Refractory systemic lupus erythematosus with chylous effusion successfully treated with sirolimus: a case report and literature review.

Chylous effusion is a rare manifestation of systemic lupus erythematosus (SLE). When it does occur in SLE, it is generally well treated with standard pharmacologic or surgical measures. We present a decade of management in a case of SLE with lung affliction and development of refractory bilateral chylous effusion and pulmonary arterial hypertension (PAH). In the first years, the patient was treated under a Sjogren syndrome diagnose. After few years, her respiratory condition worsened due to chylous effusion and PAH. Immunosuppression therapy (methylprednisolone) was reintroduced, and vasodilator therapy commenced. With this, her cardiac function remained stable, but respiratory function continuously worsened despite several therapy trials with different combinations of immunosuppressant (glucocorticoids, resochin, cyclophosphamide and mycophenolate mofetil). On top of pleural effusion worsening, the patient developed ascites and severe hypoalbuminaemia. Even though albumin loss was stabilized with monthly octreotide applications, the patient remained respiratory insufficient and in need of continuous oxygen therapy. At that point, we decided to introduce sirolimus on top of glucocorticoids and mycophenolate mofetil therapy. Her clinical status, radiological finding, and lung function gradually improved and she became respiratory sufficient at rest. The patient remains in our follow-up and has been stable on given therapy for over 3 years despite overcoming a severe COVID-19 pneumonia in 2021. This case adds to the body of evidence of sirolimus effectiveness in patients with refractory systemic lupus and is, to our best knowledge, the first case to report its successful application in a patient with SLE and refractory chylous effusion.

Early onset of nontuberculous mycobacterial pulmonary disease contributes to the lethal outcome in lung transplant recipients: report of two cases and review of the literature.

Lung transplant (LuTx) recipients represent a population at risk of nontuberculous mycobacterial pulmonary disease (NTM-PD). Yet the risk factors, the timing of NTM-PD after transplantation, and the association with allograft dysfunction all remain poorly defined. We report 2 cases of early-onset NTM-PD and review the literature, focusing on NTM-PD in LuTx recipients not colonized with NTM prior to transplantation. In addition, we summarize the main characteristics and differences between early- and late-onset disease.

Detection of an EGFR mutation in cytological specimens of lung adenocarcinoma.

OBJECTIVE: Epidermal growth factor receptors (EGFR) mutation status is crucial for the prediction of a tumour response to treatment with EGFR tyrosine kinase (EGFR-TK) inhibitors. The aim of the study was to establish a protocol for the detection of EGFR-activating somatic mutations on cytological samples collected using a standard bronchoscopy procedure and to determine the frequency of EGFR mutations among pre-selected Croatian patients with non-small cell lung cancer (NSCLC) of an adenocarcinoma histological subtype. METHODS: A total of 177 cytological samples were collected from the patients diagnosed with NSCLC. DNA was isolated from the cytological material recovered from the fixed and stained slides. EGFR mutations were analysed using the polymerase chain reaction (PCR)- mediated Sanger sequencing method. RESULTS: Out of 177 collected samples, EGFR mutation analyses were successfully performed on 167 samples (94.4%); 77 (46.1%) of these were from male and 90 (53.9%) from female patients. EGFR mutations/deletions were found in 33 (19.8%) of the tested patients; exon 19 deletions in 17 (10.2%) and point mutations of exon 21 in 16 (9.6%) patients. CONCLUSION: The PCR-mediated Sanger sequencing method was found to be reproducible and reliable. Cytological samples can be used successfully to determine the EGFR mutation status in NSCLC patients providing information for targeted therapy at an early stage of the disease.

Ki67 index is an independent prognostic factor in epithelioid but not in non-epithelioid malignant pleural mesothelioma: a multicenter study.

BACKGROUND: Estimating the prognosis in malignant pleural mesothelioma (MPM) remains challenging. Thus, the prognostic relevance of Ki67 was studied in MPM. METHODS: Ki67 index was determined in a test cohort of 187 cases from three centres. The percentage of Ki67-positive tumour cells was correlated with clinical variables and overall survival (OS). The prognostic power of Ki67 index was compared with other prognostic factors and re-evaluated in an independent cohort (n=98). RESULTS: Patients with Ki67 higher than median (>15%) had significantly (P<0.001) shorter median OS (7.5 months) than those with low Ki67 (19.1 months). After multivariate survival analyses, Ki67 proved to be-beside histology and treatment-an independent prognostic marker in MPM (hazard ratio (HR): 2.1, P<0.001). Interestingly, Ki67 was prognostic exclusively in epithelioid (P<0.001) but not in non-epithelioid subtype. Furthermore, Ki67 index was significantly lower in post-chemotherapy samples when compared with chemo-naive cases. The prognostic power was comparable to other recently published prognostic factors (CRP, fibrinogen, neutrophil-to-leukocyte ratio (NLR) and nuclear grading score) and was recapitulated in the validation cohort (P=0.048). CONCLUSION: This multicentre study demonstrates that Ki67 is an independent and reproducible prognostic factor in epithelioid but not in non-epithelioid MPM and suggests that induction chemotherapy decreases the proliferative capacity of MPM.

A randomized phase II study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel in second-line therapy of advanced non-small cell lung cancer (GALAXY-1).

BACKGROUND: This trial was designed to evaluate the activity and safety of ganetespib in combination with docetaxel in advanced non-small cell lung cancer (NSCLC) and to identify patient populations most likely to benefit from the combination. PATIENTS AND METHODS: Patients with one prior systemic therapy for advanced disease were eligible. Docetaxel (75 mg/m(2) on day 1) was administered alone or with ganetespib (150 mg/m(2) on days 1 and 15) every 3 weeks. The primary end points were progression-free survival (PFS) in two subgroups of the adenocarcinoma population: patients with elevated lactate dehydrogenase (eLDH) and mutated KRAS (mKRAS). RESULTS: Of 385 patients enrolled, 381 were treated. Early in the trial, increased hemoptysis and lack of efficacy were observed in nonadenocarcinoma patients (n = 71); therefore, only patients with adenocarcinoma histology were subsequently enrolled. Neutropenia was the most common grade ≥3 adverse event: 41% in the combination arm versus 42% in docetaxel alone. There was no improvement in PFS for the combination arm in the eLDH (N = 114, adjusted hazard ratio (HR) = 0.77, P = 0.1134) or mKRAS (N = 89, adjusted HR = 1.11, P = 0.3384) subgroups. In the intent-to-treat adenocarcinoma population, there was a trend in favor of the combination, with PFS (N = 253, adjusted HR = 0.82, P = 0.0784) and overall survival (OS) (adjusted HR = 0.84, P = 0.1139). Exploratory analyses showed significant benefit of the ganetespib combination in the prespecified subgroup of adenocarcinoma patients diagnosed with advanced disease >6 months before study entry (N = 177): PFS (adjusted HR = 0.74, P = 0.0417); OS (adjusted HR = 0.69, P = 0.0191). CONCLUSION: Advanced lung adenocarcinoma patients treated with ganetespib in combination with docetaxel had an acceptable safety profile. While the study's primary end points were not met, significant prolongation of PFS and OS was observed in patients >6 months from diagnosis of advanced disease, a subgroup chosen as the target population for the phase III study.

SUCCESSFUL TREATMENT OF PULMONARY AND LYMPHATIC MANIFESTATIONS OF LYMPHANGIOLEIOMYOMATOSIS WITH SIROLIMUS.

Lymphangioleiomyomatosis (LAM) is a rare, progressive, diffuse cystic lung disease predominantly affecting women of child bearing age. Recently treatment with sirolimus was shown to stabilize lung function decline and improve quality of life in patients with LAM. We treated three premenopausal women suffering from LAM manifesting as diffuse cystic lung disease, chylous effusions, and lymphangioleioyomas with sirolimus (1-3 mg a day; sirolimus trough levels 2.9-8.5 ng/ml). All three patients had a remarkable response to sirolimus, with resolution of effusions, improvement in lung function and shrinking of abdominal lymphangioleiomyomas. Our case series further complements the literature in that sirolimus is a safe and effective treatment for LAM and its lymphatic manifestations.

[Molecular diagnostics of lung cancer]. / A tüdorák molekuláris diagnosztikája.

Development of the target therapies of lung cancer was a rapid process which fundamentally changed the pathological diagnosis as well. Furthermore, molecular pathology became essential part of the routine diagnostics of lung cancer. These changes generated several practical problems and in underdeveloped countries or in those with reimbursement problems have been combined with further challenges. The central and eastern region of Europe are characterized by similar problems in this respect which promoted the foundation of NSCLC Working Group to provide up to date protocols or guidelines. This present paper is a summary of the molecular pathology and target therapy guidelines written with the notion that it has to be upgraded continuously according to the development of the field.

Circulating fibrinogen is a prognostic and predictive biomarker in malignant pleural mesothelioma.

BACKGROUND: To investigate the clinical utility of pretreatment plasma fibrinogen levels in malignant pleural mesothelioma (MPM) patients. METHODS: A retrospective multicenter study was performed in histologically proven MPM patients. All fibrinogen levels were measured at the time of diagnosis and clinical data were retrospectively collected after approval of the corresponding ethics committees. RESULTS: In total, 176 MPM patients (mean age: 63.5 years ± 10.4 years, 38 females and 138 males) were analysed. Most patients (n=154, 87.5%) had elevated (≥ 390 mg dl(-1)) plasma fibrinogen levels. When patients were grouped by median fibrinogen, patients with low level (≤ 627 mg dl(-1)) had significantly longer overall survival (OS) (19.1 months, confidence interval (CI) 14.5-23.7 months) when compared with those with high level (OS 8.5; CI 6.2-10.7 months). In multivariate survival analyses, fibrinogen was found to be an independent prognostic factor (hazard ratio 1.81, CI 1.23-2.65). Most interestingly, fibrinogen (cutoff 75th percentile per 750 mg dl(-1)) proved to be a predictive biomarker indicating treatment benefit achieved by surgery within multimodality therapy (interaction term: P=0.034). Accordingly, only patients below the 75th percentile benefit from surgery within multimodality therapy (31.3 vs 5.3 months OS). CONCLUSIONS: Fibrinogen is a novel independent prognostic biomarker in MPM. Most importantly, fibrinogen predicted treatment benefit achieved by surgery within multimodality therapy.

Lung Abscess: An Early Complication of Lung Transplantation in a Patient with Cystic Fibrosis.

A 22-year-old woman with cystic fibrosis (CF) developed lung abscess, as a rare complication caused by multidrug-resistant (MDR) Acinetobacter baumannii infection, after lung transplantation (LT). After 6 months of long-term antibiotic therapy, the abscess was successfully eliminated. In reviewed published literature, no previous report was found describing this kind of complication caused by MDR A. baumannii in post-LT patient with CF. In our experience, lung abscess in LT recipients with CF can be successfully treated with prolonged antibiotic therapy.

Microbiological criteria in non-tuberculous mycobacteria pulmonary disease: a tool for diagnosis and epidemiology.

SETTING: The value of microbiological criteria in diagnosing non-tuberculous mycobacteria pulmonary disease (NTM-PD) and monitoring its epidemiology is unknown. OBJECTIVES: To correlate the rate of NTM-PD based on microbiological criteria (American Thoracic Society/Infectious Diseases Society of America [ATS/IDSA] or stricter microbiological criteria) compared with the full ATS/IDSA criteria, to assess the positive predictive value (PPV) of different microbiological criteria in predicting NTM-PD, and to evaluate the clinical relevance of different NTM species. DESIGN: Retrospective study of all patients with pulmonary NTM isolates in Croatia during an 8-year period. NTM species were divided into low, intermediate and high clinical relevance groups for additional analyses. RESULTS: Good correlation between both microbiological and full ATS/IDSA criteria was observed. The PPV of stricter and ATS/IDSA microbiological criteria was respectively 93.3% and 59.8%. The usefulness of microbiological criteria varied between groups. ATS/IDSA microbiological criteria had a PPV of 89.8% in the high relevance group, while in the intermediate relevance group, the PPV of stricter and ATS/IDSA microbiological criteria was respectively 94.3% and 63.4%. CONCLUSIONS: Microbiological criteria are useful in detecting NTM-PD, allowing laboratory-based monitoring. Stricter criteria should be used for species of low clinical relevance, and less stringent criteria for species of high relevance in the local setting.

Persistent endothelial dysfunction turns the frequent exacerbator COPD from respiratory disorder into a progressive pulmonary and systemic vascular disease.

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in developed countries of the world, while the main cause of mortality and morbidity in COPD patients are acute exacerbations and cardiovascular diseases. With regard to the frequency of exacerbations the phenotype "frequent exacerbators" has been defined, which, besides a more severe clinical course and a significantly higher total mortality, is also characterised by an elevated risk of cardiovascular mortality, as some indicators show us. It is notable that during the exacerbation of COPD, next to other changes, a significant aggravation of endothelial function occurs while the ED and COPD relationship seems very complex and is still in greater part unknown. Making the pathophysiological link between the frequency of exacerbations of COPD and ED could change our understanding of the character of this type of pulmonary disease. We hypothesize that frequent exacerbator COPD is a progressive and generalised vascular disease, not only an isolated respiratory disorder with ancillary systemic effects. Our opinion is that differences in COPD phenotype do not only determine the clinical picture but could also be of key importance in defining the progressivity of the disease. ED, which in these patients persists between frequent exacerbations, could be the main cause of the progression of pulmonary disease, and not only of the high cardiovascular risk of these patients. Such a persistent ED in FE COPD, with its pro-inflammatory, vasoconstrictory and prothrombotic mechanisms, could contemporaneously induce new exacerbations of COPD, the progression of pulmonary changes and the development of systemic atherosclerosis as a main extrapulmonary manifestation in these patients. Such a model defines endothelium as a common soil of progressive pulmonary and cardiovascular changes in FE COPD. It can fully explain all the elements of the clinical course and co-morbidity in FE COPD, for which we still do not have adequate explanation.

Psychosocial characteristics of patients with bronchial asthma and coronary disease: similarities and differences.

The authors compare two groups of subjects: patients with bronchial asthma and those with coronary disease, with regard to some social characteristics, abilities and perception of factors which they conceive are important in the etiology of their disease. Data were obtained by means of a questionnaire based on a known calibrated scale. A group of 100 patients with bronchial asthma and a group of 102 patients with coronary disease were examined. The significance of the difference was tested by chi 2, t-test, Wilcoxon's test and multivariate discriminative analysis. The results showed statistically significant differences between the patients with bronchial asthma and those with coronary disease in some social and psychological characteristics and also with regard to perception of potential etiological factors of their disease. However, no difference was found in life style and habits between the coronary and asthmatic patients.

Physician/patient differences in the perception of asthma: impact on everyday life and level of the asthma control in Croatia.

The aim of the study was to compare physician/patient differences in the perception of asthma. The data were obtained by questionnaires from 156 physicians and 148 asthmatics in four urban regions in Croatia. On a "bad day", 62% of physicians and 16% of patients perceived respiratory symptoms with statistically significant difference. The patients described asthma impact in terms of reduced daily activities and experienced emotional problems. Asthma was estimated as controlled in 28% of adults and 49% of children, nevertheless, 45% of adults and 22% of children reported respiratory symptoms. The patients seem to be satisfied with asthma control that does not correspond to suppression of symptoms, whereas physicians neglect patients' emotional problems and asthma impact on everyday life. The differences in the perception of asthma may reflect differences in beliefs about health. Physicians see health as an absence of symptoms, whereas patients regard being healthy as "being able".

Perception of ecological factors in asthmatic and coronary patients.

The aim of the study was to determine whether an examined group of asthmatic patients differ significantly from a control group of coronary patients with regard to perception of two groups of etiological factors and their interaction: a) ecological factors, and b) habits and behavior of the patients. The study included 100 patients with bronchial asthma and 102 with coronary disease. A questionnaire was used to obtain data on ecological factors in the living environment of the patients and information on habits and behavior. The questionnaire was structured according to the specific needs of the study, and as a starting point known, calibrated, psychometric scales were used. Asthmatic and coronary patients did not differ with regard to their place of residence, i.e. the same number lived in the town and village, in similar ecological environments, and they also did not differ with regard to life style and habits. The study indicated statistically significant differences between asthmatic and coronary patients in their perception of several ecological and other risk factors. The asthmatic patients significantly more frequently perceived harmful ecological factors in their environment and regarded them significant for the occurrence of their disease. The coronary patients perceived their unhealthy habits and behavior as the causal factors of their disease.

Chronic lead poisoning, renal function and immune response.

The aim of this study was to investigate possible correlations between chronic, recurrent lead poisoning, renal function and immune response. The study involved 74 patients with a history of at least one lead poisoning. Fifty-three patients were occupationally poisoned, and 21 were poisoned accidentally after consumption of alcohol beverages or food from lead glazed pottery. In all patients glomerular filtration rate (GFR) was determined by measuring creatinine and DTPA clearances, and T- and B-lymphocytes were assessed as indicators of cellular and humoral immunity. A significant negative correlation was found between the number of past lead poisonings indicating increased lead body burden, and both creatinine and DTPA clearances. There was a significant positive correlation between the number of poisonings and the percentage of B-lymphocytes (r = 0.31; P < 0.05), and no correlation at all with the T-lymphocyte count. Our results show that chronic, recurrent lead poisoning with a consequently increasing lead body burden can cause an impairment in renal function and a concomitant stimulation of humoral immunity.

Contribution of lead poisoning to renal impairment.

The late effects of lead on kidney function and blood pressure were studied in 38 persons occupationally poisoned in the past and in 23 workers exposed to lead. Parameters evaluated in all subjects were: creatinine clearance, hippuran renal flow, blood lead, erythrocyte protoporphyrin, aminolevulinic acid dehydratase, and blood pressure. Out of 11 combined variables, four significant factors were identified by factor analysis. The results showed the presence of the delayed adverse effect of previous occupational lead poisoning on kidney function and blood pressure. This phenomenon is a complex interplay of lead poisoning in the past, overall duration of lead exposure, and age as a major confounding variable related to aging process of the kidneys.

Meso-2,3-dimercaptosuccinic acid in the treatment of occupationally exposed lead workers.

The aim of this study was to evaluate the efficacy of meso-2,3-dimercaptosuccinic acid (DMSA) treatment in workers with increased lead absorption and no overt symptoms of lead poisoning. Seven occupationally lead exposed male workers with blood lead concentrations (PbB) exceeding 50 micrograms/100 ml and a positive calcium disodium ethylenediaminetetraacetate (EDTA) lead mobilization test were treated with DMSA for 19 days. Individual doses were 700 mg DMSA, three times a day from day one to five, and twice a day from day six to 19. The treatment intensified urinary lead excretion, most rapidly during the first five days. The increased elimination was followed by a decline of mean PbB to 15% of the pretreatment values. However, 15 days after the treatment, the PbB concentrations rebounded, yet kept below the baseline values and did not exceed 40 micrograms/100 ml. After repeated EDTA lead mobilization test, urine lead was 23-68% of that before DMSA treatment. It can be concluded that DMSA can effectively reduce chelatable lead in occupationally exposed workers.

Geographical distribution and clinical relevance of non-tuberculous mycobacteria in Croatia.

SETTING: The clinical relevance of non-tuberculous mycobacteria (NTM) in Croatia is unknown. OBJECTIVE: To estimate the isolation rate of NTM, record geographical differences and assess the burden of pulmonary NTM disease in Croatia. DESIGN: Nationwide retrospective cohort study of all Croatian residents with NTM isolated by culture in the period from 2006 to 2010. Microbiological criteria of the American Thoracic Society were used to establish a laboratory-based case definition of possible and probable NTM disease. RESULTS: Of 1187 individuals with pulmonary NTM isolates, 8.6% met the possible and 5.5% met the probable disease criteria. We estimated an annual incidence of probable pulmonary NTM disease of 0.23 per 100,000 population. This estimated annual incidence was 0.35/100,000 in the coastal region and 0.17/100,000 in the continental region. Species distribution differed between coastal and continental Croatia. NTM isolation frequency increased over the study period. CONCLUSION: Geography plays an important role in NTM species distribution and possible disease. The overall burden of NTM pulmonary disease in Croatia is still low compared to that of tuberculosis, but it is higher in the coastal region compared to the continental region.

Individual variation in response to lead exposure: a dilemma for the occupational health physician.

Subclinical lead poisoning with no clinical symptoms is a dilemma for the occupational health physician. He is supposed to assess when and how to treat workers at risk mainly by the results of biological monitoring. The aim of this study was to demonstrate different responses of biological indices in 50 lead-exposed workers who have been working in the same plant of lead pigment production factory. Twenty-one had normal, that is, permissible blood lead concentrations (PbB), erythrocyte protoporphyrin (EP), and aminolevulinic acid activity (ALAD) measured during regular periodic examinations (group 1). No differences between two measurements were found, although they were continuously working with lead. In 18 of the 50 workers (group 2), PbB and EP concentrations increased, whereas ALAD activity decreased: those parameters improved after a 3- to 6-month cessation of lead exposure. Seven of the 50 workers also had altered values of biological indices, but their condition improved spontaneously without cessation of lead exposure (group 3), while in the remaining four workers, elevated concentrations of biological indices did not change during the observation period. The reasons for such discrepancies and indications for chelation therapy are discussed.