An unusual cause of rapidly progressive glomerulonephritis associated with ANCA vasculitis and ovarian malignancy - a relapse 39 years after initial treatment.

A 69-year-old woman presented with severe anemia, proteinuria, microscopic hematuria and rapidly progressive renal failure. She was admitted to the nephrology department due to severe deterioration of renal function with complaints of malaise, fever, dry cough and occasional epistaxis that appeared 2 months prior to admission. Histopathologic examination of a specimen from kidney biopsy and immunologic findings revealed ANCA positive pauci-immune crescentic glomerulonephritis. The patient had a history of ovarian granulosa cell tumor and lung metastases that were treated surgically with postoperative radiotherapy and chemotherapy. Thoracic computed tomography showed tissue neoplasm in the right lung and ultrasound-guided percutaneous transthoracic biopsy confirmed granulosa cell tumor. That was a relapse, thirty-nine years after initial treatment of malignant disease and twenty-four years after surgical resection of metastases from both lungs. Although the association between malignancy and vasculitis has been well known for decades, this is the first described case of ANCA vasculitis associated with any type of gynecological malignancy and glomerulonephritis.

Endotracheal stent increased survival length in patients with invasive thymic adenocarcinoma.

We reported the first case of inoperative thymic adenocarcinoma successfully palliative treated by the double-stent procedure. In a patient who expressed stridor, computed tomography was done and necrotic mediastinal mass, which protrudes into a trachea, was demonstrated. Fiberoptic bronchoscopy showed tracheal infiltration and 70% stenosis; therefore, surgical resection was inapplicable. Recanalization with repeated argon plasma coagulation and debridement of necrotic mass was performed, followed by placement of the endotracheal stent, radiotherapy, and chemotherapy. After 1 year, the patient developed gastric aspiration and tracheoesophageal fistula; therefore, the esophageal stent was placed. The outcome was lethal, but the placement of endotracheal stent significantly increased a length of survival for the patient with invasive thymic adenocarcinoma.

Rare histological subtype of pulmonary artery intimal sarcoma diagnosed by multidisciplinary approach.

Pulmonary artery intimal sarcoma (PAS) is a rare mesenchymal tumor mostly diagnosed in middle-aged women. In a 63-year-old female, the radiological findings showed cavitation in the left upper lobe of the lung and infiltrative tumor mass around the left pulmonary artery. PAS consisted of small, round tumor cells with about 80% of mitotic activity and with myxoid background and specific immunoprofile and diagnosed as undifferentiated sarcoma with round cell features type. The final diagnosis of PAS was established according to the pathohistological, chest computed tomography scan, and surgery finding.

Identification and validation of differentially expressed transcripts by RNA-sequencing of formalin-fixed, paraffin-embedded (FFPE) lung tissue from patients with Idiopathic Pulmonary Fibrosis.

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is a lethal lung disease of unknown etiology. A major limitation in transcriptomic profiling of lung tissue in IPF has been a dependence on snap-frozen fresh tissues (FF). In this project we sought to determine whether genome scale transcript profiling using RNA Sequencing (RNA-Seq) could be applied to archived Formalin-Fixed Paraffin-Embedded (FFPE) IPF tissues. RESULTS: We isolated total RNA from 7 IPF and 5 control FFPE lung tissues and performed 50 base pair paired-end sequencing on Illumina 2000 HiSeq. TopHat2 was used to map sequencing reads to the human genome. On average ~62 million reads (53.4% of ~116 million reads) were mapped per sample. 4,131 genes were differentially expressed between IPF and controls (1,920 increased and 2,211 decreased (FDR < 0.05). We compared our results to differentially expressed genes calculated from a previously published dataset generated from FF tissues analyzed on Agilent microarrays (GSE47460). The overlap of differentially expressed genes was very high (760 increased and 1,413 decreased, FDR < 0.05). Only 92 differentially expressed genes changed in opposite directions. Pathway enrichment analysis performed using MetaCore confirmed numerous IPF relevant genes and pathways including extracellular remodeling, TGF-beta, and WNT. Gene network analysis of MMP7, a highly differentially expressed gene in both datasets, revealed the same canonical pathways and gene network candidates in RNA-Seq and microarray data. For validation by NanoString nCounter® we selected 35 genes that had a fold change of 2 in at least one dataset (10 discordant, 10 significantly differentially expressed in one dataset only and 15 concordant genes). High concordance of fold change and FDR was observed for each type of the samples (FF vs FFPE) with both microarrays (r = 0.92) and RNA-Seq (r = 0.90) and the number of discordant genes was reduced to four. CONCLUSIONS: Our results demonstrate that RNA sequencing of RNA obtained from archived FFPE lung tissues is feasible. The results obtained from FFPE tissue are highly comparable to FF tissues. The ability to perform RNA-Seq on archived FFPE IPF tissues should greatly enhance the availability of tissue biopsies for research in IPF.

Chronic Obstructive Pulmonary Disease Mismatch: A Case of Tracheal Hamartoma.

OBJECTIVE: To demonstrate the diagnostic challenge of tracheal hamartoma in a patient with chronic obstructive pulmonary disease (COPD). CLINICAL PRESENTATION AND INTERVENTION: A 65-year-old man with COPD was admitted with sudden onset of asphyxia attacks related to the position of his body. Computerized tomography (CT) of the neck showed a soft tissue mass with calcification, which occluded more than two-thirds of the proximal part of the trachea. The tumor was completely removed, and histopathology confirmed hamartoma. CONCLUSION: This case report showed the detection of a primary tracheal tumor on CT. This finding enabled the correct diagnosis and led to appropriate treatment in the form of surgery.

Prolonged survival after neoadjuvant chemotherapy related with specific molecular alterations in the patients with nonsmall-cell lung carcinoma.

Lung cancer is the most common cause of neoplasia-related death worldwide. Accounting for approximately 80% of all lung carcinomas, the non-small cell lung carcinoma (NSCLC) is the most common clinical form with its two predominant histological types, adenocarcinoma (ADC) and squamous cell carcinoma (SCC). Although surgical resection is the most favorable treatment for patients with NSCLC, relapse is still high, so neoadjuvant chemotherapy (NAC) is an accepted treatment modality. In this study we examined whether some of the key molecules associated with the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathways could have predictive and prognostic value for the NAC application. To that end we examined the expression status of PTEN, pAKT, pERK and loss of heterozygosity (LOH) of PTEN in two groups of NSCLC patients, those who received and those who did not receive NAC. LOH PTEN and low pERK expression is shown to be correlated with the longest survival of patients with SCC and ADC, respectively, who received NAC. These results point that the application of NAC is beneficial in the NSCLC patients with specific molecular alterations which could further help to improve constant search for the druggable molecular targets used in personalized therapy.

Impact of HER2 codon 655 polymorphism and expression of HER2 and HER3 in non small cell lung cancer patients.

The aim of the study was to assess the expression and significance of HER2 and HER3, and Ile/Val single nucleotide polymorphism (SNP) of HER2 in lung cancer patients. Thirty seven cases of lung cancer were investigated immunohistochemically for HER2 and HER3 expression. PCR followed by restriction fragment length polymorphism (RFLP) was used to analyze the presence of HER-2 SNP at codon 655 in 20 samples. The results were compared with clinical and pathological parameters of investigated patients.We found that 100% of the cases were negative for HER2, 29.7% were with moderate or strong HER3 expression and 70.3% of the tumors-without or with low expression for HER3. Lymph node metastasis were found in 40% of HER3 positive cases (χ(2) = 4.752; p = 0.029). Moderately-differentiated tumors do not express neither of investigated markers (χ(2) = 6.719; p = 0.035). HER2 RFLP-PCR analysis showed genotype AG in five patients (25%) and the rest of 15 cases (75%) had АА (Ile/Ile) genotype. Patients with metastasis had genotype АА (Ile/Ile) in 80% and genotype AG (Ile/Val) in 20% (χ(2) = 2.857; p = 0.091).Our results indicate that SNP in HER2 codon 655 and investigation of HER2 and HER3 expression could be helpful to outline the prognosis for patients with lung adenocarcinoma.

Standard versus extended pneumonectomy for lung cancer: what really matters?

BACKGROUND: It is still not clear whether an intrapericardial pneumonectomy indicates a more advanced stage of the disease compared to a standard pneumonectomy. METHODS: This was a retrospective study of 164 patients who underwent a pneumonectomy for lung cancer. The first group consisted of 82 patients who had a standard pneumonectomy and the second group was 38 patients who had a intrapericardial pneumonectomy, for both groups in the latest 5-year period. The third group was 44 patients with had a sleeve pneumonectomy in the latest 10-year period. The groups were compared in relation to the overall and stage-related survival, influence of T and N factors, operative morbidity and mortality. The statistics used were Kaplan-Meier, U-test, t-test, χ2 test. RESULTS: There was no statistically significant difference in stage distribution between standard and intrapericardial pneumonectomies; stages I, II, IIIA and IIIB occurred for 10.9% vs. 2.6%, 30.5% vs. 26.3%, 46.4% vs. 65.8% and 12.2% vs. 5.3% of patients, respectively. For patients who had a sleeve pneumonectomy, stage IIIA was significantly more frequent. Although the overall survival (63.5% vs. 57.6%) and stage-related 5-year survival were better in the first compared to the second group, especially for stage IIIA (58.6% vs. 42.6%), these differences were not statistically significant. There were no significant differences in operative morbidity and mortality between groups 1 and 2, but both were significantly higher in the third group (35.7% and 15.9%). CONCLUSIONS: An intrapericardial pneumonectomy does not always indicate a more advanced stage of the disease. The need for an intrapericardial pneumonectomy, either established preoperatively or during the operation, as a single factor, even for marginal surgical candidates, is not strong enough to reject these patients for surgery.

Genomic profiling of thymoma using a targeted high-throughput approach.

Introduction: Thymomas and thymic carcinoma (TC) are the most common neoplasms localised in the thymus. These diseases are poorly understood, but progress made in next-generation sequencing (NGS) technology has provided novel data on their molecular pathology. Material and methods: Genomic DNA was isolated from formalin-fixed paraffin-embedded tumour tissue. We investigated somatic variants in 35 thymoma patients using amplicon-based TruSeq Amplicon Cancer Panel (TSACP) that covers 48 cancer related genes. We also analysed three samples from healthy individuals by TSACP platform and 32 healthy controls using exome sequencing. Results: The total number of detected variants was 4447, out of which 2906 were in the coding region (median per patient 83, range: 2-300) and 1541 were in the non-coding area (median per patient 44, range: 0-172). We identified four genes, APC, ATM, ERBB4, and SMAD4, having more than 100 protein-changing variants. Additionally, more than 70% of the analysed cases harboured protein-changing variants in SMAD4, APC, ATM, PTEN, KDR, and TP53. Moreover, this study revealed 168 recurrent variants, out of which 15 were shown to be pathogenic. Comparison to controls revealed that the variants we reported in this study were somatic thymoma-specific variants. Additionally, we found that the presence of variants in SMAD4 gene predicted shorter overall survival in thymoma patients. Conclusions: The most frequently mutated genes in thymoma samples analysed in this study belong to the EGFR, ATM, and TP53 signalling pathways, regulating cell cycle check points, gene expression, and apoptosis. The results of our study complement the knowledge of thymoma molecular pathogenesis.

Genetic Analysis of Lung Cancer and the Germline Impact on Somatic Mutation Burden.

BACKGROUND: Germline genetic variation contributes to lung cancer (LC) susceptibility. Previous genome-wide association studies (GWAS) have implicated susceptibility loci involved in smoking behaviors and DNA repair genes, but further work is required to identify susceptibility variants. METHODS: To identify LC susceptibility loci, a family history-based genome-wide association by proxy (GWAx) of LC (48 843 European proxy LC patients, 195 387 controls) was combined with a previous LC GWAS (29 266 patients, 56 450 controls) by meta-analysis. Colocalization was used to explore candidate genes and overlap with existing traits at discovered susceptibility loci. Polygenic risk scores (PRS) were tested within an independent validation cohort (1 666 LC patients vs 6 664 controls) using variants selected from the LC susceptibility loci and a novel selection approach using published GWAS summary statistics. Finally, the effects of the LC PRS on somatic mutational burden were explored in patients whose tumor resections have been profiled by exome (n = 685) and genome sequencing (n = 61). Statistical tests were 2-sided. RESULTS: The GWAx-GWAS meta-analysis identified 8 novel LC loci. Colocalization implicated DNA repair genes (CHEK1), metabolic genes (CYP1A1), and smoking propensity genes (CHRNA4 and CHRNB2). PRS analysis demonstrated that these variants, as well as subgenome-wide significant variants related to expression quantitative trait loci and/or smoking propensity, assisted in LC genetic risk prediction (odds ratio = 1.37, 95% confidence interval = 1.29 to 1.45; P < .001). Patients with higher genetic PRS loads of smoking-related variants tended to have higher mutation burdens in their lung tumors. CONCLUSIONS: This study has expanded the number of LC susceptibility loci and provided insights into the molecular mechanisms by which these susceptibility variants contribute to LC development.

Rare deleterious germline variants and risk of lung cancer.

Recent studies suggest that rare variants exhibit stronger effect sizes and might play a crucial role in the etiology of lung cancers (LC). Whole exome plus targeted sequencing of germline DNA was performed on 1045 LC cases and 885 controls in the discovery set. To unveil the inherited causal variants, we focused on rare and predicted deleterious variants and small indels enriched in cases or controls. Promising candidates were further validated in a series of 26,803 LCs and 555,107 controls. During discovery, we identified 25 rare deleterious variants associated with LC susceptibility, including 13 reported in ClinVar. Of the five validated candidates, we discovered two pathogenic variants in known LC susceptibility loci, ATM p.V2716A (Odds Ratio [OR] 19.55, 95%CI 5.04-75.6) and MPZL2 p.I24M frameshift deletion (OR 3.88, 95%CI 1.71-8.8); and three in novel LC susceptibility genes, POMC c.*28delT at 3' UTR (OR 4.33, 95%CI 2.03-9.24), STAU2 p.N364M frameshift deletion (OR 4.48, 95%CI 1.73-11.55), and MLNR p.Q334V frameshift deletion (OR 2.69, 95%CI 1.33-5.43). The potential cancer-promoting role of selected candidate genes and variants was further supported by endogenous DNA damage assays. Our analyses led to the identification of new rare deleterious variants with LC susceptibility. However, in-depth mechanistic studies are still needed to evaluate the pathogenic effects of these specific alleles.

Massive Relief: Papillary Adenoma of the Lung in Asymptomatic Former Smoker Patient.

Benign epithelial tumors of the lung are uncommon and can represent a diagnostic challenge. Herein, we describe one such emblematic case. A 59-year-old former smoker male was admitted to the hospital complaining of cough for a long time. A radiological examination showed a centrally excavated mass strictly connected to the visceral pleura. The patient underwent tumorectomy. At gross examination, the tumor was composed of solid and cystic areas containing clear liquid. Histological examination highlighted a sub-pleural encapsulated tumor, with foci of capsular invasion, characterized by a single layer of columnar and cuboidal epithelial cells lining moderately cellular fibro-vascular cores. A wide spectrum of immunohistochemical markers was performed. The final diagnosis was suggestive of a peripheral pulmonary papillary tumor of undetermined malignant potential. At the last follow-up, six years after surgery, no recurrence or metastases were described. Reporting this case, we would like to point out the existence of these rare entities that should be taken into account in the diagnostic process, thus avoiding potential misdiagnosis. Moreover, the presence of capsular invasion should be better investigated in order to reconsider the exact terminology of the tumor and the classification of its malignant potential.

Lung cancer in women: histological type and patient age from 1985 to 2005.

The aim of the study was to analyse changes in histological type and age of presentation in female lung cancer patients during a period of 20 years. The obtained results are compared with those available from the literature published in various parts of the world.

Solitary fibrous pleural tumor associated with loss of consciousness due to hypoglycemia.

The patient suffered loss of consciousness, dysarthria and right sided hemiparesis. The CT scan and MRI scans were negative. These findings are more in keeping with a diagnosis of Transient Ischemic Attack (TIA) or mild CVA. Hypoglycemia per se does not usually cause hemiparesis. The blood glucose level was low but I am not sure if one can conclude that hypoglycemia caused the above noted neurological signs and symptoms. The authors do not present any data to prove that this patient had "hypoglycemic coma".

Relapse in resected lung cancer revisited: does intensified follow up really matter? A prospective study.

BACKGROUND: beside the well known predominance of distant vs. loco-regional relapse, several aspects of the relapse pattern still have not been fully elucidated. METHODS: prospective, controlled study on 88 patients operated for non-small cell lung cancer (NSCLC) in a 15 months period. Stage IIIA existed in 35(39.8%) patients, whilst stages IB, IIA and IIB existed in 10.2%, 4.5% and 45.5% patients respectively. INCLUSION CRITERIA: stage I-IIIA, complete resection, systematic lymphadenectomy with at least 6 lymph node groups examined, no neoadjuvant therapy, exact data of all aspects of relapse, exact data about the outcome of the treatment. RESULTS: postoperative lung cancer relapse occurred in 50(56.8%) patients. Locoregional, distant and both types of relapse occurred in 26%, 70% and 4% patients respectively. Postoperative cancer relapse occurred in 27/35(77.1%) pts. in the stage IIIA and in 21/40(52.55) pts in the stage IIB. In none of four pts. in the stage IIA cancer relapse occurred, unlike 22.22% pts. with relapse in the stage IB. The mean disease free interval in the analysed group was 34.38 +/- 3.26 months.The mean local relapse free and distant relapse free intervals were 55 +/- 3.32 and 41.62 +/- 3.47 months respectively Among 30 pts. with the relapse onset inside the first 12 month after the lung resection, in 20(66.6%) pts. either T3 tumours or N2 lesions existed. In patients with N0, N1 and N2 lesions, cancer relapse occurred in 30%, 55.6% and 70.8% patients respectively. Radiographic aspect T stage, N stage and extent of resection were found as significant in terms of survival. Related to the relapse occurrence, although radiographic aspect and extent of resection followed the same trend as in the survival analysis, only T stage and N stage were found as significant in the same sense as for survival. On multivariate, only T and N stage were found as significant in terms of survival.Specific oncological treatment of relapse was possible in 27/50(54%) patients. CONCLUSION: the intensified follow up did not increase either the proportion of patients detected with asymptomatic relapse or the number of patients with specific oncological treatment of relapse.

Tumor characteristics, expressions of ERCC1, Bax, p53, IGF1R, Bcl2, Bcl2/Bax and prognostic factors for overall survival in patients with lung carcinoid.

PURPOSE: Neuroendocrine lung tumors (NET) include typical carcinoids (TC), atypical carcinoids (AC), large cell NE carcinoma (LCNEC) and small-cell carcinoma (SCLC), with different clinicopathological profiles and relative grades of malignancy. Although differences between carcinoids and high grade carcinomas are recognized, precise differences and behavior of TC and AC have not been clearly defined. The aim of this study was to better define the differences in the clinical behavior of TC and AC, and to establish new prognostic factors of overall survival (OS), by determining the levels of genetic expression of IGF1R, ERCC1, Bax, p53, Bcl2 and Bcl2/Bax ratio. METHODS: The histopathological diagnosis of 52 surgically resected pulmonary carcinoid tumors was made according to the WHO classification. Gene expressions were evaluated by quantitative real-time PCR. RESULTS: The confirmed prognostic factors for overall survival (OS) were pTNM T (p<0.01), pTNM N (p<0.05), clinical stage (p<0.05), type of surgery (p<0.01) and histopathological (HP) tumor type (p<0.05). Bcl2 mRNA level and Bcl2/Bax ratio were found to have a potential for discrimination of the HP type of tumor (AC vs TC, Receiver Operating Characteristics (ROC) cut-off values 0.1451 and 0.3015, respectively), but without statistically significant impact on OS. CONCLUSIONS: In patients with NETs, smaller primary tumor, absence of positive lymph nodes, and TC type of tumor predicted longer OS. Type of resection has influence on OS. Bcl2 expression and Bcl2/Bax ratio might be valuable as independent diagnostic parametars in lung carcinoids. Therapeutic approaches using attenuation of Bcl2 or upregulation of Bax might prove useful in lung NETs.

Genomic instability in patients with non-small cell lung cancer assessed by the arbitrarily primed polymerase chain reaction.

In the present study, we used DNA profiling to measure genomic instability in 22 patients with non-small cell lung cancer (NSCLC). Genomic instability was correlated with gender, the age of the patients at the time of diagnosis, the NSCLC subtype, histological grade and stage of the tumor, necrosis presence in the tumor and lymph node invasion. Genomic instability was significantly higher in patients older than 50 and those with adenocarcinoma compared to squamous-cell carcinoma. Most importantly, genomic instability significantly decreased as the tumor grade increased. Extensive genomic instability in the early carcinogenesis could be the prerequisite for NSCLC progression.

Clinical features of lung cancer in patients with connective tissue diseases: a 10-year hospital based study.

BACKGROUND: Connective tissue diseases (CTD) might be associated with various malignancies, and one of the most frequent is lung cancer (LC). Despite our understanding of pathogenesis, this association remains still unclear. The aim of the present study is to describe the clinical characteristics of patients with CTD who developed LC. METHODS: Of 375 successive patients with CTD followed up to University Hospital between 1995 and 2004, 24 patients were diagnosed with LC: 11 (46%) had systemic sclerosis (SSc), 6 (25%) rheumatoid arthritis (RA), 6 (25%) systemic lupus erythematosus (SLE), and 1 (4%) dermatomyositis. We analyzed LC stage, radiological presentation, histological type, patients' smoking status, method of diagnosis, treatment applied, and disease outcome. RESULTS: Average duration of CTD was 13.95 (range 0-30) years. Non-small cell lung cancer (NSCLC) was significantly more frequent than small-cell lung cancer (SCLC). Among patients with NSCLC, 21 patients (85%) presented with stage III or IV. With regard to treatment, 13% patients underwent surgery, 25% chemotherapy, 4% patients combined chemo- and radiotherapy and 58% patients had only supportive therapy. The median survival was 5 months (range 1-96 months). CONCLUSION: The majority of CTD patients who developed LC were diagnosed at advanced stage and had poor survival. Efforts for early detection of LC in CTD patients' group are warranted.