Prognostic factors of recurrence and disease-free survival in radically resected pulmonary carcinoids: a real-world analysis.

Background: Pulmonary carcinoids (PCs) are rare neuroendocrine lung tumors which may recur, thus worsening their otherwise favorable overall prognosis. Aiming to identify patients at risk for recurrence, we examined parameters affecting disease-free survival (DFS). Methods: A retrospective single-center analysis of 82 consecutive patients undergoing curative intent resection for primary PC tumors between 2010 and 2019 was carried out. Kaplan-Meier method was utilized for survival analysis. Independent prognostic factors were determined using multivariable Cox and logistic regression. Results: During the observation period 82 patients, 48 females (58.5%) and 34 males (41.5%) were operated, representing 84 cases of PCs, 56 typical (TCs) (66.7%) and 28 atypical (ACs) (33.3%) carcinoids. Five-year overall survival was 87.5% and 84.7%, 5-year DFS 97.5% and 74.9% (P=0.012) for TCs and ACs, respectively. Recurrences occurred in one patient (1.8%) with TCs and five patients (17.9%) with ACs (P=0.014). Using multivariable Cox regression, tumor size (cm) remained as an independent prognostic factor for reduced DFS (P=0.018). In logistic regression, nodal involvement (P=0.043) and tumor size (cm) (P=0.023) were independently associated with higher risk of recurrence. Age, sex, smoking, location, and Ki-67 index were not independently associated with recurrence or DFS. Conclusions: Recurrence in PCs after complete resection is relatively rare. However, DFS is reduced in ACs compared to TCs. Tumor size (cm) and nodal involvement appear as the most important prognostic factors associated with recurrence in PCs, independent of histologic type.

Resection of a giant mediastinal liposarcoma by median sternotomy with vascular reconstruction-a case report.

Background: Primary mediastinal liposarcoma is a rare malignancy of mesenchymal origin with local aggressive biological behavior which is often diagnosed as an incidental finding without any symptoms. Chemoresistance and low radiosensitivity of these tumors favors surgical resection as the only option for radical treatment. The potential need for extended resections of adjacent structures is not uncommon and could be challenging. Only a limited number of cases with successful vascular reconstruction for the treatment of mediastinal liposarcoma has been reported so far. Case Description: A 69-year-old female patient was admitted to our department with dry cough and a huge mediastinal mass for further investigation and treatment. Based on the results of preoperative examinations a mediastinal liposarcoma was suspected. The tumor was resected through median sternal incision with resection of the pericardium with subsequent mesh replacement and "en bloc" resection of the innominate vein with vascular graft reconstruction. The postoperative course was uneventful. Six months follow-up after surgery showed no signs of local recurrence or dissemination. Conclusions: Extended resection and vascular reconstruction for the surgical treatment of primary mediastinal liposarcoma is often necessary to ensure adequate radicality and to reduce the risk of local recurrence. Therefore, these patients should be treated in high-volume centers with sufficient experience.

Lymph Node Log-Odds Ratio Accurately Defines Prognosis in Resectable Non-Small Cell Lung Cancer.

OBJECTIVES: The ratio of positive and resected lymph nodes (LN ratio) has been shown to be prognostic in non-small cell lung cancer (NSCLC). Contrary to the LN ratio, calculating the LN log-odds ratio (LN-LOR) additionally considers the total number of resected lymph nodes. We aim to evaluate LN-LOR between positive and resected lymph nodes as a prognostic factor in operable NSCLC. METHODS: Patients with NSCLC who underwent curative intent lobectomy treated at two high-volume centers were retrospectively studied. LN-LOR was dichotomized according to impact on OS and further combined with N descriptors and correlated with clinical variables and survival. RESULTS: 944 patients were included. Cut-off analysis revealed that an LN-LOR of -0.34 significantly discriminated patients according to OS (p < 0.001, chi-squared test 41.26). When combined with N1 and N2 descriptors, LN-LOR low risk (median OS not reached and 83 months) and LN-LOR high-risk patients (median OS 50 and 59 months) had similar survival irrespective of the anatomical location of the positive lymph nodes. Multivariable Cox regression analysis revealed that age (HR 1.02, 95% CI 1.001-1.032), sex (male, HR 1.65, 95% CI 1.25-2.19), histological subtype (HR 2.11, 95% CI 1.35-3.29), pathological stage (HR 1.23, 95% CI 1.01-1.45) and LN-LOR risk groups (low risk, HR 0.48, 95% CI 0.32-0.72) were independent prognostic factors for OS. CONCLUSIONS: This retrospective two-center analysis shows that LN-LOR is significantly associated with OS in resectable NSCLC and might better reflect the biological behavior of the disease, regardless of anatomical lymph node locations. This finding may additionally support the value of extensive LN dissection.

Multimodal Treatment of Malignant Pleural Mesothelioma: Real-World Experience with 112 Patients.

Malignant pleural mesothelioma (MPM) is a rare pleural cancer associated with asbestos exposure. According to current evidence, the combination of chemotherapy, surgery and radiotherapy improves patients' survival. However, the optimal sequence and weighting of the respective treatment modalities is unclear. In anticipation of the upcoming results of the MARS-2 trial, we sought to determine the relative impact of the respective treatment modalities on complications and overall survival in our own consecutive institutional series of 112 patients. Fifty-seven patients (51%) underwent multimodality therapy with curative intent, while 55 patients (49%) were treated with palliative intent. The median overall survival (OS) of the entire cohort was 16.9 months (95% CI: 13.4−20.4) after diagnosis; 5-year survival was 29% for patients who underwent lung-preserving surgery. In univariate analysis, surgical treatment (p < 0.001), multimodality therapy (p < 0.001), epithelioid subtype (p < 0.001), early tumor stage (p = 0.02) and the absence of arterial hypertension (p = 0.034) were found to be prognostic factors for OS. In multivariate analysis, epithelioid subtype was associated with a survival benefit, whereas the occurrence of complications was associated with worse OS. Multimodality therapy including surgery significantly prolonged the OS of MPM patients compared with multimodal therapy without surgery.

Treatment of ALK-rearranged non-small-cell lung cancer with brigatinib as second or later lines: real-world observations from a single institution.

The second-generation ALK tyrosine kinase inhibitor brigatinib has recently been approved in the European Union for use after crizotinib treatment in patients with EML4-ALK-rearranged lung cancer. In the current study, brigatinib was investigated as second-line or later-line treatment in 35 patients who had developed resistance to crizotinib, ceritinib, or alectinib. Most patients (68.6%) received brigatinib as second or third line (range: second to 12th line). In the total cohort, complete and partial responses were obtained for 9.1 and 75.8%, respectively. Overall median progression-free survival was 9.9 months, whereas the largest treatment cohort (brigatinib after crizotinib failure) showed a median progression-free survival of 8.4 months. Fifty-four percent of patients with baseline brain metastases responded to brigatinib treatment. Brigatinib was highly effective after crizotinib and ceritinib failure. Six patients had received alectinib as monotherapy, second-line, or third line before brigatinib; of these, four experienced partial responses and two progressed responses. Brigatinib treatment was well tolerated.

Endomyocardial miR-133a levels correlate with myocardial inflammation, improved left ventricular function, and clinical outcome in patients with inflammatory cardiomyopathy.

AIMS: Inflammatory heart disease represents an important cause of chronic dilated cardiomyopathy (DCM). Predicting the clinical course of patients with inflammatory cardiomyopathy (iCMP) is difficult, and the prognostic value of current biological markers remains controversial. We tested whether expression of selected microRNAs in endomyocardial biopsies (EMBs) is related to LV functional recovery and clinical events in iCMP patients. METHODS AND RESULTS: EMBs were obtained from patients with iCMP (n = 76) and non-inflammatory DCM (n = 22). A set of six microRNAs implicated in inflammation (miR-155 and miR-146b), heart failure (miR-21 and miR-133a), and endothelial cell (miR-126) and skeletal muscle function (miR-206) was pre-defined. Endomyocardial expression of miR-155 and miR-133a, as quantified by reverse transcription-PCR (RT-PCR), was up-regulated in patients with iCMP as compared with patients with DCM. Levels of miR-133a (R = 0.73, P < 0.01) and miR-155 (R = 0.63, P < 0.01) correlated with inflammatory cell count on EMBs from patients with iCMP. Patients with iCMP and preserved LV function at study entry demonstrated higher expression of miR-133a than patients with reduced LV function. Also, increased expression of miR-133a was associated with less fibrosis and myocyte necrosis on EMB, and LV functional recovery during a mean follow-up of 3.1 years. Importantly, patients with iCMP and miR-133a levels in the upper tertile showed longer survival free of death, malignant arrhythmias, and hospitalizations for heart failure. CONCLUSION: The present study demonstrates that miR-133a levels correlate with macrophage infiltration, cardiac injury, improved LV function, and clinical outcome in patients with iCMP. miR-133a may serve as a potential novel biomarker and therapeutic target in human iCMP.

Rare Cause of Recurrent Pneumonia in the Left Lower Lobe.

A 52-year-old male patient was hospitalized in our department with the diagnosis of recurrent pneumonia in the left lower lobe. The patient reported possible aspiration of plastic material about 10 years ago, although repeated bronchoscopies in an external hospital had not revealed any foreign body. A multiply folded 8-cm filing strip for a ring folder was detected and successfully removed together with granulation tissue by means of rigid bronchoscopy.

Serum concentration of integrin-linked kinase in malignant pleural mesothelioma and after asbestos exposure.

OBJECTIVES: Integrin-linked kinase (ILK) is an intracellular protein implicated in chronic inflammation and neoplastic transformation. In a recently accomplished pilot study, we showed that ILK can be detected in the serum of patients with benign and malignant chest diseases, including malignant pleural mesothelioma (MPM). Interestingly, average serum ILK concentrations were 10 times higher in MPM patients when compared with the rest of the study population, and a diagnostic test solely based on serum ILK concentration could discriminate between MPM and non-MPM with considerable accuracy. This study aimed to investigate whether serum ILK concentration could also be used to discriminate between MPM and asbestos exposure only. METHODS: Using a self-developed sandwich enzyme-linked immunosorbent assay, we measured serum ILK concentrations in 101 MPM patients, and 96 asbestos-exposed, but healthy insulation workers. Seventy-three MPM patients had an epitheloid subtype (72.3%), and 42 had a Stage I or II disease (41.6%). RESULTS: When compared with asbestos-exposed individuals, MPM patients of all clinical stages had significantly higher (mean ± standard deviation, median) serum ILK concentrations (10.7 ± 13.6, median 7 ng/ml vs 3.1 ± 4.6, median 1.4 ng/ml; P < 0.001). Among MPM patients, the serum ILK concentration was significantly higher at advanced disease stages III + IV than at early stages I + II (13.7 ± 15.9, median 8.5 ng/ml vs 6.7 ± 7.8, median 3.5 ng/ml; P = 0.02). Using serum ILK to discriminate between MPM patients and asbestos-exposed individuals yielded an area under the curve of 0.69 (95% confidence interval 0.63-0.76). The corresponding sensitivity and specificity for a cut-off of 4.49 ng/ml ILK are 61.4 and 80.2%, respectively. CONCLUSIONS: These data show significant differences between MPM patients and asbestos-exposed but healthy individuals concerning their serum ILK concentration. Furthermore, since ILK levels are increased in advanced MPM stages in comparison with early MPM stages, we suggest evaluating its potential use as a marker of disease progression in MPM.

Detection of integrin-linked kinase in the serum of patients with malignant pleural mesothelioma.

OBJECTIVE: Integrin-linked kinase, which is relevant to neoplastic transformation, is highly expressed in malignant pleural mesothelioma. Recently, detection of integrin-linked kinase in serum of patients with ovarian cancer has been reported. This study asks whether integrin-linked kinase can also be detected in serum of patients with malignant pleural mesothelioma and whether serum level has diagnostic or prognostic relevance for that disease. METHODS: A sandwich enzyme-linked immunosorbent assay was designed to detect integrin-linked kinase and applied to serum samples from 46 patients with malignant pleural mesothelioma, 98 patients with other malignant chest disease, and 23 patients with benign chest disease. Integrin-linked kinase serum concentration and clinical data were correlated statistically. RESULTS: Median serum integrin-linked kinase concentration was significantly higher in malignant pleural mesothelioma (8.89 ng/mL) than in other malignant chest disease (0.66 ng/mL) or benign chest disease (0.78 ng/mL, P < .001). There was no relevant correlation of serum integrin-linked kinase with cell lysis parameters (R(2) < 0.1). Serum integrin-linked kinase concentration greater than 2.48 ng/mL had diagnostic sensitivity of 80%, specificity of 95%, positive predictive value of 85.7%, negative predictive value of 92.7%, and overall accuracy of 91% for distinction between malignant pleural mesothelioma and other diseases. Serum integrin-linked kinase concentration in malignant pleural mesothelioma was independent of histologic subtype or asbestos exposure. There was no statistically significant impact of serum integrin-linked kinase concentration on prognosis. CONCLUSIONS: Integrin-linked kinase can be detected in serum of patients with malignant pleural mesothelioma and may be a diagnostic marker for the disease.

Integrin-linked kinase, phosphorylated AKT and the prognosis of malignant pleural mesothelioma.

OBJECTIVE: Integrin-linked kinase (ILK) is a cell membrane-bound molecule implicated in the metastatic progression of many tumour types. It phosphorylates the downstream target AKT (phosphorylated AKT, pAKT), and, by doing this, it activates anti-apoptotic pathways. We have recently shown ILK expression in malignant pleural mesothelioma (MPM). To determine whether ILK expression in MPM is connected with pAKT expression, and whether ILK and pAKT expression have any influence on the patient's prognosis, we correlated ILK and pAKT expression, as assessed by immunohistochemistry, with disease-related survival in a retrospective cohort of 80 MPM patients. MATERIAL AND METHODS: The paraffin specimens of 80 MPM cases treated from 1990 to 2006 (52 surgical cases, 28 conservative cases) have been retrieved from the archive. The median (range) patients' age was 62 (28-83 years) years; the male-to-female ratio was 3:1. Fifty percent of the patients had an epitheloid subtype. The samples have been stained with anti-ILK as well as with anti-pAKT and scored by two independent pathologists. Intensity of ILK and pAKT expression has been correlated with disease-related survival. RESULTS: In total, 73 of 80 (91%) MPM samples expressed ILK; 65 of 74 (88%) MPM samples expressed pAKT. Comparing the 5-year disease-related survival according to ILK or pAKT expression, no statistically significant difference could be found between ILK and pAKT expressing or non-expressing patients. However, in the subgroup of conservatively treated MPM patients, those with strong ILK expression had a longer 5-year disease-related survival (p < 0.0001). In total, the only prognostic factor across all ILK, pAKT and therapy subgroups was the histological subtype (p = 0.01). The prognostic significance of the histological subtype has been confirmed in multivariate analysis (p = 0.005). CONCLUSION: The expression of ILK in MPM is connected with the expression of the downstream target pAKT, but neither ILK nor pAKT expression has a measurable influence on the patient's prognosis, except for certain subgroups of MPM. However, to shed light on the true prognostic impact of ILK and pAKT expression in MPM, prospective trials are needed.

Concordance between epidermal growth factor receptor status in primary non-small-cell lung cancer and metastases: a post-mortem study.

OBJECTIVES: Epidermal growth factor receptor (EGFR)-targeted therapies are a valid therapeutic option for advanced non-small-cell lung cancer (NSCLC), but unequivocally recognised predictive factors for therapeutic response are lacking. However, intrinsic resistance might occur due to loss of EGFR expression during the course of the disease or its treatment. METHODS: Paraffin-embedded tissue from cases with metastatic NSCLC obtained at autopsy was retrieved from our archive. Specimens of primary tumour (n=39; 64% adenocarcinoma) and of all corresponding metastases (n=70) were immunohistochemically stained for EGFR expression. Two observers independently scored staining intensity and evaluated the percentage of positively stained cells. Identical staining intensity and < or = 10% difference in number of stained cells were defined as perfect concordance; and one-increment difference in staining intensity and less than 30% difference in number of stained cells were defined as good concordance. RESULTS: Twenty-seven out of 39 primary tumours (69%) were EGFR-positive on immunohistochemistry (IHC), with 12/27 (44%) of positive tumours exhibiting intense or moderate EGFR expression. The median number of EGFR-expressing cells in primary tumours was 50% (range 0-100%). Overall Spearman's rank correlations for staining intensity and percentage of positively stained cells between primary tumours and paired metastases were 0.78 (p<0.001) and 0.60 (p<0.001), respectively. Perfect concordance was observed in 51% (20/39) and good concordance in 18% (7/39) of corresponding pairs, respectively, whereas 9/12 metastases showing discordant staining with their corresponding primary tumours had lacked EGFR expression. CONCLUSIONS: In most NSCLCs, EGFR status of primary tumours correlates with EGFR status of corresponding metastases. Hence, loss of EGFR expression is unlikely during disease progression, local or non-EGFR-targeting systemic treatment.

Immunoreactivity of integrin-linked kinase in primary non-small-cell lung cancer and survival after curative resection.

OBJECTIVE: Increased immunoreactivity of integrin-linked kinase (ILK) in the primary tumour is an adverse prognostic factor in a variety of preclinical and clinical models of human cancer. Here, we investigate the relationship between ILK immunoreactivity in primary non-small-cell lung cancer (NSCLC) and the survival after curative lung resection. METHODS: Tumour specimens of 138 radically operated NSCLC patients have been retrieved from the pathology archive, mounted in tissue microarrays and immunostained against ILK. The immunoreactivity against ILK has been graded in a semi-quantitative manner (negative or 1-3 positive) by two observers blinded to any patient data, and correlated to the survival data. RESULTS: In total, 88 of 138 tumours (64%) showed an ILK immunoreactivity, which varied significantly between various histological subtypes as it ranged from 46% (squamous cell carcinoma (SCC)) to 79% (adenocarcinoma) (p=0.019). The 5-year cancer-related survival of ILK-positive SCC patients was at 42 + or - 10% versus 72 + or - 9% significantly shorter than in ILK-negative patients (p=0.011). In addition, the recurrence-free survival (RFS) of ILK-positive SCC patients was also significantly shorter than of ILK-negative patients (38 + or - 10% vs 60 + or - 10%) (p=0.005). In multivariate analysis, ILK expression was a significant prognostic factor for RFS in squamous cell carcinoma (p=0.018), but not in adenocarcinoma or in the rare histology group. CONCLUSIONS: Primary NSCLC tumours show a variable ILK immunoreactivity, dependent on the histological subtype. In SCC, ILK immunoreactivity is a significantly adverse prognostic factor.

Primary synovial sarcoma of the lung as an incidental finding.

Synovial sarcoma of the lung (SSL) is a very rare but aggressive primary lung tumor. Due to its unusual histological features, it can easily be misdiagnosed, if only small biopsies of the tumor are investigated. Here, we review two recent cases of SSL diagnosed and treated in our institution. The first case is a 37-year-old male with a round nodule in the right lower lobe; he underwent a lobectomy. Histologically, the nodule resembled a biphasic tumor. Cytogenetic analysis revealed a translocation t (X; 18), and the diagnosis of primary SSL could be established. The patient is alive and disease-free since 45 months following surgery. The second case is a 41-year-old male with a cystic lesion in the right lower lobe, removed by video-assisted thoracic surgery (VATS) segmentectomy. In the tumor tissue, spindle cell-rich and cystic structures could be found, together with epithelial elements. Because the tumor contained also a translocation t (X; 18), it could be diagnosed as monophasic SSL. The patient is alive and disease-free since 11 months. Since rare diseases of the lung may present as subtle and focal changes, complete removal of suspect pulmonary lesions is always advisable.

Reactivity of integrin-linked kinase in human mesothelial cell proliferation.

Integrin-linked kinase (ILK) is a protein kinase that links integrins and growth factors to a range of signalling pathways. ILK expression and activity are increased in a variety of human cancers. However, little is known regarding the role of ILK in malignant pleural mesothelioma (MPM). In this study, we assessed the expression of ILK in samples of human MPM, and compared it with the expression of epidermal growth factor receptor (EGFR). Thirty-four samples of human malignant mesothelioma were stained with a polyclonal antibody against ILK. Two independent observers evaluated the morphological pattern and intensity of staining. The findings have been compared with the patient's characteristics. Most MPM and mesothelial cell proliferation samples (87.9%) showed cytoplasmic ILK staining of varying intensity. Normal mesothelial cells and normal lung parenchyma did not stain for ILK at all. Conversely, the percentage of positive EGFR staining was somewhat lower (75.8%). The ILK-positive patients were significantly older than the ILK-negative patients. Here we report for the first time that ILK is indeed expressed in malignant mesothelioma. For further validation of a causal association between ILK and neoplastic mesothelial transformation, these immunohistochemical results should be supplemented with clinical and molecular biological data.

Establishment of vessel-like structures in long-term three-dimensional tissue culture of myocardium: an electron microscopy study.

To assess whether long-term three-dimensional (3D) tissue culture of myocardium enables the in vitro establishment of vessel-like structures, myocardial tissue from newborn mice was incubated under conditions of 3D culture for at least 3 weeks, and studied by phase-contrast microscopy, conventional histology, immunohistochemistry, and electron microscopy. During 3 weeks of culture, a mean 24.35 +/- 3.74% of all aggregates contracted spontaneously. The contracting aggregates displayed a tissue-like architecture with small basal and apical zones, and a large central zone. The basal and apical zone consisted of immature mesenchymal cells. The underlying shell of the aggregate contained many cardiomyocytes. Vessel-like structures were found concentrated within the aggregates. Immunohistochemistry showed that up to 15% of the cells in the central zone of the aggregate were positive for the endothelial-specific BS-I lectin. Vessel-like structures were formed by cells, which often showed intracytoplasmatic lumena. Surrounding the neocapillaries, structures of a rudimentary basal membrane could be detected. A 3D culture of myocardial tissue permits the establishment of a rudimentary capillary network within the tissue aggregates, which presumably guarantees a sufficient tissue perfusion up to a maximum aggregate diameter of approximately 900 microm.