Applying a next-generation sequencing assay targeting 145 cancer-relevant genes in 40 colorectal cancer and 24 non–small cell lung cancer formalin-fixed paraffin-embedded tissue specimens identified at least one clinically relevant genomic alteration in 59% of the samples and revealed two gene fusions, C2orf44-ALK in a colorectal cancer sample and KIF5B-RET in a lung adenocarcinoma. Further screening of 561 lung adenocarcinomas identified 11 additional tumors with KIF5B-RET gene fusions (2.0%; 95% CI 0.8–3.1%). Cells expressing oncogenic KIF5B-RET are sensitive to multi-kinase inhibitors that inhibit RET.
Rhabdomyosarcoma (RMS) is the most commonly occurring type of soft tissue tumor in children. However, it is rare in adults, and therefore, very little is known about the most appropriate treatment strategy for adult RMS patients. We performed genomic analysis of RMS cells derived from a 27-year-old male patient whose disease was refractory to treatment. A peritoneal seeding nodule from the primary tumor, pleural metastases, malignant pleural effusion, and ascites obtained during disease progression, were analyzed. Whole exome sequencing revealed 23 candidate variants, and 10 of 23 mutations were validated by Sanger sequencing. Three of 10 mutations were present in both primary and metastatic tumors, and 3 mutations were detected only in metastatic specimens. Comparative genomic hybridization array analysis revealed prominent amplification in the 12q13–14 region, and more specifically, the CDK4 proto-oncogene was highly amplified. ALK overexpression was observed at both protein and RNA levels. However, an ALK fusion assay using NanoString technology failed to show any ALK rearrangements. Little genetic heterogeneity was observed between primary and metastatic RMS cells. We propose that CDK4, located at 12q14, is a potential target for drug development for RMS treatment.
To gain biological insights into lung metastases from hepatocellular carcinoma (HCC), we compared the whole-genome sequencing profiles of primary HCC and paired lung metastases.
We used whole-genome sequencing at 33X-43X coverage to profile somatic mutations in primary HCC (HBV+) and metachronous lung metastases (> 2 years interval).
In total, 5,027-13,961 and 5,275-12,624 somatic single-nucleotide variants (SNVs) were detected in primary HCC and lung metastases, respectively. Generally, 38.88-78.49% of SNVs detected in metastases were present in primary tumors. We identified 65–221 structural variations (SVs) in primary tumors and 60–232 SVs in metastases. Comparison of these SVs shows very similar and largely overlapped mutated segments between primary and metastatic tumors. Copy number alterations between primary and metastatic pairs were also found to be closely related. Together, these preservations in genomic profiles from liver primary tumors to metachronous lung metastases indicate that the genomic features during tumorigenesis may be retained during metastasis.
We found very similar genomic alterations between primary and metastatic tumors, with a few mutations found specifically in lung metastases, which may explain the clinical observation that both primary and metastatic tumors are usually sensitive or resistant to the same systemic treatments.
Cancer; Hepatocellular carcinomas (HCC); Lung metastasis; Somatic; Next-generation sequencing (NGS)
Glomus tumors of the lung are rare benign neoplasm, originating from modified smooth muscle cells. The patients are usually presented with no or non-specific symptoms such as cough, dyspnea or hemoptysis. Although surgical treatment is considered as the treatment of choice, the endobronchial therapy can be applied to the patients who are unfit for surgical excision. Herein, we describe two rare cases of glomus tumor originated at large airway (trachea and main bronchus) without respiratory symptoms and review their characteristic radiologic, macroscopic and pathological features.
Glomus Tumor; Lung; Trachea
Loss of E-cadherin, a hallmark of epithelial-mesenchymal transition (EMT), can significantly affect metastatic dissemination. However, the molecular mechanism of EMT-associated metastatic dissemination by loss of E-cadherin still remains unclear in non-small cell lung cancers (NSCLCs). In the present study, we show that the knockdown of E-cadherin was sufficient to convert A549 NSCLC cells into mesenchymal type with the concurrent up-regulation of typical EMT inducers such as ZEB1 and TWIST1. Interestingly, the EMT-induced cells by E-cadherin depletion facilitate invasion in a matrix metalloproteinase-2 (MMP2)-dependent manner with aberrant activation of EGFR signaling. We demonstrated that the elevated invasiveness was a result of the activated EGFR-MEK/ERK signaling, which in turn leads to ZEB1 dependent MMP2 induction. These results suggest that the EGFR-MEK/ERK/ZEB1/MMP2 axis is responsible for promoted invasion in EMT-induced NSCLCs. Consistently, ERK activation and loss of E-cadherin were both observed in the disseminating cancer cells at the invasive tumor fronts in NSCLC cancer tissues. Thereby, these data suggest that the EGFR-MEK/ERK signaling would be a promising molecular target to control aberrant MMP2 expression and consequent invasion in the EMT-induced NSCLCs
E-Cadherin; EGFR-MEK/ERK signaling; ZEB1; MMP2; Invasion
It has long been recognized that bronchial schwannomas are extremely rare. As such, diagnosing tumors in this extraordinary location can sometimes be problematic.
We reviewed seven cases of bronchoscopically or surgically resected endobronchial schwannomas and evaluated their clinical and pathologic features.
The present study included five female and two male patients, with ages ranging from 16 to 81 years (mean age, 44.9 years). The clinical presentation varied according to tumor size and location. Patients with more centrally (trachea or main bronchus) located tumors experienced respiratory symptoms (80%) more often than patients with more peripherally (lobar or segmental bronchus) located tumors (0%). Histologically, the tumors were composed of spindle cells that stained with S100 protein. Some of the tumors showed typical Antoni A areas with Verocay body formation. Five of six patients (83.3%) underwent complete tumor removal by rigid bronchoscopy.
Pathologists should consider endobronchial schwannoma in the differential diagnosis of a spindle cell tumor involving the bronchus. Additionally, our results showed that rigid bronchoscopy is an effective tool for tumor removal in endobronchial schwannoma patients.
Schwannoma; Neurilemmoma; Bronchi; Brnchoscopy
A pulmonary mucinous cystadenocarcinoma is an extremely rare tumor that is considered to be a cystic variant of mucin-producing lung adenocarcinoma. We present a case of pulmonary mucinous cystadenocarcinoma in a 54-year-old woman. Chest CT scans showed a 4.3-cm-sized, lobulated, well-defined, and homogeneous mass in the right middle lobe with peripheral stippled calcifications that demonstrated low-attenuation with no enhancement after contrast administration; 18F-fluorodeoxyglucose (FDG) PET/CT demonstrated mild heterogeneous FDG uptake. The mass was diagnosed as adenocarcinoma with mucin production by transbronchial lung biopsy. Right middle lobectomy was performed, and the pathologic examination disclosed a pulmonary mucinous cystadenocarcinoma.
Pulmonary mucinous cystadenocarcinoma; Lung cancer; CT; PET/CT
Deep sequencing techniques provide a remarkable opportunity for comprehensive understanding of tumorigenesis at the molecular level. As omics studies become popular, integrative approaches need to be developed to move from a simple cataloguing of mutations and changes in gene expression to dissecting the molecular nature of carcinogenesis at the systemic level and understanding the complex networks that lead to cancer development.
Here, we describe a high-throughput, multi-dimensional sequencing study of primary lung adenocarcinoma tumors and adjacent normal tissues of six Korean female never-smoker patients. Our data encompass results from exome-seq, RNA-seq, small RNA-seq, and MeDIP-seq. We identified and validated novel genetic aberrations, including 47 somatic mutations and 19 fusion transcripts. One of the fusions involves the c-RET gene, which was recently reported to form fusion genes that may function as drivers of carcinogenesis in lung cancer patients. We also characterized gene expression profiles, which we integrated with genomic aberrations and gene regulations into functional networks. The most prominent gene network module that emerged indicates that disturbances in G2/M transition and mitotic progression are causally linked to tumorigenesis in these patients. Also, results from the analysis strongly suggest that several novel microRNA-target interactions represent key regulatory elements of the gene network.
Our study not only provides an overview of the alterations occurring in lung adenocarcinoma at multiple levels from genome to transcriptome and epigenome, but also offers a model for integrative genomics analysis and proposes potential target pathways for the control of lung adenocarcinoma.
Primary leiomyoma of the respiratory tract is a rare disease. Based on our experience, we investigated its clinical characteristics and outcomes of treatment.
Between 1997 and 2008, 16 patients in our institution (nine male, seven female) were found to have primary leiomyoma of the respiratory tract. The median patient age was 46.5 years (range 17–66 years). The tumor was located in the trachea in four patients, in the carina and main bronchus in four, in the bronchus intermedius in four, in the lobar or segmental bronchus in two, and in the lung parenchyma in two.
Tumor removal through bronchoscopic intervention using Nd–YAG (neodymium–yttrium–aluminum–garnet) laser cauterization was attempted in 11 patients; it failed in two with wide-based tumors. Surgical resection was performed in seven patients. Operative procedures included tracheal resection and end-to-end anastomosis (n = 3), lobectomy (n = 3), and bilobectomy (n = 1). There were no in-hospital mortalities. During a median follow-up duration of 43.2 months, one patient who underwent bronchoscopic removal had recurrence, for which segmental resection of the trachea and main bronchus with carinal reconstruction was performed.
Bronchoscopic intervention can offer successful control of primary leiomyoma of the main airway stem; however, in cases of a wide-based tumor, bronchoscopic intervention can result in incomplete resection or recurrence. Surgical complete resection can yield satisfactory outcomes in patients with primary leiomyoma occurring in the respiratory tract.
Primary leiomyoma of the respiratory tract; Rigid bronchoscopy; Surgery
To determine the effectiveness of salvage radiation therapy (RT) in patients with loco-regional recurrences (LRR) following initial complete resection of non-small cell lung cancer (NSCLC) and assess prognostic factors affecting survivals.
Materials and Methods
Between 1994 and 2007, 64 patients with LRR after surgery of NSCLC were treated with high dose RT alone (78.1%) or concurrent chemo-radiation therapy (CCRT, 21.9%) at Samsung Medical Center. Twenty-nine patients (45.3%) had local recurrence, 26 patients (40.6%) had regional recurrence and 9 patients (14.1%) had recurrence of both components. The median RT dose was 54 Gy (range, 44-66 Gy). The radiation target volume included the recurrent lesions only.
The median follow-up time from the start of RT in survivors was 32.0 months. The rates of in-field failure free survival, intra-thoracic failure free survival and extra-thoracic failure free survival at 2 years were 52.3%, 33.9% and 59.4%, respectively. The median survival after RT was 18.5 months, and 2-year overall survival (OS) rate was 47.9%. On both univariate and multivariate analysis, the interval from surgery till recurrence and CCRT were significant prognostic factors for OS.
The current study demonstrates that involved field salvage RT is effective for LRR of NSCLC following surgery.
Concurrent chemo-radiation therapy; locoregional recurrence; non-small cell lung cancer; radiation therapy; salvage treatment
Retrospective analyses of patients with stage I-II thymic epithelial tumors (TET) who were treated with either surgery alone (S) or surgery plus postoperative radiation therapy (SRT) were conducted to evaluate the role of adjuvant radiation therapy (RT).
Materials and Methods
A total of 110 stage I-II TET patients following complete resection were included in this study. Postoperative radiation therapy was recommended for those with aggressive histologic type and/or invasive features according to the surgeons' judgment during the operation. A median dose of 54.0 Gy (range, 44 to 60 Gy) focused on the primary tumor bed was administered to 57 patients (51.8%).
In all patients, the rates of overall survival, disease-specific survival, and disease-free survival at 10 years were 91.7%, 97.1%, and 95.8%, respectively. No significant differences in disease-specific survival (100% in the S group and 93.5% in the SRT group at 10 years, p=0.12) and disease-free survival (98.1% in the S group and 94.5% in the SRT group at 10 years, p=0.41) were observed between the treatment groups, although a significantly larger number of World Health Organization (WHO)-type B2-C (p<0.001) and Masaoka stage II (p=0.03) tumors were observed in the SRT group than in the S group. No local recurrence was observed in the SRT group. No grade 2 or greater RT-related toxicities were observed in the SRT group.
Excellent outcomes were achieved in patients with stage I-II TET who underwent complete resection. Considering excellent local control and low morbidity, adjuvant RT may be considered in high risk patients with WHO-type B2-C histology and Masaoka stage II.
Thymic neoplasms; Surgery; Adjuvant radiotherapy
Thymoma is a common anterior mediastinal mass, although thymomas have occasionally been found in the neck, pulmonary hillus, or posterior mediastinum. But a thymoma within the middle mediastinum has rarely been reported. We report a thymoma arising in the middle mediastinum with a review of the literature.
Thymoma; Mediastinal neoplasms
Thymic neuroendocrine carcinomas (NECs) are uncommon, for which there is no established information available because of a limited number of epidemiological study in Asia.
We reviewed 21 cases of surgically resected thymic NECs, and evaluated their pathological and clinical features.
It showed male predominance (male/female ratio, 15/6) with wide age range from 20 to 72 years (mean age, 49 years). All 21 cases were divided into two types according to the World Health Organization criteria: atypical carcinoid (n=18) and large cell NEC (n=3). Three cases of atypical carcinoid (AC) were associated with ectopic Cushing's syndrome. All the patients (3/3) with large cell NEC (3/3) and 16.7% (3/18) of those with AC died of tumor progression. Common sites of metastasis included lung, lymph node, brain, lumbar spine, mediastinum, bone, and liver.
In conclusion, thymic neuroendocrine tumors carry a poor prognosis. Regarding the tumor classification, our results showed that a vast majority of carcinoids in the thymus correspond to ACs. In addition, our results also indicate that typical carcinoid is a very rare entity. Some cases of AC exhibited a large size, solid pattern and they showed aggressive clinical behavior, which highlights the spectrum of histologic appearances of thymic NECs.
Thymus gland; Carcinoid tumor; Carcinoma, neuroendocrine
This study was performed to discover prognostic genomic markers associated with post-operative outcome of stage I-III non-small cell lung cancer (NSCLC) that are reproducible between geographically distant and demographically distinct patient populations.
American patients (n=27) were stratified on the basis of recurrence and microarray profiling of their tumors was performed to derive a training set of 44 genes. A larger Korean patient validation cohort (n=138) was also stratified by recurrence and screened for these genes. Four reproducible genes were identified and used to construct genomic and clinicogenomic Cox models for both cohorts.
Four genomic markers, DBN1 (drebrin 1), CACNB3 (calcium channel beta 3), FLAD1 (PP591; flavin adenine dinucleotide synthetase), and CCND2 (cyclin D2), exhibited highly significant differential expression in recurrent tumors in the training set (P<0.001). In the validation set, DBN1, FLAD1 (PP591) and CACNB3 were significant by Cox univariate analysis (P≤0.035), whereas only DBN1 was significant by multivariate analysis. Genomic and clinicogenomic models for recurrence free survival (RFS) were equally effective for risk stratification of stage I-II or I-III patients (all models P<0.0001). For stage I-II or I-III patients, 5-y RFS of the low- and high-risk patients was ∼ 70 vs. 30% for both models. The genomic model for overall survival (OS) of stage I-III patients was improved by addition of pT and pN stage (P<0.0013 vs. 0.010).
A 4-gene prognostic model incorporating the multivariate marker DBN1 exhibits potential clinical utility for risk stratification of stage I-III NSCLC patients.
NSCLC recurrence; DBN1; CACNB3; FLAD1; CCND2
Video-assisted thoracic surgery (VATS) lobectomy has been performed with increasing frequency over the last decade. However, there is still controversy as to its indications, safety, and feasibility. Especially regarding lung cancer surgery, it is not certain whether it can reduce local recurrences and improve overall survival.
Materials and Methods
We retrospectively reviewed 1,067 cases of VATS lobectomy performed between 2003 and 2009, including the indications, postoperative morbidity, mortality, recurrence, and survival rate.
One thousand and sixty seven patients underwent VATS lobectomy for the following indications: non-small cell lung cancer (NSCLC) (n=832), carcinoid tumors (n=12), metastatic lung cancer (n=48), and benign or other diseases (n=175). There were 63 cases (5.9%) of conversion to open thoracotomy during VATS lobectomy. One hundred thirty one (15.7%) of the 832 NSCLC patients experienced pathologic upstaging postoperatively. The hospital mortality rate was 0.84% (9 patients), and all of them died of acute respiratory distress syndrome. One hundred forty-nine patients (14.0%) experienced postoperative complications. The median follow-up was 22.9 months for patients with NSCLC. During follow-up, 120 patients had a recurrence and 55 patients died. For patients with pathologic stage I, the overall survival rate and disease-free survival rate at 3 years was 92.2±1.5% and 86.2±1.9%, respectively. For patients with pathologic stage II disease, the overall survival rate and disease-free survival rate at 3 years was 79.2±6.5% and 61.9±6.6%, respectively.
Our results suggest that VATS lobectomy is a technically feasible and safe operation, which can be applied to various lung diseases. In patients with early-stage lung cancer, excellent survival can be also achieved.
Video-assisted thoracic surgery; Lobectomy; Lung neoplasm
Although ARS-interacting multifunctional protein 2 (AIMP2, also named as MSC p38) was first found as a component for a macromolecular tRNA synthetase complex, it was recently discovered to dissociate from the complex and work as a potent tumor suppressor. Upon DNA damage, AIMP2 promotes apoptosis through the protective interaction with p53. However, it was not demonstrated whether AIMP2 was indeed pathologically linked to human cancer. In this work, we found that a splicing variant of AIMP2 lacking exon 2 (AIMP2-DX2) is highly expressed by alternative splicing in human lung cancer cells and patient's tissues. AIMP2-DX2 compromised pro-apoptotic activity of normal AIMP2 through the competitive binding to p53. The cells with higher level of AIMP2-DX2 showed higher propensity to form anchorage-independent colonies and increased resistance to cell death. Mice constitutively expressing this variant showed increased susceptibility to carcinogen-induced lung tumorigenesis. The expression ratio of AIMP2-DX2 to normal AIMP2 was increased according to lung cancer stage and showed a positive correlation with the survival of patients. Thus, this work identified an oncogenic splicing variant of a tumor suppressor, AIMP2/p38, and suggests its potential for anti-cancer target.
Lung cancer is one of the most common cancers and a leading cause of death resulting from cancer. Despite intensive investigation, effective therapeutic targets and reliable biomarkers are still limited. Here we found that a tumor suppressor, AIMP2 (MSC p38), produces a variant lacking a part of its structure in cancer tissues. We designated it AIMP2-DX2. This smaller version of AIMP2 compromises the normal tumor suppressive activity of AIMP2 and induces tumor formation. We also found that the expression of AIMP2-DX2 was increased according to cancer progression. In addition, the patients with higher expression of AIMP2-DX2 showed lower survival than those with lower levels of this variant. Suppression of AIMP2-DX2 slowed tumor growth, suggesting it as a new therapeutic target. In summary, this work newly identified a tumor-inducing factor, AIMP2-DX2, that can be used as a therapeutic target and biomarker associated with lung cancer.
Surgical excision is the primary treatment for a thymoma. However, for advanced thymoma that extends to within the thoracic cavity and for recurrent cases with pleural dissemination (Masaoka stage IVA), the appropriate treatment is controversial. We evaluated the safety of surgery and outcomes of seven patients that underwent an en bloc extended total thymectomy and extrapleural pneumonectomy for stage IVA thymomas.
From 1994 to 2009, five patients initially diagnosed with pleural dissemination and two patients with recurrent tumors in the pleura and lungs after a total thymectomy, were identified. Seven patients had an extrapleural pneumonectomy performed. For the first operation, five patients underwent additional en bloc extended total thymectomy.
Two recurrent cases were identified 55.2 and 12.3 months after first operation. Two patients had WHO type B1-B2 tumors, two had B2, two had B2-B3, and one had a B3 tumor. The mean hospital stay was 15.3 days (range: 7-29). There was no operative mortality. Four patients had neoadjuvant chemotherapy and five were treated with adjuvant chemotherapy. The median survival was 30.6 months and the Kaplan-Meier 2-year survival was 100% (95% confidence interval: 24.6-36.6 months). One patient, who did not receive induction chemotherapy, had distant metastases after surgery.
En bloc extended total thymectomy and extrapleural pneumonectomy can be safely performed on selected patients with stage IVA thymomas and is expected to achieve complete local control. Although the treatment strategy has yet to be standardized, complete resection with appropriate systemic therapy may improve survival in otherwise fatal disease.
The EML4-ALK fusion gene has been detected in ~7% of Japanese non-small cell lung cancers (NSCLC). We determined the frequency of EML4-ALK in Caucasian NSCLCs and in NSCLC cell lines. We also determined whether TAE684, a specific ALK kinase inhibitor, would inhibit the growth of EML4-ALK containing cell lines in vitro and in vivo.
We screened 305 primary NSCLCs (both US (n=138) and Korean (n=167) patients) and 83 NSCLC cell lines using RT-PCR and by exon array analyses. We evaluated the efficacy of TAE684 against NSCLC cell lines in vitro and in vivo.
We detected 4 different variants, including two novel variants, of EML4-ALK using RT-PCR in 8/305 tumors (3%) and in 3/83 (3.6%) NSCLC cell lines. All EML4-ALK containing tumors and cell lines were adenocarcinomas. EML4-ALK was detected more frequently in NSCLC patients who were never or light (< 10 pack years) cigarette smokers compared to current/former smokers (6% vs. 1%; p=0.049). TAE684 inhibited the growth of 1 of 3 (H3122) EML4-ALK containing cell lines in vitro and in vivo, inhibited Akt phosphorylation and caused apoptosis. In another EML4-ALK cell line, DFCI032, TAE684 was ineffective due to co-activation of EGFR and ERBB2. The combination of TAE684 and CL-387,785 (EGFR/ERBB2 kinase inhibitor), inhibited growth and Akt phosphorylation and led to apoptosis in the DFCI032 cell line.
EML4-ALK is found in the minority of NSCLCs. ALK kinase inhibitors alone or in combination may nevertheless be clinically effective treatments for NSCLC patients whose tumors contain EML4-ALK.
Carcinoma, Non-Small-Cell lung; EML4-ALK; ALK; Kinase inhibitor
Mycobacterium celatum is a nontuberculous mycobacterium that rarely causes pulmonary disease in immunocompetent subjects. We describe the successful treatment of M. celatum lung disease with antimicobacterial chemotherapy and combined pulmonary resection. A 33-year-old woman was referred to our hospital with a 3-month history of a productive cough. Her medical history included pulmonary tuberculosis 14 years earlier. Her chest X-ray revealed a large cavitary lesion in the left upper lobe. The sputum smear was positive for acid-fast bacilli, and M. celatum was subsequently identified in more than three sputum cultures, using molecular methods. After 1 year of therapy with clarithromycin, ethambutol, and ciprofloxacin, the patient underwent a pulmonary resection for a persistent cavitary lesion. The patient was considered cured after receiving 12 months of postoperative antimycobacterial chemotherapy. There has been no recurrence of disease for 18 months after treatment completion. In summary, M. celatum is an infrequent cause of potentially treatable pulmonary disease in immunocompetent subjects. Patients with M. celatum pulmonary disease who can tolerate resectional surgery might be considered for surgery, especially in cases of persistent cavitary lesions despite antimycobacterial chemotherapy.
Nontuberculous mycobacteria; Mycobacterium celatum; lung disease; surgery
Pulmonary ossification has been rarely observed in pulmonary fibrosis and in some chronic respiratory diseases such as chronic obstructive pulmonary disease. We report here a metaplastic ossification in the bronchial cartilage of a patient with multi-drug resistant tuberculosis.
We report the case of a 41-year-old Asian man from Korea with chronic multi-drug resistant tuberculosis with a rare focus of bone formation from the cartilage of a bronchus subtending an active cavity. The patient had a large multi-lobed, thick-walled cavitary tuberculosis lesion in his left upper lobe. Severe infiltration of his lymphocytes and epithelioid cells, along with some giant cells and neutrophils, was observed in the patient's bronchial wall. Desquamated bronchial epithelium and acid-fast bacilli were found inside his bronchus. A small focus of bony metaplasia was found in the cartilage of his bronchial wall. Histopathological examination confirmed calcification and showed hematopoietic cells forming in his marrow cavity.
Chronic inflammation in the lungs of our patient, caused by underlying tuberculosis, probably played a role in the development of osseous metaplasia from the associated cartilage of the bronchial wall.
We present a recurrence prediction model using multiple clinical parameters in patients surgically treated for non-small cell lung cancer. Among 1,578 lung cancer patients who underwent complete resection, we compared the early-recurrence group with the 3-yr non-recurrence group for evaluating those factors that influence early recurrence within one year after surgery. Adenocarcinoma and squamous cell carcinoma were analyzed independently. We used multiple logistic regression analysis to identify the independent clinical predictors of recurrence and Cox's proportional hazard regression method to develop a clinical prediction model. We randomly divided our patients into the training and test subsets. The pathologic stages, tumor cell type, differentiation of tumor, neoadjuvant therapy and age were significant factors on the multivariable analysis. We constructed the model for the training set with adenocarcinoma (n=236) and squamous cell carcinoma (n=305), and we applied it to the test set with adenocarcinoma (n=110) and squamous cell carcinoma (n=154). It was predictive for the in adenocarcinoma (P<0.001) and the squamous cell carcinoma (P=0.037), respectively. Our results showed that our recurrence prediction model based on the clinical parameters could significantly predict the individual patients who were at high risk or low risk for recurrence.
Carcinoma, Non-Small-Cell Lung; Prognosis; Recurrence
High-dose chemotherapy and autologous stem cell rescue (HDCT/ASCR) was applied to improve the prognosis of patients with high-risk stage 3 neuroblastoma. From January 1997 to December 2006, 28 patients were newly diagnosed as stage 3 neuroblastoma. Nine of 11 patients with N-myc amplification and 5 of 17 patients without N-myc amplification (poor response in 2 patients, persistent residual tumor in 2 and relapse in 1) underwent single or tandem HDCT/ASCR. Patients without high-risk features received conventional treatment modalities only. While 8 of 9 patients underwent single HDCT/ASCR and the remaining one patient underwent tandem HDCT/ASCR during the early study period, all 5 patients underwent tandem HDCT/ASCR during the late period. Toxicities associated with HDCT/ASCR were tolerable and there was no treatment-related mortality. While the tumor relapsed in two of eight patients in single HDCT/ASCR group, all six patients in tandem HDCT/ASCR group remained relapse free. The 5-yr event-free survival (EFS) from diagnosis, in patients with N-myc amplification, was 71.6±14.0%. In addition, 12 of 14 patients who underwent HDCT/ASCR remained event free resulting in an 85.1±9.7% 5-yr EFS after the first HDCT/ASCR. The present study demonstrates that HDCT/ASCR may improve the survival of patients with high-risk stage 3 neuroblastoma.
Neuroblastoma; High-dose Chemotherapy; Autologous Stem Cell Rescue; Prognosis; N-myc
Neuroblastomas originating from different sites might have different clinical and biological characteristics. In the present study, the clinical (age, sex and stage) and biological (N-myc amplification, Shimada pathology and levels of lactate dehydrogenase, ferritin and neuron-specific enolase) characteristics of patients with newly diagnosed neuroblastoma were compared according to the site of tumor origin (extra-abdominal versus abdominal). The event-free survival rate (EFS) was also compared between the two groups. Among 143 neuroblastomas, 115 tumors originated from the abdomen, 26 from extra-abdominal sites and 2 from unknown primary sites. Frequencies of stage 4 tumor and N-myc amplified tumor were lower in the extra-abdominal group than in the abdominal group (34.6% vs. 60.0%, P=0.019 and 4.2% vs. 45.0%, P<0.001, respectively). Levels of lactate dehydrogenase, ferritin and neuron-specific enolase were significantly lower in the extra-abdominal group than in the abdominal group. The probability of 5-yr EFS (±95% confidence interval) was higher in the extra-abdominal group than in the abdominal group (94.4±10.6% vs. 69.4±9.4%, P=0.026). Taken together, neuroblastomas originating from extra-abdominal sites might be associated with more favorable clinical and biological characteristics and a better outcome than neuroblastomas originating from abdomen.
Neuroblastoma; Prognosis; Thorax; Transplantation, Autologous
Pulmonary adenocarcinoma is a common malignancy that often involves calcification; however, bone formation in primary lung adenocarcinoma is extremely rare. In ten cases of primary pulmonary adenocarcinoma with heterotopic ossification, we detected immunoreactivity against TGF-β1, osteopontin, osteocalcin and Runx2 in the fibroblastic stroma and tumor cells within the area of ossification. Our results suggest that in primary pulmonary adenocarcinoma, heterotopic ossification occurs via intramembranous bone formation. To our knowledge, only 11 other cases of pulmonary adenocarcinoma with heterotopic ossification have been reported. Here, we present ten cases of pulmonary adenocarcinoma showing heterotopic ossification with a description of previously published results and the histogenesis of heterotopic bone formation.
Lung Neoplasms; Adenocarcinoma; Choristoma; Immunohistochemistry; Metaplasia; Ossification
This study was designed to evaluate follow-up results in terms of patient prognosis for malignant pulmonary nodules depicted as pure ground-glass opacity (GGO) lesion observed at high-resolution CT (HRCT).
Materials and Methods
Surgical removal for malignant GGO nodules was accomplished in 58 patients (26 men, 32 women; mean age, 57 years; age range, 29-78 years). Patient prognoses were assessed by patient clinical status and the presence of changes in nodule size determined after a follow-up HRCT examination. Differences in patient prognoses were compared for nodule number, size, surgical method, change in size before surgical removal, and histopathological diagnosis by use of Fisher's exact test and Pearson's chi-squared test.
Of the 58 patients, 40 patients (69%) were confirmed to have a bronchioloalveolar carcinoma (BAC) and 18 patients (31%) were confirmed to have an adenocarcinoma with a predominant BAC component. Irrespective of nodule size, number, treatment method, change in size before surgical removal and histopathological diagnosis, neither local recurrence nor a metastasis occurred in any of these patients as determined at a follow-up period of 24 months (range; 12-65 months). Of 14 patients with multiple GGO nodules, all of the nodules were resected without recurrence in six patients. In the remaining eight patients, the remaining nodules showed no change in size in seven cases and a decrease in size in one case as determined after a follow-up CT examination.
Prognoses in patients with pure GGO malignant pulmonary nodules are excellent, and not significantly different in terms of nodule number, size, surgical method, presence of size change before surgical removal and histopathological diagnosis.
Bronchioloalveolar cell carcinoma; Ground-glass opacity; Lung neoplasms, CT; Lung neoplasms, therapy