Background: Correlations between volume doubling time (VDT) of primary lung cancer (PLC), histology, and ground glass opacity (GGO) components remain unclear. The purpose of this study was to evaluate and compare VDT of PLC in terms of histology and presence or absence of GGO components. Methods: A total of 371 surgically resected PLCs from 2003 to 2015 in our institute were retrospectively reviewed. The VDT was calculated both from the diameters of the entire tumor and of consolidation by using the approximation formula of Schwartz. Results: The median VDTs of adenocarcinoma, squamous cell carcinoma, and others (large cell neuroendocrine carcinomas, small cell lung carcinomas, pulmonary pleomorphic carcinomas, and large cell carcinomas combined) were 261, 70, and 70 days, respectively; these differ significantly (P<0.001). All PLCs with GGO were adenocarcinomas. The VDT of adenocarcinomas with GGO was significantly longer than that of those without GGO (median VDT: 725 and 177 days, respectively), squamous cell carcinomas, and others. When the VDT calculated from the maximum diameter of consolidation component was compared, adenocarcinomas with GGO also showed significantly slower growth than those without GGO (median VDT: 248 versus 177 days, respectively, P=0.040). Conclusions: The VDT of PLCs is longest for adenocarcinomas. VDT was significantly longer in adenocarcinomas with GGO components than in those without such components, irrespective of VDT calculated on the basis of either the entire tumor diameter or consolidation diameter.
Activating mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) loci are largely predictive of resistance to epidermal growth factor receptor (EGFR) therapy in colorectal cancer (CRC). A highly sensitive detection system for the KRAS gene mutations is urgently needed; however, conventional methods have issues with feasibility and cost performance. Here, we describe a novel detection system using a fluorescence ʻEprobe' capable of detecting low level KRAS gene mutations, via real-time PCR, with high sensitivity and simple usability. We designed our Eprobes to be complementary to wild-type (WT) KRAS or to the commonly mutated codons 12 and 13. The WT Eprobe binds strongly to the WT DNA template and suppresses amplification by blocking annealing of the primer during PCR. Eprobe-PCR with WT Eprobe shows high sensitivity (0.05-0.1% of plasmid DNA, 1% of genomic DNA) for the KRAS mutation by enrichment of the mutant type (MT) amplicon. Assay performance was compared to Sanger sequencing using 92 CRC samples. Discrepancies were analyzed by mutation genotyping via Eprobe-PCR with full match Eprobes for 7 prevalent mutations and the next generation sequencing (NGS). Significantly, the Eprobe system had a higher sensitivity for detecting KRAS mutations in CRC patient samples; these mutations could not be identified by Sanger sequencing. Thus, the Eprobe approach provides for highly sensitive and convenient mutation detection and should be useful for diagnostic applications.
Murine double minute 2 (MDM2) is a negative regulator of p53. A single‑nucleotide polymorphism (SNP) (rs2279744: c.309T>G) in the promoter region of the MDM2 gene has been shown to result in higher levels of MDM2 RNA and protein. Regarding the contribution of c.309T>G in the MDM2 gene to the lung cancer risk, previous studies are conflicting. In order to evaluate the association between c.309T>G and the lung cancer risk, a case‑control study was performed. The MDM2 genotypes were determined in 762 lung cancer patients and in 700 cancer‑free control subjects using the Smart Amplification Process. Statistical adjustment was performed for gender, age and pack‑years of smoking. The distributions of c.309T>G (T/T, T/G, G/G) were 20.1, 49.7, 30.2% in the case group and 21.7, 47.9, 30.4% in the healthy‑control group. There were no overall associations between the MDM2 genotypes and the risk of lung cancer [T/G genotype: Adjusted odds ratio (AOR), 1.30; 95% confidence interval (CI), 0.88‑1.93; and G/G genotype: AOR, 1.18; 95% CI, 0.78‑1.80]. The subgroup analysis of gender, histology, smoking status and epidermal growth factor receptor mutation status also indicated that there was no association with lung cancer. Additionally, the genotypes did not have an effect on the age at the time of diagnosis of lung cancer (P=0.25). In conclusion, the G allele frequency in the lung cancer cases was 0.551, which was similar to other studies. The results of the present study suggest that the c.309T>G is not significantly associated with lung cancer.
Somatic mutation in human epidermal growth factor receptor-related 2 gene (HER2) is one of the driver mutations in lung cancer. HER2 mutations are found in about 2% of lung adenocarcinomas (ADCs). Previous reports have been based mainly on diagnostic screening by Sanger sequencing or next-generation sequencing (NGS); however, these methods are time-consuming and complicated. We developed a rapid, simple, sensitive mutation detection assay for detecting HER2 12 base pair-duplicated insertion mutation based on the Eprobe-mediated PCR method (Eprobe-PCR) and validated the sensitivity of this assay system for clinical diagnostics. We examined 635 tumor samples and analyzed HER2 mutations using the Eprobe-PCR method, NGS, and Sanger sequencing. In a serial dilution study, the Eprobe-PCR was able to detect mutant plasmid DNA when its concentration was reduced to 0.1% by mixing with wild-type DNA. We also confirmed amplification of the mutated plasmid DNA with only 10 copies per reaction. In ADCs, Eprobe-PCR detected the HER2 mutation in 2.02% (9/446), while Sanger sequencing detected it in 1.57% (7/446). Eprobe-PCR was able to detect the mutation in two samples that were undetectable by Sanger sequencing. All non-ADC samples were wild-type. There were no discrepancies between frozen and formalin-fixed paraffin-embedded tissues in the nine samples. HER2 mutations detected by NGS data validated the high sensitivity of the method. Therefore, this new technique can lead to precise molecular-targeted therapies.
11055 Background: The MDM2 protein plays an important role in regulating cell proliferation and apoptosis by ubiquitination and proteosome-mediated degradation of p53. c.309 (rs2279744) polymorphism (T>G) in the MDM2 intronic promoter has been reported as a susceptibility and/or prognostic factor in various cancers. The purpose of this study was to investigate the risk factors for worse survival in patients with pathological (p-) stage I lung adenocarcinoma. Methods: We retrospectively reviewed 179 stage I lung adenocarcinoma patients. Clinicopathological and genetic characteristics including MDM2 SNP309, p53 codon72, as well as EGFR, KRAS, and p53 mutation were analyzed. Associations between these factors and survival outcome were analyzed by cox proportional hazards models. We further evaluated the associations of prognostic effects of SNP309 and smoking status or gene mutation status by stratified analyses. Results: A significant association was found between pleural invasion or lymphatic invasion and SNP309 TT genotype (TT vs. TG+GG, p= .027, p= .008, respectively; χ2 test) Overall-survival (OS) of patients with MDM2 TT genotype was significantly shorter than that with TG genotype and GG genotype (p= .048 and p= .009, respectively by log-rank test). A multivariate analysis of OS showed that MDM2 genotype (TT; Hazard Ratio [HR] =3.7, 95% confidential interval [CI] 1.5 to 9.2, p= .005) was an independently significant prognostic factor. Subgroup analysis also showed that TT genotype was especially associated with worse OS among smoker group (HR=6.75, 95%CI 1.90 to 24.0, p= .005), EGFR wild-type group (HR=3.75, 95%CI 1.22 to 11.6, p= .022), p53 wild-type group (HR=7.00, 95%CI 2.30 to 21.3, p= .001), and p53 codon72 RR+RPgroup (HR=5.44, 95%CI 1.91 to 15.5, p= .002). Conclusions: Our findings suggest that MDM2 TT genotype is associated with worse OS among p-stage I lung adenocarcinoma patients, particularly in the smoker group, EGFR wild-type group, p53 wild-type group, and p53 codon72 RR+RP group.
Cardiac tamponade caused by coronary artery injury is an extremely rare postlobectomy complication. Herein, we present a case of cardiac tamponade due to coronary artery injury after a left upper lobectomy for lung cancer and discuss the possible cause of coronary artery injury.
Abstract Background We have previously reported apolipoprotein A2-isoforms (apoA2-is) as candidate plasma biomarkers for early-stage pancreatic cancer. The aim of this study was the clinical development of apoA2-is. Methods We established a new enzyme-linked immunosorbent sandwich assay for apoA2-is under the Japanese medical device Quality Management System requirements and performed in vitro diagnostic tests with prespecified end points using 2732 plasma samples. The clinical equivalence and significance of apoA2-is were compared with CA19-9. Results The point estimate of the area under the curve to distinguish between pancreatic cancer ( n = 106) and healthy controls ( n = 106) was higher for apoA2-ATQ/AT [0.879, 95% confidence interval (CI): 0.832–0.925] than for CA19-9 (0.849, 95% CI 0.793–0.905) and achieved the primary end point. The cutoff apoA2-ATQ/AT of 59.5 μg/mL was defined based on a specificity of 95% in 2000 healthy samples, and the reliability of specificities was confirmed in two independent healthy cohorts as 95.3% ( n = 106, 95% CI 89.4–98.0%) and 95.8% ( n = 400, 95% CI 93.3–97.3%). The sensitivities of apoA2-ATQ/AT for detecting both stage I (47.4%) and I/II (50%) pancreatic cancers were higher than those of CA19-9 (36.8% and 46.7%, respectively). The combination of apoA2-ATQ/AT (cutoff, 59.5 μg/mL) and CA19-9 (37 U/mL) increased the sensitivity for pancreatic cancer to 87.7% compared with 69.8% for CA19-9 alone. The clinical performance of apoA2-is was blindly confirmed by the National Cancer Institute Early Detection Research Network. Conclusions The clinical performance of ApoA2-ATQ/AT as a blood biomarker is equivalent to or better than that of CA19-9.
The MDM2 protein plays an important role in the regulation of cell proliferation and apoptosis via ubiquitination and proteasome-mediated degradation of p53. The genetic polymorphism rs2279744 (c.309T>G) of the MDM2 gene is reportedly associated with susceptibility and/or prognosis in various cancers. In this study, we investigated the risk factors for worse survival in patients with lung adenocarcinoma (AC). We examined the association between c.309T>G and the prognosis of lung cancer by retrospectively reviewing 453 lung cancer patients. We studied both, clinicopathological and genetic characteristics, including the c.309T>G, p53 Arg72Pro, EGFR, KRAS, and p53 mutations. Associations between these factors and survival outcome were analyzed using Cox proportional hazards models. The frequencies of MDM2 polymorphisms were T/T, 20.8%; T/G, 48.6%, and G/G, 30.7%. The overall survival (OS) of AC patients with pathological stage I disease and the MDM2 T/T genotype was significantly shorter than that of those with the T/G or G/G genotypes (P = 0.02). Multivariate analysis revealed that the MDM2 T/T genotype was an independent, significant prognostic factor (hazard ratio [HR] = 2.23; 95% confidence interval [CI]: 1.07–4.65; P = 0.03). The MDM2 T/T genotype was predictive of poorer survival in a Japanese population. Genotyping for this polymorphism might predict the clinical outcomes of stage I AC patients.
Abstract Introduction Most thoracic surgeons encounter atypical cases or unexpected situations that usually lead them to convert minimally invasive surgery to open thoracotomy. But are there other options besides open surgery? The purpose of this study was to suggest a video‐assisted thoracic surgery ( VATS ) classification system and present tips for the application of VATS to atypical cases or unexpected situations. We have categorized VATS procedures for atypical cases or unexpected situations into two groups: the modification of techniques/instruments and the creation of additional access incisions. Methods We retrospectively reviewed VATS with optional additional techniques. We used direct visualization or monitoring as the situation demanded, switching back and forth between the monitor and direct vision. Results Of the 33 cases we reviewed, 27 patients had malignant lung disease and 6 had benign lung disease. All patients underwent lobectomies including one or more of the following: bronchoplasty ( n = 12), control of the main pulmonary artery ( n = 9), total adhesiotomy ( n = 7), combined resection with the diaphragm ( n = 3), and separation of totally fused fissures ( n = 2). The mean length of the skin incision was 8 cm, the mean total operating time was 208 min, and the mean blood loss was 173 mL No operative or hospital deaths occurred. Conclusions Veteran surgeons can instinctively deal with intraoperative variance, but we frequently see inexperienced surgeons panic and change the course of their procedures. A VATS classification system may have educational benefits for newer surgeons. We believe that the creation of a categorized coping plan will help inexperienced surgeons deal with unanticipated problems.
Our objective was to evaluate the validity of pulmonary metastasectomy for postoperative colorectal cancer with hepatic metastasis and to investigate the role of clinicopathological factors as predictors of outcome.Consecutive patients undergoing pulmonary metastasectomy for colorectal cancer with (group PH, n=27) or without (group P, n=46) a history of hepatic metastasis were included in the study. Clinicopathological variables, including sex, age, site, serum carcinoembryonic antigen level of the primary tumor, disease-free interval, prior hepatic resection, timing of pulmonary metastases, preoperative chemotherapy, type of pulmonary resection, and number, size, and location of pulmonary metastases were retrospectively collected and investigated for prognostic significance.The 5-year survivals were 59.5% (PH) and 70.0% (P) with no significant difference. Among all investigated prognostic variables, sex (female vs male) and the number of pulmonary metastases( 1 vs >1) were the most important factors affecting outcome after colorectal resection and pulmonary resection.Pulmonary resection is not contraindicated in clinical practice. The presence of female gender and a single pulmonary metastasis were favorable predictors of survival after complete pulmonary resection for metastatic colorectal cancer.
