Common inherited variants of PDCD1, CD274 and HAVCR2 genes differentially modulate the risk and prognosis of adenocarcinoma and squamous cell carcinoma.

BACKGROUND: To investigate the association between single nucleotide polymorphisms (SNPs) of PDCD1, CD274, and HAVCR2 genes with the risk and outcomes of non-small cell lung cancer (NSCLC) subtypes: squamous cell lung cancer (LUSC) and lung adenocarcinoma (LUAD). METHODS: TaqMan SNP genotyping assays or polymerase chain reaction-restriction fragment length polymorphism methods were used to determine genotypes of: PDCD1: rs36084323, rs7421861, rs11568821, rs2227981, rs10204525; CD274: rs822335, rs10815225, rs17718883, rs2297136, rs4742098, rs4143815; HAVCR2: rs10057302, rs1036199. Among 383 NSCLC patients, 112 were diagnosed with LUAD and 116 with LUSC. The control group consisted of 433 unrelated, cancer-free subjects. RESULTS: A CC genotype of rs4143815 and GG genotype of rs4742098 were associated with two times higher risk of developing LUSC (CC vs. GG + GC, OR = 2.31; 95% CI = 1.32, 4.06; P = 0.003; GG vs. AA + AG, OR = 2.26; 95% CI = 1.17, 4.36; P = 0.016, respectively). Moreover, rs4143815 was an independent predictor of the age at diagnosis of LUAD. The carriers of C allele were diagnosed 4.81 years later (95% CI = 1.47, 8.15; P = 0.006) than patients with the GG genotype. The rs10057302 CA genotype was an independent predictor of overall survival in LUSC (adjusted HR = 0.13; 95% CI = 0.02, 0.93; P = 0.043). NSCLC carriers of rs11568821 T allele had almost double the risk of death (adjusted HR = 2.05; 95% CI = 1.28, 3.29; P = 0.003) compared to carriers of CC genotype. CONCLUSIONS: Our results provided additional evidence that SNPs of genes for PD-1, PD-L1 and TIM-3 differentially modulate the risk and prognosis of LUSC and LUAD.

Metachronous Lung Cancer: Clinical Characteristics and Effects of Surgical Treatment.

The occurrence of a second lung tumor after surgical removal of lung cancer usually indicates a lung cancer metastasis, but sometimes a new lesion proves to be a new primary lung cancer, i.e., metachronous lung cancer. The goal of the present study was to conduct a clinical evaluation of patients with metachronous lung cancer and lung cancer metastasis, and to compare the early and distant outcomes of surgical treatment in both cancer types. There were 26 age-matched patients with lung cancer metastases and 23 patients with metachronous lung cancers, who underwent a second lung cancer resection. We evaluated the histological type of a resected cancer, the extent of thoracosurgery, the frequency of early postoperative complications, and the probability of 5-year survival after the second operation. The findings were that metachronous lung cancer was adenocarcinoma in 52% of patients, with a different histopathological pattern from that of the primary lung cancer in 74% of patients. In both cancer groups, mechanical resections were the most common surgery type (76% of all cases), with anatomical resections such as segmentectomy, lobectomy, or pneumectomy being much rarer conducted. The incidence of early postoperative complications in metachronous lung cancer and lung cancer metastasis (30% vs. 31%, respectively) and the probability of 5-year survival after resection of either cancer tumor (60.7% vs. 50.9%, respectively) were comparable. In conclusion, patients undergoing primary lung cancer surgery require a long-term follow-up due to the risk of metastatic or metachronous lung cancer. The likelihood of metachronous lung cancer and pulmonary lung cancer metastases, the incidence of postoperative complications, and the probability of 5-year survival after resection of metachronous lung cancer or lung cancer metastasis are similar.

Expression of Ceramide Galactosyltransferase (UGT8) in Primary and Metastatic Lung Tissues of Non-Small-Cell Lung Cancer.

Ceramide galactosyltransferase (UGT8) is an enzyme that regulates the synthesis of sphingolipids of the myelin sheath in nervous systems. The protein raises an increasing research interest as a potential marker of cancer progression in various organs. In the present study we seek to determine whether UGT8 could play a role of a therapeutic marker in non-small cell lung carcinoma (NSCLC). We addressed the issue by examining the intensity of UGT8 expression in tissue specimens of primary and corresponding metastatic lung tumors in 19 NSCLC patients undergoing surgery. The methodology was one of immunohistochemical tissue staining using light microscopy. The findings were that the majority of both lung primary and metastatic tumor tissues were positive in UGT8 signals. The cytoplasmic expression of UGT8 was found in 68.4 % of cases of primary tumors and 82.2 % of metastases, with a positive correlation between the UGT8 expression in both tumor tissues. The normal tissue adjacent to tumors showed no positive UGT8 staining. However, we failed to find any appreciable difference in UGT8 expression depending on the clinical stage of NSCLC or lymph node involvement. Nor was there any association between UGT8 expression in tumor tissues and patients' survival time. We conclude that it is unlikely that therapeutic targeting of UGT8 could inhibit cell proliferation and invasion of NSCLC. UGT8, although enhanced in NSCLC tissues, does not meet the criteria of a lung tumor marker. Thus, UGT8 cannot be considered as having diagnostic or therapeutic utility in NSCLC. The pathophysiological meaning of enhanced expression of UGT8 in lung cancer remains to be explored in further studies.

Malignant melanoma of the lung: case series.

Extracutaneous locations of primary malignant melanoma are rare. In the respiratory system most melanomas present as metastatic tumors. For the diagnosis of primary lung melanoma, strict histopathological and clinical criteria should be met. In this paper we present three cases of malignant melanoma which showed in the respiratory system. The first 2 case studies present primary lung melanomas, while the last one shows late lung metastasis of tumor originated from vaginal mucosa. The treatment of choice for localized disease as well as single metastasis is surgical excision.

Prognostic significance of SOX18 expression in non-small cell lung cancer.

Recent studies have demonstrated the involvement of SOX18 transcription factor in blood and lymphatic vessel development, as well as in wound healing processes. SOX18 expression has been noted in cancer cells of various tumours, including lung cancer. However, the exact role of SOX18 expression in non-small cell lung cancer (NSCLC) remains to be determined. The present study, therefore, assessed its expression in 198 cases of NSCLC, consisting of 94 adenocarcinomas (AC), 89 squamous cell carcinomas (SQC) and 15 large cell carcinomas (LCC). The analysis utilized immunohistochemistry (IHC) and, in 42 cases, molecular methods. SOX18 expression was also determined in NSCLC cell lines (NCI-H1703, NCI-H522 and A549) and in normal lung fibroblasts (IMR-90). SOX18 was found to be expressed in nuclei, as well as in the cytoplasm of cancer cells, in the majority of studied cases. SOX18 mRNA expression was significantly lower in NSCLC than in non-malignant lung tissue (p<0.0001). However, SOX18 protein expression levels were higher in NSCLC tissues (p<0.005) and in the examined lung cancer cell lines. No SOX18 expression was noted in the IMR-90 cell line. In paraffin sections, a positive correlation between the Ki-67 antigen and nuclear SOX18 expression (r=0.17, p<0.05) was noted. In univariate survival analysis, cytoplasmic SOX18 expression correlated with poor patient outcome in the whole study and in AC cohorts (both p<0.05). Based on these results, SOX18 may be involved in the progression of NSCLC.

Expression of Nogo isoforms and Nogo-B receptor (NgBR) in non-small cell lung carcinomas.

BACKGROUND: Nogo-B was recently shown to be involved in proliferation, apoptosis and invasiveness of cancer cells, whereas its specific receptor (NgBR) was found to be up-regulated in estrogen receptor-α positive breast cancer. No data are currently available concerning their expression in non-small cell lung carcinomas (NSCLC). MATERIALS AND METHODS: Expression of Nogo isoforms and NgBR was studied in 191 NSCLC. RESULTS: Higher Nogo-A/B immunoreactivity was noted in cancer cells of squamous cell carcinomas (SQC) compared to adenocarcinomas (p<0.001). Stage II-IV tumors had the lowest Nogo-A/B expression (p<0.0001) compared to stage I cases. Nogo-A/B expression decreased with increasing SQC malignancy grade (p=0.026). Significant NgBR mRNA down-regulation was associated with larger primary tumor size (p=0.039), lymph node involvement (p=0.039) and advancement stage (p=0.0054). Low NgBR mRNA expression predicted poor patients outcome (p=0.029). CONCLUSION: The current data may point to the involvement of Nogo isoforms and NgBR in the pathogenesis of NSCLC.

The lack of evidence for correlation of pyruvate kinase M2 expression with tumor grade in non-small cell lung cancer.

BACKGROUND: Over the last years, evidence has accumulated that an increased expression of pyruvate kinase M2 isozyme (PKM2) is related to neoplastic transformation as well that its plasma concentrations might be a marker of lung cancer progression. MATERIALS AND METHODS: In the present manuscript an immunohistochemical technique was used to detect the expression of two pyruvate kinase isoforms: PKM1 (muscle isozyme of PK) and PKM2 as well Ki-67 antigen on paraffin sections of 218 cases of non-small cell lung cancer (NSCLC) of different histological types and grades of malignancy. RESULTS: A significant correlation between expressions of both pyruvate kinase isoforms in all NSCLC types was found (r=0.42, p<0.0001). Expression levels of PKM1 and PKM2 were independent of the histological classification of the tumor and patients' clinicopathological data. CONCLUSIONS: PKM2 and PKM1 have no value as predictive markers of NSCLC regardless of the histological type and grade of malignancy.

Expression of metallothionein-III in patients with non-small cell lung cancer.

BACKGROUND: Currently, there is little knowledge concerning expression of metallothionein-III (MT-III), also known as growth-inhibitory factor, in non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: In this study, we evaluated MT-III expression in 184 patients using immunohistochemistry and in 61 cases using real-time polymerase chain reaction. RESULTS: MT-III mRNA expression was significantly higher in NSCLC as compared to non-malignant lung tissues (NMLT; p<0.0086). MT-III expression was noted in the cytoplasm and nucleus of cancer cells. Significantly lower nuclear MT-III (p<0.0001) expression and significantly higher cytoplasmic MT-III (p=0.0068) expression was noted in the pneumocytes of NMLT, as compared to NSCLC. Nuclear MT-III expression was significantly higher in G1 cases as compared to G2 (p=0.0308) and G3 (p=0.0194) cases. Low cytoplasmic MT-III expression was associated with larger primary tumour size (p=0.0378). Lower MT-III mRNA and cytoplasmic MT-III expression was associated with poor patient outcome (p=0.0410 and p=0.0347, respectively). CONCLUSION: MT-III expression may have an impact on the pathogenesis of NSCLC.

Metallothionein 1F and 2A overexpression predicts poor outcome of non-small cell lung cancer patients.

Metallothioneins (MT) are intracellular, low molecular weight proteins (6-7 kDa) involved in binding of metal ions, scavenging of free radicals, cell proliferation and apoptosis and resistance to certain chemotherapeutics. Four basic families of MT proteins are distinguished: MT-I, MT-II, MT-III, MT-IV, within each of them different isoforms occur. The study aimed at examining the expression level of nine MT isoforms: MT-1A, -1B, -1E, -1F, -1G, -1H, -1X, MT-2A and MT-IV by using real-time PCR and MT-I/II expression by immunohistochemical (IHC) technique in 69 cases of non-small cell lung cancer (NSCLC) and 12 non-malignant lung tissues (NMLT) and to correlate them with patients clinicopathological data and Ki-67 antigen expression. Out of all the analyzed cases, 62 (89.9%) demonstrated an increased MT-I/II expression. MT-1B, 1F, -1G, -1H and MT-1X were significantly up-regulated, whereas MT-1E was significantly down-regulated in NSCLC as compared to NMLT. Only in two cases MT-IV mRNA expression was noted. Significant positive correlations were observed between each particular MT isoform expressions. Higher MT-1F and MT-1A mRNA expression was associated with larger primary tumor size (P=0.0362 and P<0.0001, respectively). Moreover, up-regulated MT-1F mRNA expression was associated with higher grade of malignancy of NSCLC (P=0.0085). Higher MT-1B mRNA expression was associated with squamocellular and adenocarcinoma subtype of NSCLC (P=0.0358). Univariate analysis showed, that up-regulated MT-1F and MT-2A mRNA predicted poor patients' survival (P=0.0206 and P=0.0097, respectively). The levels of MT-1F and MT-2A mRNA could be considered as new markers of poor prognosis of NSCLC patients.

Correlation between expression of metallothionein and expression of Ki-67 and MCM-2 proliferation markers in non-small cell lung cancer.

BACKGROUND: Metallothioneins (MTs) are low molecular weight proteins present both in normal and neoplastic cells. They protect cells from the effects of heavy metals and from damage induced by free radicals. MT bind heavy metals, exert an anti-apoptotic effect and stimulate proliferation of neoplastic cells. The role of MTs in carcinogenesis has not been fully clarified yet. This study aimed at the evaluation of the intensity of metallothionein (MT-I/II) expression in various histological types of non-small cell lung cancer (NSCLC) and correlation of the expression intensity with clinical/pathological parameters and Ki-67 and minichromosome maintaince protein 2 (MCM-2) proliferation markers. PATIENTS AND METHODS: The studies were performed on archival material, originating from 145 patients, 105 men and 40 women (65 adenocarcinomas, 67 squamous cell carcinomas, 13 large cell carcinomas). RESULTS: A positive correlation was noted between expression of MT-I/II and expressions of Ki-67 (r=0.1863, p=0.0248) and MCM-2 (r=0.1766, p=0.0336) in NSCLC overall. The most pronounced expression of MT-I/II was noted in the large cell carcinomas. The expression of MT-I/II was significantly lower in the adenocarcinomas than in the squamous cell carcinomas (p=0.0028) and large cell carcinomas (p=0.0485). The expression of MT-I/II showed no differences related to individual degrees of NSCLC malignancy. Univariate analysis demonstrated no significant differences in overall survival related to the expression intensity of MT-I/II, Ki-67 or MCM-2, but the survival of the patients with high expression of MT-I/II and Ki-67 in the neoplastic cells, as compared to low expression of MT-I/II and Ki-67, was shorter (the difference approached statistical significance, p=0.067). CONCLUSION: MT-I/II expression is evident in proliferating NSCLC neoplastic cells, pointing to the prognostic importance of parallel expression of MT-I/II and Ki-67.

CT-guided fine-needle biopsy of focal lung lesions as the method for reducing the number of invasive diagnostic procedures.

BACKGROUND: CT-guided fine-needle biopsy (FNB) of focal lung lesions is one of the possibilities of obtaining histopathological diagnosis in pulmonary diseases. Its place in the algorithm is determined by the invasiveness. In case of no diagnosis after bronchoscopy or endobronchial ultrasonography (EBUS) guided biopsy, CT-guided FNB can become an alternative for more invasive procedures, such as open lung biopsy - thoracotomy. MATERIAL/METHODS: Since January 2009 until February 2010, we performed 37 CT-guided FNB in 34 patients aged 31 to 76 (mean age 60.9). Among them, there were 16 women and 18 men. All patients underwent a standard chest CT with contrast medium injection. They were diagnosed with focal lesions and they were rejected from surgery as the primary method of treatment. During biopsy, the patient was positioned prone or supine, depending on the location of lesions. After performing a scout image and initial slices, we marked the level of biopsy, using a metal marker. Next, the biopsy needle was introduced under local anesthesia. When the obtained position of the needle in the lesion was correct, the specimen was taken. After needle removal, the patient was controlled for the presence of complications (i.e. pneumothorax). Biopsy time ranged from 10 to 50 minutes. RESULTS: In 94.6% of biopsies, the specimens for histopathological and cytological examinations were obtained. In 22 (64.7%) patients, histopathological diagnoses (in 14 cases this was the non-small cell cancer and in 8, inflammatory lesions) were established which allowed us to resign from invasive thoracotomy and to introduce an appropriate treatment. In the remaining 12 patients, no diagnosis was established. Complications in the form of a minor pneumothorax occurred in 2 patients. CONCLUSIONS: Fine-needle biopsy of the focal lung lesions is an affective and a relatively safe method, which can replace the more invasive diagnostic thoracotomy in the majority of patients.