Correction: Circulating and tumor-associated caspase-4: a novel diagnostic and prognostic biomarker for non-small cell lung cancer.

[This corrects the article DOI: 10.18632/oncotarget.25049.].

Circulating and tumor-associated caspase-4: a novel diagnostic and prognostic biomarker for non-small cell lung cancer.

Late diagnosis limits therapeutic options and survival rate of non-small cell lung cancer (NSCLC) patients. Therefore the identification of biomarkers represents an emerging medical need. A highly sensitive and specific test was developed to identify/quantify a novel/selective diagnostic biomarker for NSCLC patients, caspase-4. This test was validated by using i) plasma from 125 NSCLC patients and 79 healthy (non-pathological) subjects, ii) plasma from 139 smokers and iii) from 70 chronic-obstructive pulmonary disease (COPD) patients. Caspase-4 quantification was also assessed in the lung tumor mass of 98 paired NSCLC patients compared to 10 non-tumor lung tissues (i.e. tuberculosis). Circulating caspase-4 was detected in both healthy and NSCLC patients; however at different range values: 2.603-3.372 ng/ml for NSCLC patients (95% CI) compared to 0.3994-0.6219 ng/ml for healthy subjects (95% CI). The sensitivity of the test ranged from 97.07% to 100%; the specificity was 88.1% with a positive predictive value of 92.54%, accuracy of 95.19% and AUC of 0.971. Smokers (95% CI, 0.3947-0.6197 ng/ml) and COPD patients (95% CI, 1.703-2.995 ng/ml) showed intermediate values of circulating caspase-4. Tissue levels of caspase-4 in the tumor mass showed that 72 (72.7%) out of 99 patients were positive. More importantly, higher levels (cut-off value = 0.307 ng/ml) of caspase-4 in the tumor mass were associated to reduced overall survival (median 0.92 years) compared to NSCLC patients with lower levels (median 3.02 years). We report for the first time caspase-4 as a novel diagnostic and prognostic biomarker, opening new therapeutic perspectives for NSCLC patients.

Influence of antiviral therapy on the liver stiffness in chronic HBV hepatitis.

PURPOSE: The aim of this study was to evaluate the effects of antiviral therapy on liver stiffness measurement (LSM). METHODS: Two hundred HBV patients were enrolled from four hospital centers in southern Italy; median age was 50.7 (25-75) males were 68%; 171 patients underwent to liver biopsy and 200 patients had LSM at baseline and 189 at the end of follow-up. One hundred and forty-nine patients were treated with nucleos(t)ide analogs, while 51 patients were untreated. The cutoffs of the LSM, related to the fibrosis stages, were as follows: non-advanced fibrosis ≤ 8.1 kPa and advanced fibrosis ≥ 8.2 Kpa. RESULTS: At baseline, the median value of LSM was 14.1 kPa for advanced fibrosis/cirrhosis and 6.9 kPa for non-advanced fibrosis. LSM was performed at 24 months from the start of therapy. The treated patients (68% received Entecavir and 32% Tenofovir) showed a decrease in liver stiffness measurement of 1.5 kPa (p < 0.001) in non-advanced fibrosis and of 6 kPa (p < 0.001) in advanced fibrosis/cirrhosis. In the patients not undergoing antiviral treatment, no statistically significant change of the LSM was observed (p = 0.26). A logistic binary regression model showed that the only independent factor associated with a significant change in the LSM was the liver stiffness value at baseline (odd ratio 2.855; 95% CI 1.456-5.788; (p = 0.007). CONCLUSION: Long-term antiviral therapy induced a significant reduction of liver stiffness measurement and this result may be related to the reduction of liver fibrosis.

Sarcoidosis and colon cancer: a possible association.

Sarcoidosis is a multisystem inflammatory disease characterized by non-caseating granulomas which mainly affect the pulmonary lymphatic system and lungs; although any organs can be interested. The association between sarcoidosis and cancer is still controversial, but many studies demonstrated an increased risk of cancer in patients with sarcoidosis, whereas few cases of sarcoidosis occurring after cancer have been reported. This report outlines and describes clinical, biologic and radiologic features of 3 patients with a history of surgical treatment and adjuvant chemotherapy for colon cancer, followed by a diagnosis of sarcoidosis some years later. The history of cancer and the lymph nodes positivity found through PET scan induced us to hypothesize a relapsing cancer disease. However, this hypothesis was not confirmed by the lymph nodes biopsy, which is the core method of diagnosis of sarcoidosis. (Sarcoidosis Vasc Diffuse Lung Dis 2018; 35: 376-380).

Pre-surgical bronchoscopic treatment for typical endobronchial carcinoids.

Carcinoids are tumors that originate from diffuse neuroendocrine system cells (APUD cells) and represent 1-2% of all pulmonary tumors. Although surgical resection remains the mainstay of treatment, bronchoscopic radical resection of typical carcinoids in selected cases exhibiting endoluminal growth and small implant base has also been explored. Bronchoscopic removal of endobronchial lesions may also reduce the risk of post-obstructive infections and improve pulmonary function, allowing the patient to undergo surgery in better clinical and respiratory state. In this paper we have evaluated the impact on surgical planning and outcome of preoperative bronchoscopic resection in treatment of endobronchial typical carcinoids. Our observations further support the role of bronchoscopic treatment before surgery in endobronchial typical carcinoids.

Role of FDG-PET scan in staging of pulmonary epithelioid hemangioendothelioma.

In this report we describe a case of pulmonary epithelioid hemangioendothelioma (PEH) in a young woman. The neoplasm manifested with dry cough, chest pain, finger clubbing, and multiple bilateral pulmonary nodules on chest x-ray and computed tomographic (CT) scan. She underwent thoracoscopy, and the histological features of the lung biopsies were initially interpreted as consistent with a not-well-defined interstitial lung disease. Our patient was clinically and radiologically stable over a period of four years, after which the disease progressed to involve not only the lung but also mediastinal lymph nodes, liver and bone. Fiberoptic bronchoscopy showed subtotal occlusion of the right middle and lower lobe bronchi. The histologic examination of bronchial biopsies revealed a poorly differentiated neoplasm immunohistochemically positive for vimentin and vascular markers CD31, CD34 and Factor VIII. A diagnosis of malignant hemangioendothelioma was made. Positron emission tomography (PET) is more sensitive than CT scan and bone scintigraphy in detecting PEH metastases. Furthermore, 18-fluorodeoxyglucose (FDG) uptake seems to be related to the grade of malignancy of PEH lesions. Therefore, we suggest that FDG-PET should be included in the staging system and follow-up of PEH.

Primary paraganglioma of the lung: a case report.

INTRODUCTION: Primary paraganglioma of the lung is a rare tumor of which few cases are reported in literature. Both solitary and diffuse primary pulmonary paragangliomas are described. The solitary form of this tumor is rare. CASE PRESENTATION: We report the case of a 63-year-old Caucasian man with cough, intermittent palpitations and dyspnea. A contrast-enhanced computed tomography scan of his chest revealed a rounded, high-density lesion with irregular profiles measuring 24mm in diameter in the middle lobe. The lesion was suggestive of malignancy. Fine-needle aspiration cytology was performed. The results of the cytological tests were positive for malignant cells. Surgical resection was the choice of treatment. The results of the biochemical tests and postoperative histological examination allowed a definitive diagnosis: primary pulmonary paraganglioma. CONCLUSIONS: Paragangliomas are identified and characterized with the use of computed tomography and other imaging methods, but for a definitive diagnosis, histopathological evaluation is necessary. We report a rare case of a primary pulmonary paraganglioma that was treated surgically. This case report adds valuable knowledge to the literature on pulmonary paragangliomas.

Expression of Formyl-peptide Receptors in Human Lung Carcinoma.

BACKGROUND/AIM: Formyl-peptide receptors (FPRs) are expressed in several tissues and cell types. The identification of markers involved in cell growth may further allow for molecular profiling of lung cancer. We investigated the possible role of FPRs as molecular markers in several types of lung carcinomas which is the main cause of cancer death worldwide. MATERIALS AND METHODS: Tumor tissue samples were collected from six patients affected by lung cancer. Biopsies were analyzed for expression of FPR isoforms both in tumoral and peritumoral tissue by real-time polymerase chain reaction (PCR), western blot and immunofluorescence. RESULTS: Real-time PCR, western blot and immunofluorescence analyses showed that FPR expression is lower in types of human lung cancer tissues when compared to the surrounding peritumoral tissues. CONCLUSION: The study of the mechanistic basis for the control of FPR expression in normal peritumoral versus tumoral tissues could provide the basis for new diagnostic and therapeutic interventions.

Primary cardiac angiosarcoma in a 25-year-old man: excision, adjuvant chemotherapy, and multikinase inhibitor therapy.

Primary cardiac tumors do not occur frequently, and only one quarter of them, chiefly sarcomas, are malignant. Patients with angiosarcoma typically have a shorter survival time than do patients with other sarcomas, and the prognosis for survival depends strictly on the stage of the disease at the time of diagnosis and the possibility of complete surgical excision. Chemotherapy and radiotherapy have well-established postoperative roles because of the high probability of metastasis. We report the case of a 25-year-old man who presented with pericardial effusion and echocardiographic evidence of an intracavitary right atrial mass but without the bulky, infiltrative growth typical of this location of the disease. Malignancy was suggested by the clinical presentation, the location of the mass in the right side of the heart, and the absence of conditions favoring thrombus formation. After complete surgical excision, the mass was confirmed to be an angiosarcoma. Conventional adjuvant chemotherapy and maintenance therapy with inhibitors of CD117 (c-kit) and vascular endothelial growth factor relieved the patient's clinical symptoms and enabled his long-term, disease-free survival. In addition to reporting this case, we discuss aspects of the diagnosis and treatment of angiosarcoma.

Non-small cell lung cancer evaluated with quantitative contrast-enhanced CT and PET-CT: net enhancement and standardized uptake values are related to tumour size and histology.

BACKGROUND: Personalized cancer therapy remains a challenge. In this context, we attempted to identify correlations between tumour angiogenesis, tumour metabolism and tumour cell type. To this aim, we used single=phase multidetector computed tomography (MDCT) and hybrid positron emission tomography-computed tomography (PET/CT) to determine whether net enhancement and standardized uptake value (SUVmax) were correlated with tumour size and cytology in patients affected by non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: Our study included 38 patients (30 men, 8 women, mean age 70) with a NSCLC measuring between 3 cm and 7 cm, using a 16-slice multidetector CT (Brilliance Philips) and with PET-CT (Biograph 16 Siemens Medical Solutions). The following lesion parameters were evaluated: maximum diameter, medium density before contrast injection (CTpre), medium density after contrast injection (CTpost average), density in the most enhanced part of the lesion after contrast (CTpost max), net enhancement, SUVmax, age, and cytology. Correlation coefficient and p-value were computed for each pair of variables. In addition, correlations were computed for each pair of variables, and for all combinations of tumour types. We focused on subsets of data with more than 10 observations, and with correlation r>0.500 and p<0.05. RESULTS: A weak correlation (r=0.32; p=0.048) was found between SUVmax and tumour size; the correlation was stronger for masses larger than 31 mm (r=0.4515; p=0.0268). No other correlations were found among the variables examined. CONCLUSIONS: Our data may have prognostic significance, and could lead to more appropriate surgical treatment and better treatment outcome.

CD34 Expression in the Stromal Cells of Alveolar Adenoma.

The alveolar adenoma of the lung is a rare benign tumor characterized by a proliferation of both the alveolar epithelial cells and the mesenchymal septal cells. Immunohistochemically, the epithelial cells stain for cytokeratin (CK) AE1AE3, CK7, thyroid transcription factor 1 (TTF1), and surfactant apoprotein confirming the derivation by the type 2 pneumocytes. The stromal cells are negative for these markers but they show focally smooth muscle and muscle-specific actin positivity. We describe two cases that showed immunohistochemically a CD34 positivity of the mesenchymal septal cells. This aspect has been previously described in a two cases report, but not emphasized by the authors as a distinctive feature of the lesion. We consider this CD34 positivity as a marker of immaturity or stemness of the lesional septal spindle cells, that could be responsible of the different phenotypic and morphological profile of the interstitial cells, that could be, therefore, considered neoplastic and not reactive.

BARD1: an independent predictor of survival in non-small cell lung cancer.

BRCA1 mRNA overexpression is correlated with poor survival in NSCLC. However, BRCA1 functions depend on the interaction with BARD1 for its stability, nuclear localization and ubiquitin ligase activity. Expression of alternatively spliced BARD1 isoforms that lack the BRCA1-interaction domain was found upregulated and correlated with poor prognosis in breast and ovarian cancer. These BARD1 isoforms are essential for proliferation of cancer cells in vitro. We investigated whether BARD1 isoforms are expressed in NSCLC. While in lung tissues from healthy controls BARD1 expression was undetectable on the mRNA level and protein level, we found two novel isoforms in addition to previously identified mRNAs expressed in all NSCLC samples tested. Furthermore, the pattern of BARD1 isoform expression was similar in tumor and morphologically normal peri-tumor tissues, and only one novel isoform π was specifically upregulated in tumors. Immunohistochemistry revealed that all 100 NSCLC cases tested expressed isoform-specific BARD1 epitopes, while BARD1 expression was undetectable in biopsies from healthy controls. Statistical analysis showed that the expression of epitopes PVC and WFS, present on isoform π, or epitope WFS alone, expressed on isoforms π, κ and ß, were significantly correlated with decreased patient survival. These findings were corroborated in a mouse model of chemically induced lung cancer. Immunostaining of mouse tumors showed that BARD1 epitopes PVC and WFS were specifically upregulated in invasive, but not in confined lung tumors. Thus, BARD1 isoforms might be involved in tumor initiation and invasive progression and might represent a novel prognostic marker for NSCLC.