer this pivotal question.

The scimitar syndrome: clinical spectrum and surgical treatment.

We present seven patients with the scimitar syndrome. The clinical and anatomical spectrum is described. Two different types of scimitar vein was recognized. a) simple classical vein running from the middle of the right lung to the cardiophrenic angle (5 patients) and b) double arched vein in the upper and lower lung zone, with ample drainage into the left atrium and inferior caval vein (2 patients). Four patients required surgical treatment. Indications, diagnostic procedures and surgical management are discussed. In two patients, thrombosis and fibrosis occurred in the scimitar vein that had been reimplanted in the left atrium, necessitating pneumonectomy.

Linkage between Toll-like receptor (TLR) 2 promotor and intron polymorphisms: functional effects and relevance to sarcoidosis

The intracellular pathogens Propionibacterium acnes and Mycobacterium tuberculosis have been leading suspects as the cause of sarcoidosis, a systemic disorder characterized by the formation of non‐caseating granulomas. Toll‐like receptor (TLR) 2 is important in the innate immune response against both pathogens, and is therefore of interest in sarcoidosis research. In the present study, three single nucleotide polymorphisms and one dinucleotide repeat polymorphism in the TLR‐2 gene were genotyped in 419 sarcoidosis patients, divided into a study cohort and a validation cohort, and 196 healthy controls. In the study cohort we found a significant increase in prevalence of the AA‐genotype at promotor location −16934 in patients with chronic disease compared to patients with acute/self‐remitting sarcoidosis (34·5% versus 15·9%, respectively, P = 0·006, Pc = 0·019). These results could not be confirmed in our validation cohort, implicating a possible role for TLR‐2 genetics in only a small percentage of sarcoidosis patients. Furthermore, linkage was found between the promotor polymorphism −16934 A/T and the number of GT repeats in intron 1 (P < 0·0001). After in vitro stimulation of peripheral blood mononuclear cells (PMBCs) with different TLR‐2 agonists, a correlation between induction of TNF‐α (P = 0·008), interleukin (IL)‐12 (P = 0·008) as well as IL‐6 (P = 0·02), and the number of GT repeats was observed. In conclusion, the data show that polymorphisms in TLR‐2 might be important in a small group of sarcoidosis patients and that their functional consequences explain partly some of the variance in cytokine pattern observed in different clinical phenotypes of this disease.

Relationship between cells obtained by bronchoalveolar lavage and survival in idiopathic pulmonary fibrosis.

BACKGROUND--The relationship between cell types in bronchoalveolar lavage (BAL) fluid and the clinical course of patients with idiopathic pulmonary fibrosis (IPF) has been the subject of several studies. However, the results of these studies are not conclusive. The aim of this study was to investigate the relationship between the absolute and relative cell numbers in BAL fluid from patients with IPF and their survival. METHODS--Results obtained from the initial BAL fluid analyses of all histologically proven cases of IPF (n = 49) were selected retrospectively. Coxs proportional hazards survival analysis was used for estimating the relationship between absolute and relative cell numbers and survival. RESULTS--A negative relationship was found between both the absolute numbers and percentages of eosinophils in BAL fluid samples and survival. No such relationship was demonstrated for the absolute numbers or the percentages of any other cell type. CONCLUSIONS--Although this study has restrictions, these findings suggest a negative relationship between the absolute numbers and percentages of eosinophils in BAL fluid samples and survival in patients with IPF.

Toll-like receptor (TLR) 4 polymorphism Asp299Gly is not associated with disease course in Dutch sarcoidosis patients.

The aetiology of sarcoidosis, a systemic disorder characterized by the formation of non‐caseating granulomas in variable organs, remains enigmatic. Clarification is hampered by heterogeneity in disease phenotypes and course, due partly to the influence of a variety of genetic and environmental factors. Multiple studies have pointed towards bacteria as possible causative agents. Toll‐like receptors (TLR) are innate immunity receptors important in the immune response against pathogens. TLR‐4, together with CD14 and MD‐2, is an essential receptor for the recognition of lipopolysaccharide (LPS), unique to the cell wall of Gram‐negative bacteria. Recently, an association between TLR‐4 polymorphism Asp299Gly, leading to a change in the extracellular domain of the receptor and possible hyporesponsiveness to LPS, and a chronic course of sarcoidosis was found in German patients. In the present study this polymorphism was genotyped in 156 Dutch sarcoidosis patients and 200 healthy Dutch controls using dual‐labelled fluorescent oligonucleotides. No differences were found in allelic distributions between patients and controls (P = 0·79) or within the different clinical entities of the sarcoidosis group (P = 0·44). Importantly, there were no differences between the Dutch and German sarcoidosis patients (P = 0·62). However, the allelic distribution of the Asp299Gly polymorphism differed significantly between both control groups (P = 0·04). This study highlights the importance of testing a reported gene association in a distinct population when performing genetic association studies.

Angiotensin-converting enzyme inhibitor use and pneumonia risk in a general population

The aim of the present study was to assess whether the use of angiotensin-converting enzyme (ACE) inhibitors is associated with a decreased risk of hospitalisation for community-acquired pneumonia (CAP) in a general, essentially white population. Data were obtained from the Dutch PHARMO Record Linkage System. Cases were defined as patients with a first hospital admission for CAP. For each case, up to four population controls were matched by age and sex. The study population comprised 1,108 patients with a first hospital admission for CAP and 3,817 matched controls. After adjusting for several confounders, ACE inhibitor use was not associated with a decreased incidence of pneumonia (adjusted odds ratio (OR) 1.12; 95% confidence interval (CI) 0.88–1.43). Additionally, no significant association was observed in patients with diabetes, respiratory diseases, heart failure, or patients with both of the last two conditions. Furthermore, adjustment of treatment effects on pneumonia risk using stratification on balancing score also showed no significant association between ACE inhibitor use and pneumonia risk within the different strata (overall adjusted OR 1.09; 95% CI 0.87–1.36). In contrast with previous findings in Asian populations, the current authors were not able to confirm the beneficial effect of angiotensin-converting enzyme inhibitors on pneumonia risk in a general, essentially white population.

Surgery for combined type small cell lung carcinoma

BACKGROUND Combined type small cell lung cancer (SCLC) has been reported to occur in, at most, 1% of all cases of SCLC. These tumours consist of SCLC with a component of squamous cell carcinoma and/or adenocarcinoma. The survival of patients with combined and pure SCLC after surgical resection was assessed. METHODS From 1977 to 1994 2115 patients with bronchogenic carcinoma underwent pulmonary resection. From this group 26 patients (1.2%) were diagnosed as having combined SCLC and 74 patients (3.5%) as having pure SCLC. RESULTS From the 26 patients with combined SCLC (mean age 66.4 years) three were classified as pT1N0M0, eight as pT2N0M0, four as postoperative stage II, and 11 as postoperative stage III. Histological examination showed a component of squamous cell carcinoma in 21 patients. There were 18 (69%) lobectomies, seven (27%) pneumonectomies, and one (4%) segmentectomy. In all patients surgery was thought to be curative. Overall hospital mortality was 4% (n = 1). Cumulative five year survival was 31% for all hospital survivors with combined SCLC postoperative stage I, 50% for those with pT1N0M0, and 25% for those with pT2N0M0 disease. No patients with postoperative stage II and III disease survived for five years. In the 74 patients with pure SCLC hospital mortality was 3% (n = 2); cumulative five year survival was 39% in patients with postoperative stage I disease, 46% for those with pT1N0M0 and 35% for those with pT2N0M0. When compared with pure SCLC, no significant differences in five year survival were evident in patients with postoperative stage I disease. CONCLUSIONS Surgical resection in patients with combined SCLC postoperative stage I yields a cumulative five year survival of 31% while for those with stage II and III disease there were no survivors at five years. In patients with stage I combined or pure SCLC surgery can offer a long term disease free interval or may even be curative.