A single-institution retrospective study of comprehensive genomic profiling tests based on C-CAT findings for advanced solid cancers.

BACKGROUND: In recent years, as the availability of precision therapies expands, there is increasing reliance on genomic profiling assays to help identify the most appropriate treatment options for patients with advanced cancers. We retrospectively investigated the results of comprehensive genomic profiling tests from the time insurance coverage began until recently and examined the status of genetic analysis. METHODS: We retrospectively reviewed the analysis results of 300 patients with advanced solid tumors who consented to comprehensive genomic profiling tests from October 2019 to December 2022. RESULTS: Of the 300 patients who underwent comprehensive genomic profiling tests, analysis results for 274 patients were obtained, and were reviewed by the Clinical Genome Expert Panel. Six specimens (2%) were discontinued due to patient deaths and deteriorations in general condition. The three most frequently occurring actionable genomic alterations observed were TP53 (47.4%), KRAS (28.1%) and CDKN2A (20.4%). The most common druggable variant was CDKN2A, which was noted in 52 (19%) of 274 patients. The next most common were PIK3CA, BRAF, KRAS and PTEN. The cancer types that showed a greater median number of actionable alterations comprised thyroid cancer, pancreatic cancer and colorectal cancer. CONCLUSIONS: In conclusion, comprehensive genomic profiling tests have the potential to be valuable in identifying genomic abnormalities. Even if there is no effective treatment at present, it may lead to a treatment in the future. Comprehensive genomic profiling tests should be considered for any cancer.

Preoperative evaluation of visceral pleural invasion in peripheral lung cancer utilizing deep learning technology.

PURPOSE: This study aimed to assess the efficiency of artificial intelligence (AI) in the detection of visceral pleural invasion (VPI) of lung cancer using high-resolution computed tomography (HRCT) images, which is challenging for experts because of its significance in T-classification and lymph node metastasis prediction. METHODS: This retrospective analysis was conducted on preoperative HRCT images of 472 patients with stage I non-small cell lung cancer (NSCLC), focusing on lesions adjacent to the pleura to predict VPI. YOLOv4.0 was utilized for tumor localization, and EfficientNetv2 was applied for VPI prediction with HRCT images meticulously annotated for AI model training and validation. RESULTS: Of the 472 lung cancer cases (500 CT images) studied, the AI algorithm successfully identified tumors, with YOLOv4.0 accurately localizing tumors in 98% of the test images. In the EfficientNet v2-M analysis, the receiver operating characteristic curve exhibited an area under the curve of 0.78. It demonstrated powerful diagnostic performance with a sensitivity, specificity, and precision of 76.4% in VPI prediction. CONCLUSION: AI is a promising tool for improving the diagnostic accuracy of VPI for NSCLC. Furthermore, incorporating AI into the diagnostic workflow is advocated because of its potential to improve the accuracy of preoperative diagnosis and patient outcomes in NSCLC.

Quality of life with docetaxel plus cisplatin versus paclitaxel plus carboplatin in patients with completely resected non-small cell lung cancer: quality of life analysis of TORG 0503.

PURPOSE: The TORG0503 study was undertaken to select a preferred platinum-based third-generation regimen for patients with completely resected non-small cell lung cancer (NSCLC). This study aimed to describe the quality of life (QOL) analysis of that study. METHODS: Patients with completely resected NSCLC were randomized to receive three cycles of docetaxel plus cisplatin (DC) or paclitaxel plus carboplatin (PC) on day 1 every 3 weeks. QOL was assessed at three time points (baseline, after two cycles, and after three cycles) using the Functional Assessment of Cancer Therapy-taxane (FACT-Taxane). The adjusted odds ratio (OR) and 95% confidence interval (CI) were calculated by logistic regression analysis that was adjusted for the baseline score in the FACT-Taxane total score and each subscale to evaluate treatment (PC vs. DC) effectiveness. RESULTS: QOL data from 104 patients (DC, n = 56 patients; PC, n = 48) were analyzed. In the FACT-Taxane total score, the baseline-adjusted OR (95% CI) of not worse QOL for the DC group was 3.3 (1.4-8.3) compared with the PC group. In the taxane subscale, the baseline-adjusted OR (95% CI) was 6.2 (2.6-16.0). CONCLUSION: Total QOL was maintained better in the DC group than in the PC group, especially the taxane subscale that consists of neurotoxicity and taxane components in spite of no treatment-related death in both arms between DC and PC. We might recommend DC as the control regimen for the next clinical trial from the viewpoint of QOL, similar to the primary outcomes in TORG0503.

Predictive value of EGFR mutation in non-small-cell lung cancer patients treated with platinum doublet postoperative chemotherapy.

The mutation status of tumor tissue DNA (n = 389) of resected stage II-III non-squamous non-small-cell lung cancer (Ns-NSCLC) was analyzed using targeted deep sequencing as an exploratory biomarker study (JIPANG-TR) for the JIPANG study, a randomized phase III study of pemetrexed/cisplatin (Pem/Cis) vs vinorelbine/cisplatin (Vnr/Cis). The TP53 mutation, common EGFR mutations (exon 19 deletion and L858R), and KRAS mutations were frequently detected. The frequency of the EGFR mutation was significant among female patients. Patients with an EGFR mutation-positive status had a significantly shorter recurrence-free survival (RFS) time (24 mo vs not reached) (HR, 1.64; 95% CI, 1.22-2.21; P = .0011 for EGFR mutation status). Multivariable analysis identified both the pathological stage and EGFR mutation status as independent prognostic factors for RFS (HR, 1.78; 95% CI, 1.30-2.44; P = .0003 for disease stage; and HR, 1.57; 95% CI, 1.15-2.16; P = .0050 for EGFR mutation status). This study demonstrated that the EGFR mutation has either a poor prognostic or predictive impact on a poor response to postoperative chemotherapy with platinum doublet chemotherapy for stage II-III Ns-NSCLC patients. This result supports a role for mandatory molecular diagnosis of early-stage Ns-NSCLC for precision oncology and signifies the importance of adjuvant for the 3rd generation tyrosine kinase inhibitor rather than platinum-based chemotherapy. This study is registered with the UMIN Clinical Trial Registry (UMIN 000012237).

Clinical Impact of Sarcopenia 1 Year After Surgery for Patients with Early-Stage Non-small Cell Lung Cancer.

BACKGROUND: Sarcopenia is associated with prognostic outcomes for patients with various solid tumors, whereas the clinical significance of sarcopenia 1 year after surgery (post-sarcopenia) for non-small cell lung cancer (NSCLC) has not been investigated. This study aimed to clarify the clinical impact of post-sarcopenia and factors associated with post-sarcopenia in NSCLC patients without preoperative sarcopenia. METHODS: This study enrolled 443 patients with clinical stage 1 or 2 NSCLC (234 patients without preoperative sarcopenia [NS group] and 209 patients with preoperative sarcopenia [S group]) who underwent computed tomography (CT) at two time points (before surgery and a year afterward) or more. The study assessed CT images at the L3 level to calculate the psoas muscle area index (PAI). The PAI cutoff value for sarcopenia was defined as 6.36 cm2/m2 for the men and 3.92 cm2/m2 for the women. RESULTS: In the NS group, the diagnosis for 40.1% of the women and 52.6% of the men was post-sarcopenia (NS-S group). The overall survival (OS) for the S and NS-S cohorts was worse than for the non-sarcopenic patients before and after surgery (p < 0.001 and p = 0.017, respectively). In the multivariable analysis, sarcopenia, either before or after surgery (hazard ratio, 3.272; p = 0.002), in the NS group was independently associated with OS, whereas the factors associated with post-sarcopenia were male sex (p = 0.002), aging (p < 0.001), and low body mass index (p < 0.001). CONCLUSIONS: Sarcopenia, either before or after surgery, is prognostic in early-stage NSCLC. Male sex, aging, and low body mass index (BMI) are associated with post-sarcopenia.

Tumor mutation burden as a biomarker for lung cancer patients treated with pemetrexed and cisplatin (the JIPANG-TR).

The JIPANG study is a randomized phase III study of pemetrexed/cisplatin (Pem/Cis) versus vinorelbine/cisplatin (Vnr/Cis) for completely resected stage II-IIIA non-squamous non-small cell lung cancer (Ns-NSCLC). This study did not meet the primary endpoint (recurrence-free survival, RFS) but Pem/Cis had a similar efficacy to Vnr/Cis with a better tolerability. Tumor mutation burden (TMB) is thought to have a predictive value of immune checkpoint inhibitors. However, the relevance of TMB to cytotoxic chemotherapy remains unknown. This exploratory study investigates the relationship between tumor mutation profiles and clinical outcome of Pem/Cis. Formalin-fixed, paraffin-embedded tumor tissues (n = 389) were obtained from the patients. Mutation status of tissue DNA was analyzed by targeted deep sequencing. Epidermal growth factor receptor (EGFR) mutations were detected frequently in Ns-NSCLC (139/374). Patients without any EGFR mutations experienced longer RFS in the Pem/Cis arm versus Vnr/Cis arms. Pem/Cis in patients with high TMB (≥12-16 mut/Mb) tended to have improved survival. In patients with wild-type EGFR, TMB ≥ 12 mut/Mb was significantly associated with improved RFS with Pem/Cis versus Vnr/Cis (not reached vs 52.5 months; hazard ratio (HR) 0.477). It could be proposed that TMB was predictive of RFS benefit with Pem/Cis versus Vnr/Cis in Ns-NSCLC. Further investigation is required to determine whether TMB combined with EGFR mutation status could be used as a predictive biomarker.

First-line pembrolizumab vs chemotherapy in metastatic non-small-cell lung cancer: KEYNOTE-024 Japan subset.

This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE-024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations and a programmed death-ligand 1 (PD-L1) tumor proportion score of 50% or greater evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum-based chemotherapy (four to six cycles). The primary end-point was progression-free survival; secondary end-points included overall survival and safety. Of 305 patients randomized in KEYNOTE-024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). The hazard ratio (HR) for progression-free survival by independent central review (data cut-off date, 10 July 2017) was 0.25 (95% confidence interval [CI], 0.10-0.64; one-sided, nominal P = .001). The HR for overall survival (data cut-off date, 15 February 2019) was 0.39 (95% CI, 0.17-0.91; one-sided, nominal P = .012). Treatment-related adverse events occurred in 21/21 (100%) pembrolizumab-treated and 18/19 (95%) chemotherapy-treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3-5 events. Immune-mediated adverse events and infusion reactions occurred in 11 patients (52%) and four patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3-5 events. Consistent with results from KEYNOTE-024 overall, first-line pembrolizumab improved progression-free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non-small-cell lung cancer without EGFR/ALK alterations and a PD-L1 tumor proportion score of 50% or greater. The trial is registered with ClinicalTrials.gov: NCT02142738.

Prognostic Significance of Ground-Glass Opacity Components in 5-Year Survivors With Resected Lung Adenocarcinoma.

BACKGROUND: Reports on the prognosis for 5-year survivors with lung adenocarcinoma after resection are sparse. This study aimed to identify factors associated with overall survival (OS) and cancer-specific survival (CSS) for 5-year survivors with completely resected lung adenocarcinoma, and to determine whether preoperative imaging factors, including the presence of ground-glass opacity (GGO) components, affect late recurrence in long-term survivors. METHODS: Complete resection of lung adenocarcinoma was performed for 1681 patients between January 2000 and December 2013. Of these patients, 936 who survived 5 years or longer after surgery were identified, and factors associated with OS and CSS were determined using the Cox proportional hazard model. RESULTS: Multivariable analysis demonstrated that lymph node metastasis (p < 0.01) and absence of GGO components (p < 0.01) were independently associated with OS and CSS for the 5-year survivors. The absence of GGO components was significantly associated with OS (p < 0.01) and CSS (p < 0.01) also for the 5-year survivors with stage 1 disease (n = 782) and for the 5-year survivors without recurrence (n = 809). The incidence of recurrence anytime during the 10-year postoperative follow-up period differed significantly between the 5-year survivors with and without GGO components. CONCLUSIONS: The absence of GGO components was significantly associated with an unfavorable prognosis for the 5-year survivors with completely resected lung adenocarcinoma regardless whether they had recurrences not.

The Correlation Between Fissureless Technique and Prolonged Air Leak for Patients Undergoing Video-Assisted Right Upper Lobectomy.

PURPOSE: We aimed to assess the clinical usefulness of the fissureless technique, which avoided dissection of the lung parenchyma over the pulmonary artery, in preventing prolonged air leak after video-assisted thoracic surgery right upper lobectomy (VATS RUL). METHODS: Perioperative outcomes, including the frequency of prolonged air leak after fissureless technique or traditional fissure dissection technique, which dissected the lung parenchyma through the fissure, were compared in patients who underwent VATS RUL (n = 213) between January 2016 and March 2020. We adopted our fissural grade to evaluate the degree of fused fissure ranging from II (light incomplete fissure) to IV (severe incomplete fissure), which covered all fissural grades in 213 patients. RESULTS: Fifty-four and 159 patients underwent fissureless and traditional techniques, respectively. Significant differences in the incidence of prolonged air leak (p = 0.037), time to air leak cessation (p = 0.047), and duration of chest tube placement (p = 0.017) were observed between fissureless and traditional technique groups. On multivariable analysis, traditional technique (p = 0.005), and greater fissural grade (III vs II, p = 0.020; IV vs II, p = 0.001) were significantly associated with prolonged air leak. CONCLUSIONS: Fissureless technique during VATS RUL can be a superior alternative to the traditional technique to prevent prolonged air leak in treating incomplete fissures.

Powered articulation by the SigniaTM stapling system for stapling position adjustments: optimizing safe surgical margins in thoracoscopic sublobar resection.

Accumulation of experience and advances in techniques and instruments have enabled surgeons to perform video-assisted thoracic surgery (VATS) safely for sublobar resection, including segmentectomy and wedge resection. A key to successful VATS sublobar resection is to have adequate resection margins and the appropriate use of articulated surgical staplers is essential for this purpose. The SigniaTM stapling system (Covidien Japan, Tokyo) has been used extensively in the fields of thoracic surgery. Its features include high maneuverability with fully powered articulation, rotation, clamping, and firing, which the surgeon can control with one hand. We introduce the "sliding technique" using the SigniaTM system, which allows for adjustment of the resection lines of the pulmonary parenchyma to optimize safe surgical margins with minimal stapler movement, and without repetitively moving the stapler in and out of the pleural cavity, during VATS sublobar resection.

Ubiquitin C-terminal hydrolase-L1 has prognostic relevance and is a therapeutic target for high-grade neuroendocrine lung cancers.

High-grade neuroendocrine lung cancer (HGNEC), which includes small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) of the lung is a rapidly proliferating, aggressive form of lung cancer. The initial standard chemotherapeutic regimens of platinum doublets are recommended for SCLC and have been frequently used for LCNEC. However, there are currently no molecularly targeted agents with proven clinical benefit for this disease. The deubiquitinating enzyme ubiquitin C-terminal hydrolase-L1 (UCHL1) is a neuroendocrine cell-specific product that is known as a potential oncogene in several types of cancer, but little is known about the biological function of UCHL1 and its therapeutic potential in HGNEC. In this study, we found that preclinical efficacy evoked by targeting UCHL1 was relevant to prognosis in HGNEC. UCHL1 was found to be expressed in HGNEC, particularly in cell lines and patient samples of SCLC, and the combined use of platinum doublets with selective UCHL1 inhibitors improved its therapeutic response in vitro. Immunohistochemical expression of UCHL1 was significantly associated with postoperative survival in patients with HGNEC and contributed towards distinguishing SCLC from LCNEC. Circulating extracellular vesicles (EV), including exosomes isolated from lung cancer cell lines and serum from early-stage HGNEC, were verified by electron microscopy and nanoparticle tracking analysis. Higher levels of UCHL1 mRNA in EV were found in the samples of patients with early-stage HGNEC than those with early-stage NSCLC and healthy donors' EV. Taken together, UCHL1 may be a potential prognostic marker and a promising druggable target for HGNEC.

First-line pembrolizumab vs chemotherapy in metastatic non-small-cell lung cancer: KEYNOTE-024 Japan subset.

This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE-024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations and a programmed death ligand 1 (PD-L1) tumor proportion score of 50% or higher evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum-based chemotherapy (four to six cycles). The primary end-point was progression-free survival; secondary end-points included overall survival and safety. Of 305 patients randomized in KEYNOTE-024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). Median progression-free survival was 41.4 (95% confidence interval [CI], 4.2-42.5) months with pembrolizumab and 4.1 (95% CI, 2.8-8.3) months with chemotherapy (hazard ratio [HR], 0.27 [95% CI, 0.11-0.65]; one-sided, nominal P = .001). Median overall survival was not reached (NR) (95% CI, 22.9-NR) and 21.5 (95% CI, 5.2-35.0) months, respectively (HR, 0.39 [95% CI, 0.17-0.91]; one-sided, nominal P = .012). Treatment-related adverse events occurred in 21/21 (100%) pembrolizumab-treated and 18/19 (95%) chemotherapy-treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3-5 events. Immune-mediated adverse events and infusion reactions occurred in 11 pembrolizumab-treated patients (52%) and four chemotherapy-treated patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3-5 events. Consistent with results from KEYNOTE-024 overall, first-line pembrolizumab improved progression-free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non-small-cell lung cancer without EGFR/ALK alterations and a PD-L1 tumor proportion score of 50% or higher. The trial is registered with Clinicaltrials.gov: NCT02142738.

Plasma screening for the T790M mutation of EGFR and phase 2 study of osimertinib efficacy in plasma T790M-positive non-small cell lung cancer: West Japan Oncology Group 8815L/LPS study.

BACKGROUND: Liquid biopsy allows the identification of patients whose tumors harbor specific mutations in a minimally invasive manner. No prospective data have been available for the efficacy of osimertinib in patients with non-small cell lung cancer (NSCLC) who develop resistance to first- or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and who test positive for the TKI resistance-conferring T790M mutation of EGFR by liquid biopsy. Therefore, a phase 2 study was conducted to assess the efficacy and safety of osimertinib in such patients. METHODS: Eligible patients had advanced or recurrent NSCLC with known TKI-sensitizing mutations of EGFR, had documented disease progression after treatment with at least 1 first- or second-generation EGFR TKI, and were positive for the T790M mutation in plasma according to the Cobas EGFR Mutation Test v2 (Roche Diagnostics) or droplet digital polymerase chain reaction analysis. Patients were treated with osimertinib (80 mg/d) until disease progression. The primary endpoint was the overall response rate (ORR) in patients positive for T790M in plasma by the Cobas assay. RESULTS: Between June 2016 and November 2017, 276 patients were screened for their T790M status with a liquid biopsy. Seventy-four patients were positive for T790M in plasma, and 53 of these individuals were enrolled in the study. The ORR for evaluable patients positive for T790M in plasma by the Cobas assay (n = 49) was 55.1% (95% confidence interval [CI], 40.2%-69.3%). The median progression-free survival for all evaluable patients (n = 52) was 8.3 months (95% CI, 6.9-12.6 months). CONCLUSIONS: The results demonstrate the utility of liquid biopsy for the detection of T790M with the Cobas EGFR Mutation Test v2. Plasma genotyping with this assay is informative for treatment selection in clinical practice when tumor sampling is not feasible.

A combination therapy of photodynamic therapy (PDT) and airway stent placement using a transparent silicone stent.

The aim of this study was to evaluate the feasibility of a combination therapy of photodynamic therapy (PDT) and airway stent placement using a transparent silicone stent (gold studded stent [GSS]). Laser irradiation (664 nm, continuous wave) was performed through the GSS using a straight and cylindrical fiber 1.0 cm away from a power meter. There are two types of GSS: the TD type for the trachea and the BD type for the bronchus. Laser outputs were set to 150 mW, 180 mW, 210 mW, 240 mW, 270 mW, and 300 mW. The laser powers passing through the both types of GSS were measured three times for each outputs and the averages were calculated. Based on the results, animal experiment was performed using two female pigs. Under general anesthesia, a GSS (BD type) was inserted into trachea of pigs, and PDT using NPe6 as a photosensitizer was performed by 100 J/cm2 laser irradiation on parts of the trachea with and without a GSS. Immediately after and 1 week after PDT, pig tracheas were harvested and histological analysis was performed. Histological analysis of areas with or without the stent showed edematous changes between the cartilage and submucosal layer immediately after PDT, and necrotic changes 1 week later. The effectiveness of NPe6-PDT for pigs' trachea covered by the stent was same as trachea without the stent. The use of a GSS may enable PDT to be effective even in the area covered by the stent.

Performance of Oncomine Fusion Transcript kit for formalin-fixed, paraffin-embedded lung cancer specimens.

Gene fusions play an important role in the carcinogenesis of lung adenocarcinoma. The recent association of four oncogenic driver genes, ALK, ROS1, RET, and NTRK1, as lung tumor predictive biomarkers has increased the need for precision medicine. We used formalin-fixed, paraffin-embedded tissue samples of non-small cell lung cancer from 150 EGFR mutation-negative cases and 10 fusion status-known cases and compared the performance of the Oncomine Dx Fusion Transcript Test (ODxFT) with FISH break-apart for the detection of ALK, RET, and ROS1 fusion genes. RNA was extracted from the paraffin-embedded tissue samples with or without macrodissection under hematoxylin and eosin staining, and the ALK fusion gene was independently determined using these assays. Fusion detection analyses were successfully carried out using ODxFT in 150 cases, with only one invalid case. ALK fusion genes were detected at a frequency of 7.3% (11/150) in the lung cancer specimens. Concordance rate between the ODxFT and ALK-FISH analyses was 99.3% (148/149). Sensitivity and specificity were 91.7% and 99.3%, respectively. All the samples with a known fusion status were accurately matched between the two assays. Our results show a high concordance rate between the ODxFT and ALK-FISH analyses. ODxFT was thus validated as an effective method for detecting clinically significant ALK fusion genes in paraffin-embedded tissue samples.

Repression of Smad3 by Stat3 and c-Ski/SnoN induces gefitinib resistance in lung adenocarcinoma.

Cancer-associated inflammation develops resistance to the epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancers (NSCLCs) harboring oncogenic EGFR mutations. Stat3-mediated interleukin (IL)-6 signaling and Smad-mediated transforming growth factor-ß (TGF-ß) signaling pathways play crucial regulatory roles in cancer-associated inflammation. However, mechanisms how these pathways regulate sensitivity and resistance to EGFR-TKI in NSCLCs remain largely undetermined. Here we show that signal transducer and activator of transcription (Stat)3 represses Smad3 in synergy with the potent negative regulators of TGF-ß signaling, c-Ski and SnoN, whereby renders gefitinib-sensitive HCC827 cells resistant. We found that IL-6 signaling via phosphorylated Stat3 induced gefitinib resistance as repressing transcription of Smad3, whereas TGF-ß enhanced gefitinib sensitivity as activating transcription of Smad3 in HCC827 cells with gefitinib-sensitizing EGFR mutation. Promoter analyses showed that Stat3 synergized with c-Ski/SnoN to repress Smad2/3/4-induced transcription of the Smad3 gene. Smad3 was found to be an apoptosis inducer, which upregulated pro-apoptotic genes such as caspase-3 and downregulated anti-apoptotic genes such as Bcl-2. Our results suggest that derepression of Smad3 can be a therapeutic strategy to prevent gefitinib-resistance in NSCLCs with gefitinib-sensitizing EGFR mutation.

Tumor volume determines the feasibility of cell-free DNA sequencing for mutation detection in non-small cell lung cancer.

Next-generation sequencing (NGS) and digital PCR technologies allow analysis of the mutational profile of circulating cell-free DNA (cfDNA) in individuals with advanced lung cancer. We have now evaluated the feasibility of cfDNA sequencing for mutation detection in patients with non-small cell lung cancer at earlier stages. A total of 150 matched tumor and serum samples were collected from non-small cell lung cancer patients at stages IA-IIIA. Amplicon sequencing with DNA extracted from tumor tissue detected frequent mutations in EGFR (37% of patients), TP53 (39%), and KRAS (10%), consistent with previous findings. In contrast, NGS of cfDNA identified only EGFR, TP53, and PIK3CA mutations in three, five, and one patient, respectively, even though adequate amounts of cfDNA were extracted (median of 4936 copies/mL serum). Next-generation sequencing showed a high accuracy (98.8%) compared with droplet digital PCR for cfDNA mutation detection, suggesting that the low frequency of mutations in cfDNA was not due to a low assay sensitivity. Whereas the yield of cfDNA did not differ among tumor stages, the cfDNA mutations were detected in seven patients at stages IIA-IIIA and at T2b or T3. Tumor volume was significantly higher in the cfDNA mutation-positive patients than in the negative patients at stages T2b-T4 (159.1 ± 58.0 vs. 52.5 ± 9.9 cm3 , P = 0.014). Our results thus suggest that tumor volume is a determinant of the feasibility of mutation detection with cfDNA as the analyte.

Correlation between whole tumor size and solid component size on high-resolution computed tomography in the prediction of the degree of pathologic malignancy and the prognostic outcome in primary lung adenocarcinoma.

BACKGROUND: The presence of ground glass opacity (GGO) on high-resolution computed tomography (HRCT) is well known to be pathologically closely associated with adenocarcinoma in situ. PURPOSE: To determine whether it is more useful to evaluate the whole tumor size or only the solid component size to predict the pathologic high-grade malignancy and the prognostic outcome in lung adenocarcinoma. MATERIAL AND METHODS: Using HRCT data of 232 patients with adenocarcinoma who underwent curative resection, we retrospectively measured the whole tumor and solid component sizes with lung window setting (WTLW and SCLW) and whole tumor sizes with a mediastinal window setting (WTMW). RESULTS: There was significant correlation between the WTLW and the measurements of pathological whole tumor (pWT) (r = 0.792, P < 0.0001). The SCLW and WTLW values significantly correlated with the area of pathological invasive component (pIVS) (r = 0.762, P < 0.0001 and r = 0.771, P < 0.0001, respectively). The receiver operating characteristics area under the curve for WTLW, SCLW, and WTMW used to identify lymph node metastasis or lymphatic or vascular invasion were 0.693, 0.817, and 0.824, respectively. Kaplan-Meier curves of disease-free survival (DFS) and overall survival (OS) were better divided according to SCLW and WTMW, compared with WTLW. Multivariate analysis of DFS and OS revealed that WTMW was an independent prognostic factor (HR = 0.72, 95% confidence interval [CI] = 0.58-0.90, P = 0.004 and HR = 0.74, 95% CI = 0.57-0.96, P = 0.022, respectively). CONCLUSION: The predictive values of the solid tumor size visualized on HRCT especially in the mediastinal window for pathologic high-grade malignancy and prognosis in lung adenocarcinoma were greater than those of whole tumor size.

Surgical outcomes of patients with locally advanced thymic epithelial tumor undergoing induction therapy followed by surgery: a narrative review.

Background and Objective: Thymic epithelial tumors (TETs), including thymomas and thymic cancers, are relatively rare malignancies originating from the thymus. Although complete surgical resection is the cornerstone of treatment for these tumors, the optimal management strategy for locally advanced cases remains uncertain. Neoadjuvant therapies, with their potential to improve the likelihood of complete resection, are promising, particularly in marginally operable cases. However, the current evidence supporting this approach is lacking. This review of the existing literature on the efficacy of induction therapy followed by surgical resection for stage III or IV locally advanced TETs aimed to provide an up-to-date perspective and highlighting directions for future clinical research. Methods: PubMed was searched using the keywords "surgery," "survival", "thymoma", "thymic cancer", and "induction therapy". Relevant articles including case series, retrospective studies, prospective studies, and review articles were reviewed and selected for this comprehensive narrative review. Key Content and Findings: This review included primarily revealed retrospective studies and a limited number of prospective phase II trials on induction therapy followed by surgery for stage III or IV locally advanced TETs. No randomized phase III studies were identified, indicating that a comprehensive evaluation of the benefits of induction therapy on overall survival (OS) has not yet been conducted. Induction therapies for both invasive thymoma and thymic cancer included chemotherapy, radiotherapy, and chemoradiotherapy, with anthracycline-based combination chemotherapies being the primary option. For exclusively invasive thymomas, the median rate of complete surgical resection and the 5-year OS rate were reported as 76% and 85%, respectively. Literature focusing on induction therapy for TETs, which includes both thymoma and thymic cancers, indicates that the rates of complete resection and 5-year OS are 76% and 70%, respectively. Conclusions: Our narrative review of retrospective and prospective studies highlighted promising long-term OS rates in patients with advanced TETs who underwent induction therapy followed by surgical resection. These findings support this multimodal treatment strategy in selected patients with stage III and IV TETs.