Efficacy and safety of nintedanib and docetaxel in patients with previously treated lung non-squamous non-small cell lung cancer: a multicenter retrospective real-world analysis.

BACKGROUND: The standard first-line systemic treatment for patients with non-oncogene addicted advanced nonsquamous non-small cell lung cancer (NSCLC) is immunotherapy with immune checkpoint inhibitors (ICI) and/or chemotherapy (ChT). Therapy after failing ICI +/- ChT remains an open question, and docetaxel plus nintedanib represent a valid second line option. PATIENTS AND METHODS: A multicenter retrospective trial of real-life treatment patterns and outcomes of patients with advanced lung adenocarcinoma treated with docetaxel plus nintedanib after the failure of ICI and/or ChT was performed. Patients from 2 Slovenian and 1 Croatian oncological center treated between June 2014 and August 2022 were enrolled. We assessed objective response (ORR), disease control rate (DCR), median progression free survival (PFS), median overall survival (OS), and safety profile of treatment. RESULTS: There were 96 patients included in the analysis, with ORR of 18.8%, DCR of 57.3%, median PFS of 3.0 months (95% CI: 3.0-5.0 months), and a median OS of 8.0 months (95% CI: 7.0-10.0 months). The majority of patients (n = 47,49%) received docetaxel plus nintedanib as third-line therapy. The ORR for this subset of patients was 19.1%, with a DCR of 57.4%. The highest response rate was observed in patients who received second-line docetaxel plus nintedanib after first-line combination of ChT-ICI therapy (n = 24), with an ORR of 29.2% and DCR of 66.7% and median PFS of 4.0 months (95% CI: 3.0-8.0 months). Fifty-three patients (55.2%) experienced adverse events (AEs), most frequently gastrointestinal; diarrhea (n = 29, 30.2%), and increased liver enzyme levels (n = 17, 17.7%). CONCLUSIONS: The combination of docetaxel and nintedanib can be considered an effective therapy option with an acceptable toxicity profile for patients with advanced NSCLC after the failure of ICI +/- ChT.

Personality and Stigma in Lung Cancer Patients.

BACKGROUND: Stigma in lung cancer has been associated with diagnostic and treatment delay and with poor outcomes. Personality has impact on the perception of someone's life situation and interacts with psychosocial variables and coping strategies. The vulnerability to stigma is still under-researched. The aim of this study was to investigate this vulnerability by examining the associations between stigma and personality dimensions (i.e., temperament and character traits). SUBJECTS AND METHODS: Seventy six (76) inpatients of the two teaching hospitals with the diagnosis of non-small-cell lung cancer were consecutively included in the study. Patients were assessed with self-reporting scales: Cataldo Lung Cancer Stigma Scale (CLCSS) and Temperament and Character Inventory (TCI). Sociodemographic and clinical data were also collected. RESULTS: Personality dimensions Self-directedness and Persistence showed to be significant predictors of stigma in the linear regression (R=0.519; F=3.104; P=0.007). Stigma and personality dimensions were not associated with age, gender, tumor stage and smoking status. CONCLUSION: Stigma is associated with particular character (i.e., Self-directedness) and temperament (i.e., Persistence) dimensions. Given the negative clinical outcomes of stigma in lung cancer patients, personality should be taken into account during screening and treatment planning phases.

Neutrophil-to-lymphocyte ratio can predict outcome in extensive-stage small cell lung cancer.

Background The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) were analyzed in various carcinomas and their potential prognostic significance was determined. The objective of present study was to determine the correlation between these parameters and the survival of patients with small cell lung cancer (SCLC), since very few studies have been published on this type of carcinoma. Patients and methods One hundred and forty patients diagnosed with SCLC at University Hospital Center Zagreb, between 2012 and 2016 were retrospectively analyzed. Extensive-stage disease (ED) was verified in 80 patients and limited-stage disease (LD) in 60 patients. We analyzed the potential prognostic significance of various laboratory parameters, including NLR, PLR, and LMR, measured before the start of treatment. Results Disease extension, response to therapy, chest irradiation and prophylactic cranial irradiation (PCI), as well as hemoglobin, monocyte count, C-reactive protein (CRP), and lactate dehydrogenase (LDH) showed a prognostic significance in all patients. When we analyzed the patients separately, depending on the disease extension, we found that only skin metastases as well as LDH and NLR values, regardless of the cut-off value, had a prognostic significance in ED. Meanwhile, the ECOG performance status, chest irradiation, PCI, and hemoglobin and creatinine values had a prognostic significance in LD. Conclusions NLR calculated before the start of the treatment had a prognostic significance for ED, while PLR and LMR had no prognostic significance in any of the analyzed groups of patients.

Prognostic value of lactates in relation to gas analysis and acid-base status in patients with pulmonary embolism.

AIM: To assess the prognostic value of lactate level for mortality in patients with pulmonary embolism (PE) and Pulmonary Embolism Severity Index (PESI) I-III and its independence of gas-analysis parameters and acid-base status. METHODS: This prospective observational study was conducted at the University Clinical Hospital Mostar from 2013 to 2017. On the first day after PE diagnosis, 1.5 mL of arterial blood was collected from 103 patients with PE. Partial pressure of oxygen in arterial blood, partial pressure of carbon dioxide in arterial blood, blood pH value, concentration of bicarbonates in arterial blood (HCO3-), base deficit, and oxygen saturation were analyzed. Lactate levels were assessed using blood samples taken from the cubital vein. Logistic regression analysis was used to assess the predictive value of gas-analysis variables, lactate level, PESI score, age, and sex for in-hospital death due to PE. RESULTS: The mortality in the group of PE patients was 19.1% (18 of 103 patients). Lactate level was an independent predictor of mortality (P=0.002, odds ratio 0.06). HCO3- was also found to be a significant predictor (P=0.022, odds ratio 2.4). Lactates were independent of other variables. Other gas-analysis parameters were not significant predictors of mortality. CONCLUSION: In PE patients at low-intermediate risk of mortality (PESI I-III), lactate level was associated with a short-term mortality, independently of other gas-analytic parameters. Oxford Centre for Evidence-based Medicine level of evidence: 2.

Erlotinib for coexisting typical bronchial carcinoid and advanced lung adenocarcinoma: does the epidermal growth factor receptor mutation status matter?

Adenocarcinoma (AC) is the most common type of primary pulmonary malignancy. Lung carcinoid, however, is a rare neuroendocrine tumor. Their coexistence is extremely uncommon. We report the unique case of synchronous advanced lung AC of the right upper lobe (stage IIIB) and typical endobronchial carcinoid tumor in the contralateral lower lobe in a 49-year-old white female who had never smoked. PET-computed tomography scan revealed a fluorine-18-fluorodeoxyglucose-avid AC lesion, whereas the carcinoid tumor was fluorine-18-fluorodeoxyglucose occult. After two lines of platinum-based combination chemotherapies and radiotherapy, the AC progressed, and oral tyrosine kinase inhibitor therapy with erlotinib was initiated in third line. On erlotinib, the AC remained stable for 50 months until disease progression, whereas the carcinoid completely regressed. Molecular testing of the rebronchoscopied AC revealed an exon 19 deletion mutation in the epidermal growth factor receptor (EGFR) gene, whereas the carcinoid was retrospectively EGFR mutation negative. The patient eventually succumbed to ileus caused by intra-abdominal spread of disease, surviving a remarkable 80 months with good performance status throughout most of the follow-up period. To the best of our knowledge, this is the first reported case of synchronous primary lung cancers with different EGFR mutation status, describing an unexpected response of an EGFR-wild-type carcinoid to third-line erlotinib.

Trends in incidence of lung cancer in Croatia from 2001 to 2013: gender and regional differences.

AIM: To provide an overview of the lung cancer incidence trends in the City of Zagreb (Zagreb), Split-Dalmatia County (SDC), and Croatia in the period from 2001 to 2013. METHOD: Incidence data were obtained from the Croatian National Cancer Registry. For calculating incidence rates per 100 000 population, we used population estimates for the period 2001-2013 from the Croatian Bureau of Statistics. Age-standardized rates of lung cancer incidence were calculated by the direct standardization method using the European Standard Population. To describe incidence trends, we used joinpoint regression analysis. RESULTS: Joinpoint analysis showed a statistically significant decrease in lung cancer incidence in men in all regions, with an annual percentage change (APC) of -2.2% for Croatia, 1.9% for Zagreb, and -2.0% for SDC. In women, joinpoint analysis showed a statistically significant increase in the incidence for Croatia, with APC of 1.4%, a statistically significant increase of 1.0% for Zagreb, and no significant change in trend for SDC. In both genders, joinpoint analysis showed a significant decrease in age-standardized incidence rates of lung cancer, with APC of -1.3% for Croatia, -1.1% for Zagreb, and -1.6% for SDC. CONCLUSION: There was an increase in female lung cancer incidence rate and a decrease in male lung cancer incidence rate in Croatia in 2001-20013 period, with similar patterns observed in all the investigated regions. These results highlight the importance of smoking prevention and cessation policies, especially among women and young people.

Synchronous Adie's syndrome and type 1 antineuronal nuclear antibody (anti-Hu)-related paraneoplastic neurological syndromes as predictors of complete response in limited-stage small-cell lung cancer: A case report.

Adie's syndrome (AS) and paraneoplastic sensorimotor neuropathy with cerebellar ataxia (PSN CA) are extremely rare, rapidly progressive, autoimmune diseases associated with the development of antibodies against neuronal-specific Hu proteins that are abnormally expressed in small-cell lung cancer (SCLC). We herein present the unique case of a 55-year-old obese woman, previous heavy smoker, who, during treatment with standard cisplatin-etoposide chemotherapy for limited-stage SCLC, developed simultaneous AS and worsening symptoms consistent with PSN CA that led to significant neurological disability and severe axonal electrophysiological pattern on nerve conduction studies. Serology confirmed the presence of low-titre type 1 antineuronal nuclear antibodies (ANNA-1), previously referred to as anti-Hu antibodies. Following plasmapheresis, immunosuppressive therapy and physical rehabilitation, the neurological symptoms progressively improved. The tumour completely regressed, with no recurrence detected on subsequent radiological examinations. The aim of this case was to highlight the importance of a multidisciplinary team approach for early recognition and rapid treatment of paraneoplastic neurological syndromes (PNS) as key to achieving significant recovery and marked improvement of the neurological deficit. This report extends the literature by confirming earlier studies showing that the presence of serum ANNA-1 in SCLC, an aggressive type of pulmonary carcinoma that is challenging to treat, may portend a more favourable prognosis and response to chemotherapy. Thus, patients with SCLC and new-onset neurological symptoms should be tested for ANNA-1. The role of a multimodality approach to treating PNS is also emphasized.

The case of synchronous occurrence of primary adenocarcinoma and squamous cell carcinoma in the same lobe of the lung.

Synchronous occurrence of multiple lung cancers in the same lobe of the lung is very rare. Most of the tumors diagnosed in this way have the same histologic type. With imaging methods it is difficult to determine if the multiple lung lesions present hematogenous spread of lung cancer (or cancer from other origin) or these lesions present the second primary lung cancer. We report a rare and unusual case of synchronous occurrence of primary adenocarcinoma and squamous cell carcinoma in the same lobe of the lung. Our case demonstrates that in case of synchronous occurrence of multiple lung lesions each lesion should be sampled and histologic type of every lesion should be determined so the further treatment can be planned accordingly.

Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio help identify patients with lung cancer, but do not differentiate between lung cancer subtypes.

AIM: To assess the diagnostic value of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in lung cancer (LC). We compared the ratios between healthy participants and all LC patients, as well patients with different pathohistological LC subtypes. METHODS: We retrieved the data on neutrophil, lymphocyte, and platelet levels in 449 patients with different pathohistological LC subtypes (non-small cell LC, small-cell LC, atypical or metastatic LC, neuroendocrine, and sarcomatoid carcinoma) and 47 healthy controls. NLR and PLR were calculated by dividing the absolute number of neutrophils or platelets with the absolute number of lymphocytes. RESULTS: There were significant differences in both NLR and PLR (P<0.001) between all LC patients and the control group, but there were no differences between patients with different LC subtypes. Reciever operating characteristics analysis for NLR showed the optimal cut-off value of 2.71, with a sensitivity of 77.05% and specificity of 87.23%. The optimal cut-off value for PLR was 182.31, with a sensitivity of 51.09% and specificity of 91.49%. CONCLUSION: The results showed that the NLR and PLR may have added value in the early diagnosis of LC, but further research is needed to confirm these results.

SOCIODEMOGRAPHIC CHARACTERISTICS INFLUENCE PAIN PERCEPTION IN NON-SMALL CELL LUNG CANCER PATIENTS.

BACKGROUND: Lung cancer is the most common malignant disease in men and the third most common in women worldwide. Pain in these patients is a leading and debilitating symptom, among others. OBJECTIVES: The aim of this research was to determine the relationship between the sociodemographic characteristics and pain perception, as measured by visual analogue scale for pain, in patients with non-small cell lung cancer. METHODS: This observational, single centre study included both a cross-sectional and prospective cohort design. RESULTS: Forty-one patients with a median age of 61 years (range 56-68) were included. This study showed that subjective perception of pain is related to age and place of residence. Younger patients ( ≤ 60 years old, p=0.026) and those residing in cities (p=0.03 1) reported feeling worse pain. Age was independently and statistically associated with the relative relief of pain after analgesic therapy (Wald=5.914; ss=1; p=0.015). CONCLUSION: Age, lifestyle, place of residence, and mentality should be considered when evaluating pain percep- tion in patients suffering from chronic pain related to malignant disease in order to provide the best possible medical treat- ment with the goal of improving quality of life.

Smoking behaviors and lung cancer epidemiology: a cohort study.

BACKGROUND: Lung cancer is the most common cancer in the world. According to the latest available data, in the year 2012 Croatia was among 20 countries with the highest incidence of lung cancer. Although tobacco smoking is a proven cause of lung cancer, recent data show that more than one quarter of adult inhabitants of Croatia are everyday smokers. The purpose of this study was to present epidemiology and treatment modalities of lung cancer in the Department for mediastinal tumors, Clinic for lung diseases Jordanovac, and to make a comparison between the available data from Croatia and the rest of the world. SUBJECTS AND METHODS: The study cohort included 212 newly diagnosed lung cancer patients who had referred to our Department from January 2012 until December 2012. Features such as age, gender, cytology and histology of the tumor, stage at diagnosis and applied therapy were evaluated respectively. RESULTS: Approximately two-thirds of all newly diagnosed lung cancers occurred in men. Out of the study cohort, 12.3% were diagnosed with small cell lung cancer (SCLC) and 87.7% were diagnosed with non-small cell lung cancer (NSCLC). The majority of the patients diagnosed with NSCLC had adenocarcinoma (47.9%), followed by squamous cell carcinoma (33.9%) and large cell carcinoma (15%). Only a small number of patients diagnosed and treated for lung cancer in our Department had never smoked tobacco. The majority of those patients were women and the most common histological type found was adenocarcinoma. CONCLUSION: The number of patients who had potentially operable disease at presentation was around 10%. That is why, in most cases, therapeutic options were confined to palliative chemotherapy or radiotherapy. Attention should be directed to an early detection of lung cancer patients, which could provide better treatment options and improve overall survival.

[Pharmacotherapy of severe asthma]. / Lijecenje teske astme.

Severe asthma affects 5-10% of the asthma population. Exact pathophysiology of severe asthma mechanisams is complex and not fully understood. Cellular inflammation of the airways with neutrophils is a characteristic feature and is considered relevant to the pathogenesis of the disease, but all components of the airway wall have been reported to be thickened in severe asthma with or without cellular inflammation. Clinically it usually involves women with severe non-allergic asthma, late onset of asthma patients and aspirin induced asthma. Severe asthma rarely affects allergic asthma patients. Although majority of adults with mild or moderate asthma can be treated by inhaled glucocorticoids either alone or in combination with beta 2 agonists bronchodilators, patients with severe asthma require high doses of inhaled glucocorticoids or continuous oral use of glucocorticoids. Treatment of severe asthma should be started with high doses of inhaled steroids, 2000 microg of beclomethasone or its equivalents in addition to long acting beta 2 agonists, leukotriene receptor antagonists, theophylline and long acting anticholinergic drugs. Due to significant short-term and longterm oral glucocorticoids side effects it is essential to emphasize the importance of alternative therapies in severe asthma: treatment with omalizumab, macrolide antibiotics, tumor necrosis factor alpha inhibitors, cytokine receptors inhibitors and bronchial thermoplasty. Although there is a significant improvement in the treatment of severe asthma, the challenge remains to determine therapeutic strategy for appropriate phenotype in view of the heterogeneity of severe asthma.

Temperament and character and quality of life in lung cancer patients.

AIM: The aim of this study was to test whether personality variables are independently associated with health-related quality of life (HRQOL) in lung cancer patients. METHODS: In a cross-sectional study, 86 non-small cell lung cancer patients and 73 healthy subjects matched for gender and age were assessed with the Temperament and Character Inventory. In the patient group QOL was assessed with EORTC QLQ-C30. We used multiple linear regressions to determine whether personality dimensions predict HRQOL. Data on tumor stage, patient age, education and marital status were also collected. RESULTS: Lung cancer patients differed from healthy controls in the temperament dimension of persistence and the character dimension of self-transcendence. The temperament dimension of harm avoidance and the character dimension of cooperativeness were significant predictors of QOL functional scales and global health status. CONCLUSIONS: In lung cancer patients, the personality dimensions of harm avoidance and cooperativeness showed associations with most QOL dimensions. Personality factors are relevant for patients' QOL perception and should be included in cancer patients' QOL assessment.

Changing pattern of sensitization in Croatia to aeroallergens in adult population referring to allergy clinic during a period of 15 years.

Published data indicate that during the last decades there is a possible change in the pattern of sensitization to different aeroallergens in adult population with atopy. The aim of this investigation was based on the hypothesis that during last 15 years there has been a change in the structure of prevalence of sensitization to different aeroallergens in adult population of Zagreb and its surroundings with atopy. Medical records from outpatient allergy clinic were screened for the period 1991-2004. We included 794 patients during years 1991-1994, 814 patients during years 1995-1999, and 969 patients during years 2000-2004. Following data were analyzed: age, gender, education level, residence, referral diagnosis, dominant symptoms, results of skin-prick test (SPT), total and specific serum immunoglobulin E. As risk factors for allergic sensitization we determined the decade of birth (p < 0.0001), male gender (p < 0.008), level of education (p < 0.0001), and place of residence (p < 0.05). Proportion of sensitized individuals to pollen significantly increased from the period 1991-1994 towards 2000-2004 (p < 0.001 for the trend) with a significant increase in the proportion of sensitized individuals to weed pollen (p = 0.002 for the trend) while the proportion of sensitized to other two groups of pollen (grasses and trees) was not significantly different. A significant increase in the proportion of sensitized individuals was determined for sensitization to ragweed pollen (p = 0.004 for the trend), and to mugwort (p = 0.005 for the trend). Despite all its limitations primarily based on the selection bias the results of this study are conclusive about the significant change in the proportion of sensitization to different aeroallergens and different pollen groups and individual pollen species during the investigated 15-year time interval.

Altered iron metabolism, inflammation, transferrin receptors, and ferritin expression in non-small-cell lung cancer.

The involvement of iron and inflammation parameters on overall survival in non-small-cell lung cancer (NSCLC) patients was studied. Furthermore, transferrin receptors 1 (TfR1) and ferritin expression in tumor tissue, tumor stroma, and normal lung tissue were analyzed. Iron metabolism and inflammation parameters were determined by automated laboratory measurements at the time of diagnosis. TfR1 and ferritin expression were determined by immuno-histochemical methods. About 50% of patients survived 12 months only. At the time of diagnosis more than half of the patients had anemia and significantly elevated serum ferritin. Iron content of serum ferritin (ICF) was below the reference values in 90% of patients. Furthermore, ICF showed positive correlation with iron metabolic parameters and survival but negative correlation with serum ferritin and ESR. The expression of TfR1 and ferritin in tumor cells was observed in 88% or 62% of patients, respectively. Tumor stroma was TfR1 negative and sporadically ferritin positive. Tumor tissue ferritin expression showed negative correlation with serum iron and hematokrit (Ht), and positive correlation with ferritin, erythrocyte sedimentation rate (ESR), alpha-1 globulin, and alpha-2 globulin. Positive correlation was found between TfR1 expression in tumor tissue and alpha-globulin. The correlation between TfR1/ferritin expression in tumor tissue and ICF or survival was not observed. Therefore, we conclude that elevated serum ferritin in sera of NSCLC patients is the result of inflammation and oxidative stress rather than body iron overload. Higher expression of ferritin in tumor tissue may be the consequence of iron deficiency or local toxicity induced by environmental factors.

[Guidelines for diagnosis and management of asthma in adults of the Croatian Respiratory Society]. / Smjernice Hrvatskoga pulmoloskog drustva za dijagnosticiranje i lijecenje astme u odraslih.

The global use of guidelines for proper diagnosis and management of asthma was worldwide aimed toward obtaining effective control of asthma. Until now, the most often used guidelines in Croatia were the ones issued by the Global Initiative for Asthma (GINA). Their implementation significantly improved and uniformed the diagnosis and management of asthma at different levels of the national health system. The obtained level of knowledge has enabled the making of local guidelines which acknowledge economic, cultural and even traditional specificities of Croatia. It was supposed that Croatian medical professionals would more effectively use guidelines they actively supported to prepare and which were appropriated to local work environment and medicines available. Therefore, based on current scientific evidence, the Croatian Respiratory Society has prepared Croatian Guidelines for Diagnosis and Management of Asthma in Adults purposed for wide use among Croatian doctors and other health professionals.

Montelukast in asthma treatment in Croatia.

The aim of this study was to determine the efficacy and safety of montelukast added to previous medication in the treatment of a mild and moderate asthma. Data were obtained via questionnaires given to the physicians and given further to their patients. Patients were divided in two groups, first followed 4 weeks (612 patients) and second followed 8 weeks (91 patients). We found out that there was a significant improvement in FEV1 (forced expiratory volume in first second) and general condition of patients and decreased number of salbutamol inhalations after using montelukast. In the second group of patients we find out the same significant improvement in FEV1, general condition and decrease in salbutamol inhalations after 4 weeks of using montelukast and further improvement after the next month of therapy. We conclude that montelukast is an efficient drug with little side effects and with a good compliance. Montelukast managed to achieve a good asthma control; therefore it has a significant place in asthma therapy.

Primary pulmonary botryomycosis: case report.

A case is presented of pulmonary botryomycosis in a 61-year-old man with a massive right-side pulmonary infiltrate which looked like a tumor (on X-ray). Microscopic examination of a transbronchial biopsy specimen revealed chronic suppurative inflammation, which did not regress despite intensive antibiotic therapy for a period of two months. Histological analysis of specimens taken during surgery for hemoptysis revealed pulmonary botryomycosis. The disease was diagnosed on the basis of characteristic eosinophilic granules in which the bacteria are surrounded by protein material (Splendore-Hoeppli phenomenon). Pulmonary actinomycosis was excluded. The case demonstrates that pulmonary botryomycosis can have the appearance of a mass which resembles pulmonary carcinoma on X-ray, and may also be mistaken for pulmonary actinomycosis. For this reason, pulmonary botryomycosis, although rare, should be excluded during differential diagnosis of hemoptysis or pulmonary infiltrates.