Harim Kim, Jonghoon Kim, Soohyun Hwang, You Jin Oh, Joong Hyun Ahn, Min-Ji Kim, Tae Hee Hong, Sung Goo Park, Joon Young Choi, Hong Kwan Kim, Jhingook Kim, Sumin Shin, Ho Yun Lee
Received March 7, 2024 Accepted June 22, 2024 Published online June 26, 2024
Purpose This study aimed to develop a magnetic resonance imaging (MRI)–based radiomics model to predict high-risk pathologic features for lung adenocarcinoma: micropapillary and solid pattern (MPsol), spread through air space, and poorly differentiated patterns.
Materials and Methods As a prospective study, we screened clinical N0 lung cancer patients who were surgical candidates and had undergone both 18F-fluorodeoxyglucose (FDG) positron emission tomography–computed tomography (PET/CT) and chest CT from August 2018 to January 2020. We recruited patients meeting our proposed imaging criteria indicating high-risk, that is, poorer prognosis of lung adenocarcinoma, using CT and FDG PET/CT. If possible, these patients underwent an MRI examination from which we extracted 77 radiomics features from T1-contrast-enhanced and T2-weighted images. Additionally, patient demographics, maximum standardized uptake value on FDG PET/CT, and the mean apparent diffusion coefficient value on diffusion-weighted image, were considered together to build prediction models for high-risk pathologic features.
Results Among 616 patients, 72 patients met the imaging criteria for high-risk lung cancer and underwent lung MRI. The magnetic resonance (MR)–eligible group showed a higher prevalence of nodal upstaging (29.2% vs. 4.2%, p < 0.001), vascular invasion (6.5% vs. 2.1%, p=0.011), high-grade pathologic features (p < 0.001), worse 4-year disease-free survival (p < 0.001) compared with non-MR-eligible group. The prediction power for MR-based radiomics model predicting high-risk pathologic features was good, with mean area under the receiver operating curve (AUC) value measuring 0.751-0.886 in test sets. Adding clinical variables increased the predictive performance for MPsol and the poorly differentiated pattern using the 2021 grading system (AUC, 0.860 and 0.907, respectively).
Conclusion Our imaging criteria can effectively screen high-risk lung cancer patients and predict high-risk pathologic features by our MR-based prediction model using radiomics.
Junghoon Shin, Sehhoon Park, Kyung Hwan Kim, Eui-Cheol Shin, Hyun Ae Jung, Jong Ho Cho, Jong-Mu Sun, Se-Hoon Lee, Yong Soo Choi, Jin Seok Ahn, Jhingook Kim, Keunchil Park, Young Mog Shim, Hong Kwan Kim, Jae Myoung Noh, Yong Chan Ahn, Hongryull Pyo, Myung-Ju Ahn
Cancer Res Treat. 2024;56(4):1084-1095. Published online April 30, 2024
Purpose Optimal treatment for stage IIIA/N2 non–small cell lung cancer (NSCLC) is controversial. We aimed to assess the efficacy and safety of adjuvant pembrolizumab for stage IIIA/N2 NSCLC completely resected after neoadjuvant concurrent chemoradiation therapy (CCRT).
Materials and Methods In this open-label, single-center, single-arm phase 2 trial, patients with stage IIIA/N2 NSCLC received adjuvant pembrolizumab for up to 2 years after complete resection following neoadjuvant CCRT. The primary endpoint was disease-free survival (DFS). Secondary endpoints included overall survival (OS) and safety. As an exploratory biomarker analysis, we evaluated the proliferative response of blood CD39+PD-1+CD8+ T cells using fold changes in the percentage of proliferating Ki-67+ cells from days 1 to 7 of cycle 1 (Ki-67D7/D1).
Results Between October 2017 and October 2018, 37 patients were enrolled. Twelve (32%) and three (8%) patients harbored EGFR and ALK alterations, respectively. Of 34 patients with programmed cell death ligand 1 assessment, 21 (62%), nine (26%), and four (12%) had a tumor proportion score of < 1%, 1%-50%, and ≥ 50%, respectively. The median follow-up was 71 months. The median DFS was 22.4 months in the overall population, with a 5-year DFS rate of 29%. The OS rate was 86% at 2 years and 76% at 5 years. Patients with tumor recurrence within 6 months had a significantly lower Ki-67D7/D1 among CD39+PD-1+CD8+ T cells than those without (p=0.036). No new safety signals were identified.
Conclusion Adjuvant pembrolizumab may offer durable disease control in a subset of stage IIIA/N2 NSCLC patients after neoadjuvant CCRT and surgery.
Il-Hyun Park, Dae-Soon Son, Yoon-La Choi, Ji-Hyeon Choi, Ji-Eun Park, Yeong Jeong Jeon, Minseob Cho, Hong Kwan Kim, Yong Soo Choi, Young Mog Shim, Jung Hee Kang, Suzy Park, Jinseon Lee, Sung-Hyun Kim, Byung-Chul Lee, Jhingook Kim
Cancer Res Treat. 2024;56(1):81-91. Published online June 20, 2023
Purpose Recently, we developed allele-discriminating priming system (ADPS) technology. This method increases the sensitivity of conventional quantitative polymerase chain reaction up to 100 folds, with limit of detection, 0.01%, with reinforced specificity. This prospective study aimed to develop and validate the accuracy of ADPS epidermal growth factor receptor (EGFR) Mutation Test Kit using clinical specimens.
Materials and Methods In total 189 formalin-fixed paraffin-embedded tumor tissues resected from patients with non–small cell lung cancer were used to perform a comparative evaluation of the ADPS EGFR Mutation Test Kit versus the cobas EGFR Mutation Test v2, which is the current gold standard. When the two methods had inconsistent results, next-generation sequencing–based CancerSCAN was utilized as a referee.
Results The overall agreement of the two methods was 97.4% (93.9%-99.1%); the positive percent agreement, 95.0% (88.7%-98.4%); and the negative percent agreement, 100.0% (95.9%-100.0%). EGFR mutations were detected at a frequency of 50.3% using the ADPS EGFR Mutation Test Kit and 52.9% using the cobas EGFR Mutation Test v2. There were 10 discrepant mutation calls between the two methods. CancerSCAN reproduced eight ADPS results. In two cases, mutant allele fraction was ultra-low at 0.02% and 0.06%, which are significantly below the limit of detection of the cobas assay and CancerSCAN. Based on the EGFR genotyping by ADPS, the treatment options could be switched in five patients.
Conclusion The highly sensitive and specific ADPS EGFR Mutation Test Kit would be useful in detecting the patients who have lung cancer with EGFR mutation, and can benefit from the EGFR targeted therapy.
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Purpose Guidelines recommend that non–small cell lung cancer (NSCLC) patients with suspected hilar lymph node (LN) metastases should undergo invasive mediastinal LN staging prior to surgical treatment via endosonography. We evaluated the diagnostic performance of endosonography for detecting occult mediastinal metastases (OMM) and determined the factors associated with OMM in NSCLC patients with radiological N1.
Materials and Methods Patients with confirmed primary NSCLC with radiological N1 who underwent endosonography for nodal staging assessment from January 2013 to December 2019 were retrospectively analyzed.
Results The prevalence of OMM was found to be 83/279 (29.7%) and only 38.6% (32/83) were diagnosed via endosonography. However, five of them were confirmed as N3 by endosonography. The overall diagnostic sensitivity, negative predictive value, accuracy, and area under the curve of endosonography were 38.6%, 79.4%, 81.7%, and 0.69, respectively. In multivariable analysis, central tumor (adjusted odds ratio [aOR], 2.05; 95% confidence interval [CI], 1.15 to 3.68; p=0.016), solid tumor (aOR, 10.24; 95% CI, 1.32 to 79.49; p=0.026), and adenocarcinoma (aOR, 3.01; 95% CI, 1.63 to 5.55; p < 0.001) were related to OMM in radiological N1 NSCLC patients.
Conclusion Although the sensitivity of endosonography for detecting OMM was only 40%, the prevalence of OMM was not low (30%) and some cases even turned out to be N3 diseases. Clinicians should be aware that OMM may be more likely in patients with central, solid, and adenocarcinomatous tumor when performing nodal staging in radiological N1 NSCLC via endosonography.
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Cancer Res Treat. 2023;55(1):94-102. Published online June 9, 2022
Purpose This multi-center, retrospective study was conducted to evaluate the long-term survival in patients who underwent surgical resection for small cell lung cancer (SCLC) and to identify the benefit of adjuvant therapy following surgery.
Materials and Methods The data of 213 patients who underwent surgical resection for SCLC at four institutions were retrospectively reviewed. Patients who received neoadjuvant therapy or an incomplete resection were excluded.
Results The mean patient age was 65.29±8.93 years, and 184 patients (86.4%) were male. Lobectomies and pneumonectomies were performed in 173 patients (81.2%), and 198 (93%) underwent systematic mediastinal lymph node dissections. Overall, 170 patients (79.8%) underwent adjuvant chemotherapy, 42 (19.7%) underwent radiotherapy to the mediastinum, and 23 (10.8%) underwent prophylactic cranial irradiation. The median follow-up period was 31.08 months (interquartile range, 13.79 to 64.52 months). The 5-year overall survival (OS) and disease-free survival were 53.4% and 46.9%, respectively. The 5-year OS significantly improved after adjuvant chemotherapy in all patients (57.4% vs. 40.3%, p=0.007), and the survival benefit of adjuvant chemotherapy was significant in patients with negative node pathology (70.8% vs. 39.7%, p=0.004). Adjuvant radiotherapy did not affect the 5-year OS (54.6% vs. 48.5%, p=0.458). Age (hazard ratio [HR], 1.032; p=0.017), node metastasis (HR, 2.190; p < 0.001), and adjuvant chemotherapy (HR, 0.558; p=0.019) were associated with OS.
Conclusion Adjuvant chemotherapy after surgical resection in patients with SCLC improved the OS, though adjuvant radiotherapy to the mediastinum did not improve the survival or decrease the locoregional recurrence rate.
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Cancer Res Treat. 2021;53(4):1057-1071. Published online March 9, 2021
Purpose
Survival probability changes over time in cancer survivors. This study examined conditional survival in patients undergoing curative resection for non-small cell lung cancer (NSCLC).
Materials and Methods
Five-year conditional recurrence-free survival (CRFS), conditional overall survival (COS), and conditional relative survival (CRS) up to 10 years after surgery were calculated in patients who underwent NSCLC resection from 1994 to 2016. These rates were stratified according to age, sex, year of diagnosis, pathological stage, tumor histology, smoking status, comorbidity, and lung function.
Results
Five-year CRFS increased from 65.6% at baseline to 90.9% at 10 years after surgery. Early differences in 5-year CRFS according to stratified patient characteristics disappeared, except for age: older patients exhibited persistently lower 5-year CRFS. Five-year COS increased from 72.7% to 78.3% at 8 years and then decreased to 75.4% at 10 years. Five-year CRS increased from 79.0% at baseline to 86.8% at 10 years. Older age and higher pathologic stage were associated with lower 5-year COS and CRS up to 10 years after surgery. Female patients, those with adenocarcinoma histology, non-smokers, patient without comorbidities and had good lung function showed higher COS and CRS.
Conclusion
CRFS improved over time, but significant risk remained after 5 years. CRS slightly improved over time but did not reach 90%, suggesting significant excess mortality compared to the general population. Age and stage remained significant predictors of conditional survival several years after surgery. Our conditional survival estimates should help clinicians and patients make informed treatment and personal life decisions based on survivorship status.
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Cancer Res Treat. 2018;50(1):95-102. Published online March 17, 2017
Purpose
Data are limited on programmed death ligand 1 (PD-L1) expression in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC).
Materials and Methods
We retrospectively evaluated the relationship between PD-L1 expression and recurrence-free survival (RFS) and overall survival in 319 patients with EGFR-mutant NSCLC who were treated at Samsung Medical Center from 2006 to 2014. Membranous PD-L1 expression on tumor cells was measured using the PD-L1 IHC 22C3 pharmDx antibody and reported as tumor proportion score (TPS). Kaplan-Meier methods, log-rank test, and Cox proportional hazards models were used for survival analysis.
Results
All patients had ≥ 1 EGFR mutation—54% in exon 19 and 39% in exon 21. Overall, 51% of patients had PD-L1–positive tumors. The prevalence of PD-L1 positivity was higher among patients with stages II-IV versus stage I disease (64% vs. 44%) and among patients with other EGFR mutations (75%) than with L858R mutation (39%) or exon 19 deletion (52%). PD-L1 positivity was associated with shorter RFS, with an adjusted hazard ratio of 1.52 (95% confidence interval [CI], 0.81 to 2.84; median, 18 months) for the PD-L1 TPS ≥ 50% group, 1.51 (95% CI, 1.02 to 2.21; median, 31 months) for the PD-L1 TPS 1%-49% group, and 1.51 (95% CI, 1.05 to 2.18) for the combined PD-L1–positive groups (TPS ≥ 1%) compared with the PD-L1–negative group (median, 35 months).
Conclusion
PD-L1 expression is associated with disease stage and type of EGFR mutation. PD-L1 positivity might be associated with worse RFS among patients with surgically treated EGFR-mutant NSCLC.
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Cancer Res Treat. 2017;49(4):880-889. Published online December 12, 2016
Purpose
The optimal adjuvant therapy modality for treating pN2 non-small cell lung cancer patients has not yet been established. In this study, the authors investigated clinical outcomes following three different adjuvant therapy modalities.
Materials and Methods
From January 2006 to December 2012, 240 patients with cN0/1 disease were found to have pN2 disease following curative resection and received one of three adjuvant therapy modalities:thoracic radiation therapy (TRT) and concurrent chemotherapy (CTx) (CCRT) (group I), CCRT plus consolidation CTx (group II), and CTx alone (group III). TRT was delivered to 155 patients (groups I/II), and full dose CTxwas delivered to 172 patients either as a consolidative or a sole modality (group II/III).
Results
During 30 months of median follow-up, 44 patients died and 141 developed recurrence. The 5-year overall survival (OS), locoregional control (LRC), distant metastasis-free survival (DMFS), and disease-free survival (DFS) rates of all patients were 76.2%, 80.7%, 36.4%, and 29.6%, respectively. There was no difference in OS among groups. TRT (groups I/II) significantly improved LRC, full dose CTx (groups II/III) did DMFS, and CCRT plus consolidation CTx (group II) did DFS, respectively.
Conclusion
The current study could support that TRT could improve LRC and full dose CTx could improve DMFS and that CCRT plus consolidation CTx could improve DFS.
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PURPOSE 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%). RESULTS 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. CONCLUSION 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.
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PURPOSE To evaluate the prognostic implication of histopathologic findings on the surgical specimens of N2 positive stage IIIA non-small cell lung cancer (NSCLC) patients who were treated with preoperative concurrent radiochemotherapy (CRCT) and surgery. MATERIALS AND METHODS: From May 1997 to April 2000, 48 patients with N2 positive stage IIIA NSCLC were treated with preoperative CRCT and surgery. Retrospective analyses were performed on 33 patients who underwent surgical resection. The thoracic radiation therapy (TRT) dose was 45 Gy over 5 weeks with a 1.8 Gy daily fraction using 10 MV X-rays. Chemotherapy consisted of two cycles of intravenous cisplatin (100 mg/m2, on days 1 and 29) and oral etoposide (50 mg/m2/day, on days 1~14 and 29~42), concurrently delivered with TRT. Surgery was performed around 4 weeks of the completion of CRCT. The median follow up was 18 months. The histopathologic findings, including the proportions of viable tumor cells, fibrosis, and necrosis, as well as the tumor and nodal statuses on the surgical specimens following the preoperative CRCT, were analyzed. RESULTS: The 3-year overall survival, disease-free survival, and local control rates were 46.1%, 49.5%, and 85.5%, respectively.
Post-surgical stages decreased in 18 patients (54.5%), including 3 pathologic complete responses, were unchanged in 13 (39.4%), and increased in two (6.1%). On univariate analyses, the low proportion of the viable tumor cells was the only factor favorably affecting the overall survival rate (p=0.0386), and the histologic type of squamous cell carcinoma was a favorable factor affecting disease free survival rate (p=0.0452). On multivariate analyses, however, no factor affected the overall survival, disease free survival, or local control rates. CONCLUSION: The histopathologic findings of the proportion of viable tumor cells, fibrosis, and necrosis on the surgical specimens following preoperative CRCT had few prognostic implications on uni-and multi-variate analyses. Furthermore, the primary tumor and nodal responses to preoperative CRCT did not influence the outcomes. Longer-term follow-up with a larger number of patients, however, is awaited.
PURPOSE This research was designed to evaluate the chronic effect of isolated lung perfusion (ILP) with cisplatin on dogs. MATERIALS AND METHODS Fifteen dogs were divided into three groups. Group I was in ILP without cisplatin, group II with 2.5 mg/kg and group III with 5.0 mg/kg of cisplatin for 30 minutes respectively. Serial blood samples were taken before and after ILP for quantitative analysis of serum lactate dehydrogenase (LDH) and blood urea nitrogen/creatinine (BUN/Cr). The specimens from the lung were obtained 2 weeks after ILP. RESULTS There were no statistic significant differences in LDH concentration according to the time interval among the groups. The LDH concentration peaked at 1 week after ILP and declined thereafter to the pre-ILP concentration. The concentration of BUN/Cr was in normal range.
Histologic examination showed no pathologic change. No significant histopathologic differences were found in the pulmonary parenchyme and vasculature among the groups. All of the dogs survived without complication 2 weeks after ILP. CONCLUSION In ILP with cisplatin of 5.0 mg/kg in normal dog, the toxicity of cisplatin itself was not observed. With further study about the technique of ILP with cisplatin it would be effective to deliver high concentration of cisplatin into the target tissue minimizing lung damage.
PURPOSE The biologic behavior of tumor cells is partially controlled by the microenvironment.
We investigated the expression levels of several genes involved in metastasis and drug response in RENCA cells growing in ectopic (skin) and orthotopic (kidney) sites. MATERIALS AND METHODS Murine renal carcinoma cells were injected into kidney (orthotopic) and subcutis (ectopic) of syngeneic mice. Mice were treated with doxorubicin (DXR) (8 mg/kg) on days 8 and 15 after tumor cell implantation. Drug response was measured both in vivo and ex vivo by measuring tumor size and MTT assay. We also performed an in situ mRNA hybridization to estimate the expression levels of mdr (multidrug resistance), EGFR (epidermal growth factor receptor) and type IV collagenase. RESULTS RENCA cells growing in the kidney of syngeneic mice produced metastatic lesions in the lung (57% of mice), while the same cells growing in the subcutis did not. Tumors growing in the kidney were more resistant to DXR than tumors growing in the subcutis. MTT assays revealed that tumor cells derived from kidney were more resistant to DXR than those cells from subcutis. In situ hybridization analyses showed that transcripts of EGFR and type IV collagenase genes in kidney tumors were higher than those of subcutaneous tumors but mdr expression showed no difference between the two tumors. CONCLUSION These results demonstrate that the organ environment influences the drug responsive ness and the expression of EGFR and type IV collagenase genes in murine renal cell carcinoma cells.
PURPOSE Cancer gene therapeutic strategy using p53 tumor suppresser gene have been suggested to be effective in many solid tumors including non-small cell lung cancer (NSCLC).
To test generalized applicability, we tested a number of non-small cell lung cancer cell lines for their sensitivity to adenoviral-mediated wild-type p53 gene transfer. MATERIALS AND METHOD Replication-incompetent recombinant adenovirus encoding wild- type p53 (Avp53) under the control of the human cytomegalovirus (CMV) promoter was constructed and the cytotoxic effectiveness was evaluated in various NSCLC cell lines. Because 20 moi (multiplicity of infection; number of active virus particle/cell number) of Avp53 showed highly-effective cytotoxicity in p53-deleted cell lines (NCI-H1299, and NCI-H358), same amount was used for other cell lines. RESULTS Variable degree of cytotoxicity were observed in cell line with p53 mutation, but almost no effect were observed in those with will-type p53. Neither the infectivity of adenovirus, which was observed by x-gal stain after adenoviral mediated lac Z gene, nor the expression of p53 protein in infected cell, which was observed by western blot, was not the useful marker to expect the cytotoxic effect of Avp53. However, in responsive cell lines with Avp53, prominent expression of p21 protein, which was observed by western blot, was noticed. CONCLUSION In conclusion, adenoviral-mediated wild-type p53 transfer may not be applicable to every patient with non-small cell lung cancer, especially when the tumor has wild-type p53 gene. Better method to predict the effectiveness before application and strategy to widen the applicable extent is needed.