Disseminated typical bronchial carcinoid tumor.

INTRODUCTION: Bronchial carcinoids belong to a rare type of lung tumors. If they do not expose outstanding neuroendocrine activity, they develop without clearly visible symptoms. They are often detected during a routine examination. According to their clinical pathological features, they are divided into typical and atypical tumors. Typical bronchial carcinoids metastasize to distant organs very rarely. Localized forms are effectively treated by surgery. The methods of conservative treatment should be applied in other cases. CASE REPORT: We presented a 65-year-old patient with carcinoid lung tumor detected by a routine examination. Additional analysis (chest X-ray, computed tomography of the chest, ultrasound of the abdomen, skeletal scintigraphy, bronhoscopy, histopathological analysis of the bioptate of bronchial tumor, as well as bronchial brushing cytology and immunohistochemical staining performed with markers specific for neuroendocrine tumor) proved a morphologically typical lung carcinoid with dissemination to the liver and skeletal system, which is very rarely found in typical carcinoids. CONCLUSION: The presented case with carcinoid used to be showed morphological and pathohistological characteristics of typical bronchial carcinoid. With its metastasis to the liver and skeletal system it demonstrated unusual clinical course that used to be considered as rare phenomenon. Due to its frequent asymptomatic course and varied manifestation, bronchial carcinoid could be considered as a diagnostic challenge requiring a multidisciplinary approach.

Nitrofurantoin-induced immune-mediated lung and liver disease.

INTRODUCTION: Nitrofurantoin, a furan derivative, introduced in the fifties has widely been used as an effective agent for the treatment and prevention of urinary tract infections (UTI). Spectrum of adverse reactions to nitrofurantoin is wide, ranging from eosinophilic interstitial lung disease, acute hepatitis and granulomatous reaction, to the chronic active hepatitis, a very rare adverse effect, that can lead to cirrhosis and death. CASE REPORT: We presented a 55-year- old female patient with eosinophilic interstitial lung disease, severe chronic active hepatitis and several other immune- mediated multisystemic manifestations of prolonged exposure to nitrofurantoin because of the recurrent UTI caused by Escherichia coli. We estimated typical radiographic and laboratory disturbances, also restrictive ventilatory changes, severe reduction of carbon monoxide diffusion capacity and abnormal liver function tests. Lymphocytic-eosinophylic alveolitis was consistent with drug-induced reaction. Hepatitis was confirmed by liver biopsy. After withdrawal of nitrofurantoin and application of high dose of glicocorticosteroids, prompt clinical and laboratory recovery was achieved. CONCLUSION: Adverse drug reactions should be considered in patients with concomitant lung and liver disease. The mainstay of treatment is drug withdrawal and the use of immunosuppressive drugs in severe cases. Consideration should be given to monitor lung and liver function tests during long term nitrofurantoin therapy.

Primary pulmonary alveolar proteinosis.

INTRODUCTION: Pulmonary alveolar proteinosis is an uncommon disease characterized by the accumulation of surfactant proteins and phospholipids within the alveolar spaces. Acquired disease can be idiopathic (primary) and secondary. The prevalence of acquired pulmonary alveolar proteinosis is about 0.37 per 100,000 persons. Common symptoms are dyspnea and cough. Chest X-ray shows bilateral perihilar infiltrates. Open-lung biopsy is the gold standard for the diagnosis. Treatment includes whole-lung lavage, application of granulocyte-macrophage colony-stimulating factor and lung transplantation. CASE REPORT: We reported a 51 year-old man with primary form of the disease. It was the second case of this extremely rare disease in the past 30 years in our clinic. The symptoms were long-lasting dry cough, fever and physical deterioration. Chest Xray revealed bilateral pulmonary infiltrates; computed tomography showed patchy ground-glass opacification with interlobular thickening. The diagnosis was established by open lung biopsy. Additional tests were performed to exclude secondary form of the disease. CONCLUSION: We presented a rare clinical entity with typical clinical features and clinical and radiological course of the disease, in order to improve differential diagnostic approach to patients with bilateral lung infiltrations. In patients with pulmonary alveolar proteinosis timely diagnosis and adequate treatment can improve a prognosis.

Trace metal concentrations in Mediterranean blue mussel and surface sediments and evaluation of the mussels quality and possible risks of high human consumption.

The concentrations of trace metals (Fe, Zn, Mn, Ni, Cu, Co and Cr) were determined for the first time in Mediterranean blue mussels (Mytilus galloprovincialis) and surface sediments. The mussel and sediment samples were collected from five sites on the Montenegrin coastal area (southeastern Adriatic Sea) in the fall of 2005 and 2006. The collected samples were digested with a microwave digestion system. The maximum Fe, Zn, Mn, Ni, Cu, Co and Cr mean concentrations in the mussel samples were 603.0, 345.0, 85.0, 18.9, 17.2, 9.1 and 4.2mg/kg of sample dry weight, respectively. The maximum Fe, Mn, Cr, Ni, Zn, Cu and Co concentrations in the sediment samples were 40867, 943.0, 382.0, 336.0, 67.2, 24.8 and 16.9mg/kg of sample dry weight, respectively. A correlation between the metal levels found in the mussel soft tissues with those found in sediments, for both 2005 and 2006, could be established, except for the levels of Zn observed.

[The Mounier-Kuhn syndrome].

BACKGROUND: The Mounier-Kuhn syndrome (MKS) or tracheobronchomegaly (TBM) is a rare condition of unknown frequency, up to now about 100 cases have been reported. It presents by marked dilatation of the trachea and major bronchi, recurrent respiratory infections and consecutive bronchiectasis and scars in lung parenchyme. Sometimes enlargement of transversal colon may be present. Diagnosis is usually made radiologically. CASES REPORT: We rewieved two patients 77 and 72 years old with typical clinical presentation and enlarged upper airways, in whom diagnosis of MKS was established by chest multislice computed tomography (MSCT). Transversal diameter of trachea was 30 mm in the first patient and 33 mm in the other one. Complications of syndrome (tracheal diverticulosis in the first patient, and pulmonary fibrosis, bulous emphysema and bronchiectasis in both patients) also were seen. Lung function tests showed mixed ventilation disorder, and disturbance of respiratory gases values in arterial blood samples. CONCLUSION: The Mounier-Kuhn syndrome is rare disorder, although diagnosis is often missed. Clinical presentation is similar to chronic obstructive pulmonary disease or bronchiectasis. Computed tomography is gold standard for diagnosis. Therapy is presumely supportive.

[Risk factors for brain metastases after definitive chemoradiation for locally advanced non-small cell lung cancer].

BACKGROUND/AIM: As therapy for locally advanced nonsmall cell lung carcinoma (NSCLC) improves, brain metastases (BM) still remain a great problem. The aim of the study was to analyze risk factors for BM in patients with locally advanced NSCLC after chemoradiation therapy. METHODS: Records for 150 patients with non-resectable stage IIIA/IIIB NSCLC treated with combined chemoradiation therapy were analyzed. All of them had negative brain metastases imaging result before the treatment. Incidence of BM was examined in relation to age, sex, histological type, stage, performance status scale of wellbeing of cancer patients, weight loss, chemotherapy regimen and chemotherapy timing. RESULTS: One- and 2-year incidence rates of BM were 19 and 31%, respectively. Among pretreatment parameters, stage IIIB was associated with a higher risk of BM (p < 0.004) vs. stage IIIA. Histologically, the patients with nonsquamous tumors had an exceptionally high 2-year BM risk rate of 32% (p < 0.02). Examining treatment-related parameters, 1-year and 2-year actuarial risk of BM were 27 and 39%, respectively, in the patients receiving chemotherapy before radiotherapy and 15 and 20%, respectively, when radiotherapy was not delayed (p < 0.03). On multivariate analysis, timing of chemotherapy (p < 0.05) and stage IIIA vs. IIIB (p < 0.01) remained statistically significant. CONCLUSION: Patients with IIIB stage, nonsquamous NSCLC, particularly those receiving sequential chemotherapy, had significantly high BM rates.

[K-ras mutation predictive significance in platinum based chemotherapeutic protocols in patients with advanced non-small cell lung cancer].

BACKGROUND/AIM: K-ras oncogene is mutated in about 20% of lung cancer. The purpose of this study was to investigate the predictive significance for therapeutic response of K-ras mutations in advanced non-small cell lung cancer (NSCLC) patients. METHODS: Bronchial aspirate samples were assessed prior to platinum-based chemotherapy start in 39 patients with stage IIIb or IV NSCLC. K-ras mutations at codons 12 and 13 were analyzed by single strand conformation polymorphisam (SSCP) and allele specific oligonucleozide hybridisation of polymerase chain reaction (PCR) of the patient's DNA present in bronchial aspirate. After two cycles of chemotherapy the patients were subjected to response evaluation. RESULTS: Of 39 patients 10 (25.5%) demonstrated K-ras mutations, while 29 (74.4%) patients had not. There were no significant differences between these two groups of patients with respect to baseline patient caracteristics. Partial response to the therapy had 16 (41%), no changes 14 (36%), and progressive disease 9 (23%) patients. There was a tendency to higher response rate for patients without K-ras mutations versus those with mutations, but not statistically significant (p = 0.14). CONCLUSION: There was no significant predictive value for therapeutic response of K-ras mutations for advanced non-small cell lung cancer.

[Symptoms, physical findings and bronchial hypersensitivity in patients with bronchial asthma and normal spirometry].

BACKGROUND/AIM: The diagnosis of bronchial asthma, a chronic inflammatory disease of the respiratory tract, is made on the basis of anamnesis, pathologic auscultatory findings of the lungs, lung function disturbances, skin tests, as well as the basic indices of immunologic condition in bronchial trunk. The aim of the study was to find out correlation of objective indices of the disease and than relation with the symptoms in the patients with bronchial asthma. METHODS: The study included 60 young male non smokers with long lasting symptoms of bronchial asthma including shortness of breath, wheezing, hard breathing, nonproductive or productive cough, weakness and night hard breathing. There were no symptoms of respiratory infection over the past two months and lung radiography and spirometry were normal Based on the results of nonspecific bronchoprovocative test two groups of the patients were formed, group I (n=30) with positive histamine test (average value of the inhaled histamine concentration with FEV1 drop by 20% in regard with the initial value (PC20) = 2.99 +/- 0.51 mg/ml of histamine) and group II (n=30) with negative histamine test (PC20(a) = 14.58 +/- 6.34 mg/ml of histamine). RESULTS: The obtained spirometry results revealed a statistically significant difference in values of FEV1 between groups: I group--FEV1 3.2%; II group--EV1 = 101.8%; (p .05, Wilcoxon test), although all the FEV1 values were normal Regarding the presence of the most common symptoms there was not statistically significant difference between the groups (p>0.05, chi-square test). Pathologic auscultatory lung findings were found in 73.4% of the patients in the group I and 27.5% of the patients in the group II. There was statistically significant difference (p<0.05, chi-squared test). A positive correlation between the degree of hypersensitivity and lung physical findings was confirmed (p<0.05 Spearman's rho), but there was no correlation with FEV1 values. CONCLUSION: There is a correlation with lung pathologic physical findings, lower values of FEV1 (in a range of normal values) and the degree of nonspecific bronchial sensitivity as objective indices of activity of bronchial asthma. There is no correlation of these parameters with patient's symptoms as subjective indices of bronchial asthma.

[Lung involvement in systemic connective tissue diseases].

BACKGROUND/AIM: Systemic connective tissue diseases (SCTD) are chronic inflammatory autoimmune disorders of unknown cause that can involve different organs and systems. Their course and prognosis are different. All of them can, more or less, involve the respiratory sistem. The aim of this study was to find out the frequency of respiratory simptoms, lung function disorders, radiography and high-resolution computerized tomography (HRCT) abnormalities, and their correlation with the duration of the disease and the applied treatment. METHODS: In 47 non-randomised consecutive patients standard chest radiography, HRCT, and lung function tests were done. RESULTS: Hypoxemia was present in nine of the patients with respiratory simptoms (20%). In all of them chest radiography was normal. In five of these patients lung fibrosis was established using HRCT. Half of all the patients with SCTD had simptoms of lung involment. Lung function tests disorders of various degrees were found in 40% of the patients. The outcome and the degree of lung functin disorders were neither in correlation with the duration of SCTD nor with therapy used (p > 0.05 Spearmans Ro). CONCLUSION: Pulmonary fibrosis occures in about 10% of the patients with SCTD, and possibly not due to the applied treatment regimens. Hypoxemia could be a sing of existing pulmonary fibrosis in the absence of disorders on standard chest radiography.

[Influence of chemiotherapeutic protocol and neuroendocrine differentiation on metastatic non-small cell lung cancer treatment results].

BACKGROUND/AIM: In 40-50% of patients with non-small cell lung cancer (NSCLC) at the time of making a diagnosis, the disease is yet at IIIb and IV stage. Standard in the treatment of these patient is the application of systemic chemiotherapy based on CIS/Carboplatin preparations. The aim of this study was to determine the influence of two different chemiotherapeutic protocols and neuroendocrine differentiation on treatment response and survival in patients with metastatic NSCLC. METHODS: We examined 85 patients with metastatic NSCLC, of which 51 with stage IIIb, and 34 with stage IV of the disease. The histologic diagnosis of NSCLC was determined by tissue assays using hematoxylin eosin method. Neuroendocrine differentiation was determined by immunohistochemical analysis of neuron-specific enolase (NSE), chromogranin A, and synapthophysin expression using monoclonal mouse anti-human bodies (DAKO, Denmark). According to chemiotherapeutic protocol, the patients were randomly assigned into combined Taxol + Cisplatin group (Tax + Cis, n = 35), and Cyclophosphamide + Etoposide + Carboplatin group (CEP, n = 50). The treatment was conducted within 4-6 chemiotherapeutic cycles. The efficacy was assessed after the therapy regimen and median survival time was assessed after the randomization. RESULTS: A total of 31 (36.47%) patients had a favourable therapeutic response, both partial and complete response (54.2% in the Tax + Cis group and 24% in CEP group of patients, respectively, p < 0.001). The median survival time in both groups was 13.1 months (15.3 months in the Tax + Cis group and 10.6 months in the CEP group, respectively, p < 0.001). A one-year follow-up survival period was confirmed in 40% of patients (60% only in the Tax + Cis group). A total of 23 (27.05%) patients with metastatic NSCLC had neuroendocrine differentiation. The disease progression or stable disease was noted only in patient with NSCLC without neuroendocrine differentiation (n = 42, 67.7%, p < 0.001). The median survival time in patients with NSCLC and neuroendocrine differentiation was 14.8 months, without neuroendocrine differentiation 10.7 months (p < 0.001). The patients with NSCLC and neuroendocrine differentiation in the CEP group had a longer one-year follow-up survival period than patients in Tax + Cis group (p < 0.001). In Tax-Cis group of patients, there was no significant difference in one-year follow-up survival period with neuroendocrine differentiation. CONCLUSION: Better therapeutic response and longer median survival time in metastatic NSCLC was obtained using Tax + Cis as compared to CEP protocol. Similar effect was noted using CEP protocol in patients with NSCLC and neuroendocrine differentiation.

[Neuroendocrine differentiation as a survival prognostic factor in advanced non-small cell lung cancer].

BACKGROUND/AIM: Neuroendrocine lung tumors are histologically heterogenous group of cancers with different clinical progression. In non-small cell lung cancer (NSCLC) neuroendocrine differentiation exists in 10-30% of patients. The aim of this study was to determine the frequency and influence of neuroendocrine differentiation on survival of treated patients with advanced non-small cell lung cancer (NSCLC). METHODS: A clinical trial included 158 patients (74% males and 26% females), with the diagnosis of NSCLC, determined by histological verification. The patients were treated by combined chemo - and X-ray therapy in stage III (without pleural effusion) or chemotherapy only in stage III (with pleural effusion) and stage IV. Chemotherapy was conducted until progression of the disease, but no more than six cycles. When the progression had been noted in stage III (without pleural effusion), the treatment was continued with X-ray therapy. Neuron specific enolase, chromogranin A, as well as synapthophysin expression in tissue examples were determined by immunohistochemical analysis with monoclonal mouse anti-human-bodies. Survival was assessed within a year and two years follow-up examination. RESULTS: A total of 53 patients (34%) had NSCLC with neuroendocrine differentiation, confirmed rather in large cell lung cancer and lung adenocarcinoma (66.7% and 40%, respectively). Neuron specific enolase, chromogranin A and synapthophysin expression was noted in 45 (28.50/0), 34 (21.5%) and 33 (20.1%) patients, respectively. The one year and two years follow-up survival periods were confirmed in 39% and 17% of patients respectively. The median survival time in the patients with the neuroendocrine expression as compared to those without the expression was 15.6 vs 10.8 months; one year survival time with the expression compared to those without the expression achieved in 62% vs 27% of the patients, (< 0.001); a two-year survival time noted in 30% of the patients (p = 0.000). One year follow-up survival time was longer in the patients with neuron specific enolase and chromogranin A expression lung cancer (p < 0.001). Synapthophysin expression was not statisticaly significant for survival (p > 0.05). CONCLUSION: The results of this study suggest that almost the third of the advanced NSCLC has neuroendocrine differentiation. The median survival time of the treated patients is longer when the tumor is associated with neuron specific enolase and chromogranin A expression.

[Transitional type of Castleman's disease manifested as the POEMS syndrome]. / Kastlemanova bolest prelaznog tipa ispoljena kao POEMS sindrom.

BACKGROUND: Castleman's disease is an atypical lymphoproliferative disorder characterized by angiofollicular hyperplasia of lymph nodes. Histologically, it can be classified into a hyaline-vascular type, plasma-cell type, and transitional (mixed-cell) type, while clinically localized type has been classified as unicentric, or generalized (multicentric) form of the disease. CASE REPORT: This paper presents a 21 year old male patient with multicentric Castleman's disease, a transitional (mixed-cell) type. The disease was manifested by fever, generalized enlargement of peripheral lymph nodes, breast glands enlargement, hyperemia of the face, and weakness of the lower extremities. We found mediastinal lymphadenopathy, pleural and pericardial effusions, sensorimotor peripheral neuropathy and polyclonal hypergammaglobulinemia. The simultaneous presence of these manifestations of the disease (sensomotor peripheral neuropathy, lymphadenopathy, effusions, endocrinopathy, polyclonal gammaglobulinemia and skin changes) is indentified as POEMS syndrome. The diagnosis of Castleman's disease was based on the results of histopathologic analysis of mediastinal lymph node biopsies after thoracotomy. The patient was treated with corticosteroids (prednisone 80 mg daily for 2 weeks followed by 60 mg daily). A partial response was achieved after 4 months of treatment. CONCLUSION: A transitional type of multicentric Castleman's disease may be present itself as POEMS syndrome. The effect of corticosteroid therapy in this form of the disease is unpredictable.

[Allergic granulomatous angiitis]. / Alergijski angiitis i granulomatoza.

Allergic granulomatous angiitis (AGA)--Churg-Strauss syndrome, is a rare autoimmune disease characterized by three distinct clinical phases: prodromal, eosinophilic, and vasculitic, and most of respiratory symptoms and signs begin in the first two phases of the disease. Two female patients of different age, who fulfilled the diagnostic criteria for AGA, and were in different phases and with the different duration of the disease are presented. The first patient (24 years of age) was admitted to the hospital due to aggravation of asthma, heart failure, and polyneuropathy. The second one (45 years of age) was also hospitalized due to the worsening of asthma, polyneuropathy, and fever. Both were treated continuously with glucocorticoids. The older patient also received a total of six pulse doses of cyclophosphamide. Satisfactory response to such a treatment was achieved in both cases.

[Primary ciliary dyskinesia]. / Primarna cilijarna diskinezija.

In patients with chronic respiratory diseases that last since the early childhood, primary ciliary dyskinesia (PCD) needs to be considered. Four patients reviewed in this paper were with typical disease history and clinical picture, as well as clear ciliary axonema damage. Complete examination was performed in all the patients, including bronchoscopy with bronchography, and the examination of the biopsy samples of respiratory airways' mucous membrane, obtained by transmission electron microscope (TEM). In two of the patients spermatozoa were also examined by TEM. Large anatomic defects of airways were found in all the patients, but pulmonary function was normal (except in one case), representing one of PCD's significant characteristics. First two cases fulfilled the criteria for Kartagener's syndrome, which was initially sufficient for the diagnosis of PCD.

[Potential role of cholesterol in distinguishing malignant from benign pleural effusion]. / Moguci znacaj holesterola u razlikovanju malignog od nemalignog pleurnog izliva.

Cholesterol and carcinoembryonic antigen (CEA) levels in pleural effusion and sera, were measured in 199 patients with pleural effusions of various origins. Malignant cause was found in 93, and nonmalignant in 106 patients. Mean cholesterol level in sera of patient with malignant disease was 5.0 +/- 0.93 mmol/L, and in nonmalignant group 4.34 +/- 1.32 mmol/L. The difference was not statistically significant. Mean cholesterol level in nonmalignant pleural effusions was higher thAn those in malignant (2.51 +/- 1.23 mmol/L; and 2.28 +/- 1.06 mmol/L), but the difference was also not significant. Average pleural fluid/serum cholesterol ratio (Holl/S) in nonmalignant group was 0.61 +/- 0.32 and in malignant group 0.46 +/- 0.22. The difference between those mean values was significant. Higher ratio, at the cut off value of 0.5 was found in 79/106 and in 25/93 malignant patients. Calculated sensitivity was 75%, specificity 73%, positive predictive value 76%, negative predictive value 65% and accuracy 69%. Significant negative correlation between Holi/S and pleural fluid CEA was found (p < 0.05). It was assumed that pleural fluid/serum cholesterol ratio lower than 0.5 could be of great benefit, as an additional test in the differentiation of malignant from benign pleural effusion.

[Chylous effusions]. / Hilozni izlivi.

This paper presents 4 patients with chylothorax, and one patient with bilateral chylothorax and chyloperitoneum. The chylous effusions were of benign etiology, developed as a complication of miliary tuberculosis (1 patient), after L-2 vertebral body fracture (1 patient), and idiopathic (2 patients). The diagnosis was confirmed by the presence of chylomicrons and high content of triglycerides in the effusion, ranged 11.9-29.1 mmol/l. Lymphangiography showed multiple abnormalities of lymphatic system, the obstruction of ductus thoracicus, dilatation and convulsion of lymphatic channels, but the site of lymphatic leak was not detected. The treatment included an extended period of pleural and peritoneal drainage with total parenteral nutrition (1 patient), pleurodesis using Corynebacterium parvum (2 patients), and surgical partial parietal pleurectomy with continuous drainage (1 patient). The treatment was successful in all patients.

[Phonation bronchoscopy]. / Fluorescencijska bronhoskopija.

BACKGROUND: Fluorescence bronchoscopy is one of the methods of the early detection of lung cancer that involves the large airways. The method is based on the detection of the altered autofluorescence of malignantly transformed tissue, and confirmed by biopsy and histopathologic examination. METHOD: Fluorescence bronchoscopy was performed in 18 patients, mean age of 51.2 years (male n = 12, female n = 6) due to the suspected lung cancer. Fluorescence bronchoscopy was performed using the Xillix LIFE-Lung System, Vancouver, Canada. After conventional white-light bronchoscopy, the tracheobronchial tree was illuminated by blue light (442 nm) using helium-cadmium laser, and the results of autofluorescence were classified into three classes. Normal mucosa was of green fluorescence (Class I), abnormal mucosa was red or dark brown fluorescence (Class II and II), which was the indication for performing biopsy. RESULTS: Normal endoscopy findings were established in 15 patients by conventional bronchoscopy. In the same group, by fluorescence bronchoscopy, Class I of fluorescence (normal finding) was found in 9 patients, while Class II changes occurred in 6 patients. Histopathologic analysis of bronchial mucosa with Class II changes was performed detecting planocellular carcinoma in situ in one patient. Tumor-like changes were detected in 3 patients by conventional bronchoscopy, and were determined as Class III changes by fluorescence bronchoscopy. By the biopsy of these chages carcinoma was documented in 2 patients while in one patient metaplasia of epithelium and granulation tissue around aspirated foreign body was detected. CONCLUSION: Fluorescence bronchoscopy is one of the methods for detecting metaplasia, carcinoma in situ and cancerous changes of bronchial epithelium in the large airways. However, the high rate of falsely positive findings represents a limitation of this method.