Neuroendocrine and squamous cell phenotypes of NUT carcinoma are potential diagnostic pitfalls that discriminating it from mimickers, such as small cell and squamous cell carcinoma.

INTRODUCTION: NUT carcinoma is a rare cancer associated with a poor prognosis. Because of its rarity, its diagnosis is challenging and is usually made by excluding other diagnoses. Immunohistochemical analysis is a reliable technique that contributes to a correct diagnosis, but overestimating the expression of neuroendocrine (NE) markers may result in an incorrect diagnosis. In this study, we established the immunohistochemical phenotypes of NUT carcinoma compared with tumors that mimic its phenotype to identify potential diagnostic pitfalls. METHODS: Eight cases of NUT carcinoma were examined along with eight basaloid squamous cell carcinomas and thirteen cases of small cell carcinoma using an immunohistochemical panel consisting of various antibodies. RESULTS: Of the eight NUT carcinomas, three patients had a smoking history. All the cases examined for INSM1 were positive (6/6, 100%), although the staining was somewhat weak. Among the NE markers, synaptophysin was variably positive in two NUT carcinomas (2/6, 33%); however, all cases were negative for ASCL1, chromogranin A, and CD56. Moreover, the squamous cell markers, p40 and CK5/6, were weakly expressed in 4/6 (67%) and 3/6 (50%) of the NUT carcinomas, respectively. CONCLUSIONS: For tumors with an ambiguous morphology, applying the neuroendocrine phenotype of NUT carcinoma may be misleading; particularly, when distinguishing it from small-cell carcinoma. Similarly, null or weak expression of squamous cell markers may be observed in NUT carcinoma, but this differs from squamous cell carcinoma, which consistently demonstrates strong positivity for squamous cell markers.

Optimal Treatment Strategy for Oligo-Recurrence Lung Cancer Patients with Driver Mutations.

BACKGROUND: The efficacy of local therapies for lung cancer patients with postoperative oligo-recurrence has been reported. However, whether local therapies should be chosen over molecular targeted therapies for oligo-recurrence patients with driver mutations remains controversial. Therefore, we aimed to investigate the optimal initial treatment strategy for oligo-recurrence in lung cancer patients with driver mutations. METHODS: Among 2152 patients with lung adenocarcinoma who underwent surgical resection at our institute between 2008 and 2020, 66 patients with driver mutations who experienced cancer oligo-recurrence after surgery and were treated with local or molecularly targeted therapy as an initial therapy after recurrence were evaluated. Oligo-recurrence was characterized by the presence of 1 to 3 recurrent lesions. These patients were investigated, focusing on their post-recurrence therapies and prognoses. RESULTS: The median follow-up period was 71 months. Local and molecular targeted therapies were administered to 41 and 25 patients, respectively. The number of recurrence lesions tended to be lower in the initial local therapy group than in the molecular targeted therapy group. In the initial local therapy group, 23 patients (56%) subsequently received molecular targeted therapies. The time from recurrence to the initiation of molecular targeted therapy was significantly longer in the local therapy group than in the molecular targeted therapy group (p < 0.001). There was no significant difference in post-recurrence overall survival (hazard ratio, 1.429; 95% confidence interval, 0.701-2.912; log-rank, p = 0.324) and post-recurrence progression-free survival (hazard ratio, 0.799; 95% confidence interval, 0.459-1.390; log-rank, p = 0.426) in the initial local ablative therapy group compared with the initial molecular targeted therapy group. CONCLUSIONS: Local therapies as a first-line treatment did not show statistically significant differences in post-recurrence survival or progression-free survival compared with molecular targeted therapies. However, local therapies as an initial treatment should be considered preferably, as they can cure the recurrence and can delay the start of administration of molecular targeted therapies.

Prediction of Tumor PD-L1 Expression in Resectable Non-Small Cell Lung Cancer by Machine Learning Models Based on Clinical and Radiological Features: Performance Comparison With Preoperative Biopsy.

OBJECTIVE: We investigated if PD-L1 expression can be predicted by machine learning using clinical and imaging features. METHODS: We included 117 patients with c-stage I/II non-small cell lung cancer who underwent radical resection. A total of 3951 radiomic features were extracted by defining the tumor (within tumor contour), rim (contour ±3 mm) and exterior (contour +10 mm) on preoperative contrast computed tomography. After feature selection by Boruta algorithm, prediction models of tumor PD-L1 expression (22C3: ≥1%, <1%) of resected specimens were constructed using Random Forest: radiomics, clinical, and combined models. Their performance was evaluated by 5-fold cross-validation, and AUCs were compared using Delong test. Next, study groups were categorized as patients without biopsy (training set), and those with biopsy (test set). Predictive ability of biopsy was compared to each prediction model. RESULTS: Of 117 patients (66 ± 10 years old, 48% male), 33 (28.2%) had PD-L1≥1%. Mean AUC of PD-L1≥1% for the validation set in radiomics, clinical, and combined models were 0.80, 0.80, and 0.83 (P = .32 vs. clinical model), respectively. The diagnosis of malignancy was made in 22 of 38 (58%) patients with attempted biopsies, and PD-L1 was measurable in 19 of 38 (50%) patients. Diagnostic accuracies of PD-L1≥1% from 19 determinable biopsies and 38 all attempted biopsies were 0.68 and 0.34, respectively. These were out performed by machine learning: 0.71, 0.71, and 0.74 for radiomics, clinical, and combined models, respectively. CONCLUSIONS: Our machine learning could be an adjunctive tool in estimating PD-L1 expression prior to neoadjuvant treatment, particularly when PD-L1 is indeterminable with biopsy.

MIG6 loss confers resistance to ALK/ROS1 inhibitors in NSCLC through EGFR activation by low-dose EGF.

Although tyrosine kinase inhibitor (TKI) therapy shows marked clinical efficacy in patients with anaplastic lymphoma kinase-positive (ALK+) and ROS proto-oncogene 1-positive (ROS1+) non-small cell lung cancer (NSCLC), most of these patients eventually relapse with acquired resistance. Therefore, genome-wide CRISPR/Cas9 knockout screening was performed using an ALK+ NSCLC cell line established from pleural effusion without ALK-TKI treatment. After 9 days of ALK-TKI therapy, sequencing analysis was performed, which identified several tumor suppressor genes, such as NF2 or MED12, and multiple candidate genes. Among them, this study focused on ERRFI1, which is known as MIG6 and negatively regulates EGFR signaling. Interestingly, MIG6 loss induced resistance to ALK-TKIs by treatment with quite a low dose of EGF, which is equivalent to plasma concentration, through the upregulation of MAPK and PI3K/AKT/mTOR pathways. Combination therapy with ALK-TKIs and anti-EGFR antibodies could overcome the acquired resistance in both in vivo and in vitro models. In addition, this verified that MIG6 loss induces resistance to ROS1-TKIs in ROS1+ cell lines. This study found a potentially novel factor that plays a role in ALK and ROS1-TKI resistance by activating the EGFR pathway with low-dose ligands.

Clinical characteristics of patients with KRAS mutation detected by liquid biopsy.

BACKGROUND: KRAS mutation positive lung cancer is known to be clinically characterized by older age, males, and smokers. It is reported to be more common in mucinous adenocarcinoma, but all reports are based on analysis of tissue samples. Recently, blood samples have become available for analysis, suggesting a low detection rate of circulating tumor DNA in histological types, especially mucinous adenocarcinoma. In this study, we investigated the clinical characteristics of KRAS mutation-positive cases in the analysis of blood specimens, as these remain unclear. METHODS: The clinical background of patients with KRAS mutation among those who underwent next-generation sequencing (NGS) analysis using blood samples was evaluated. RESULTS: NGS analysis was performed on 214 blood samples. KRAS mutations were detected in blood samples in 33 cases (15.4%), of which 31 cases (14.5%) had a histological pathology diagnosis. Mucinous adenocarcinoma accounted for 28.6% of cases with positive blood and tissue specimens, 10.0% of cases with positive blood specimens only, and 57.1% of cases with positive tissue specimens only. Mucinous adenocarcinoma tended to be less common in cases with positive blood specimens. In KRAS-positive patients with lung metastasis only, only one nonmucinous adenocarcinoma had a positive blood sample, and the others all had mucinous adenocarcinomas with positive tissue samples only. CONCLUSION: The results showed that the detection rate of KRAS-positive lung cancers detected by blood and tissue samples differs, and that the detection rate of blood samples may be poor, especially in the case of mucinous adenocarcinoma with lung metastases only.

Ringlike Peripheral Increased Iodine Concentration for the Differentiation of Primary Lung Cancer and Pulmonary Metastases on Contrast-Enhanced Dual-Energy CT.

BACKGROUND. Differentiation of primary lung cancers and pulmonary metastases may present a diagnostic dilemma given overlapping CT findings. OBJECTIVE. The purpose of this study was to compare the utility of ringlike peripheral increased iodine concentration and conventional findings for differentiating primary lung cancers from pulmonary metastases on dual-energy CT (DECT). METHODS. This retrospective study included 93 patients (64 men, 29 women; median age, 70 years) who underwent resection of a primary lung cancer (n = 68) or pulmonary metastasis (n = 25) corresponding to a solid lesion on preoperative contrast-enhanced DECT performed between April 2020 and March 2021. Venous phase 120-keV single-energy images, equilibrium phase 66-keV virtual monoenergetic images, and iodine concentration maps were reconstructed. Two radiologists independently assessed lesions for spiculated margins, air bronchograms, rim enhancement, and thin ringlike peripheral high iodine concentration; differences were resolved by consensus. Inter-reader agreement and diagnostic performance were assessed. Multivariable logistic regression analysis incorporated additional patient and lesion characteristics. RESULTS. Interobserver agreement, expressed as kappa, was 0.26 for spiculated margins, 0.60 for air bronchograms, 0.56 for rim enhancement, and 0.80 for ringlike peripheral high iodine concentration. Pulmonary metastases, compared with primary lung cancers, exhibited significantly higher frequency of ringlike peripheral high iodine concentration (52% vs 19%; p = .004) but no significant difference in frequency of spiculated margins (49% vs 32%; p = .17), air bronchograms (36% vs 51%; p = .24), or rim enhancement (4% vs 4%; p > .99). Sensitivity and specificity for diagnosing pulmonary metastasis were 68% and 49% for absence of spiculated margins, 64% and 51% for absence of air bronchograms, 4% and 96% for presence of rim enhancement, and 52% and 81% for presence of ringlike peripheral high iodine concentration. In multivariable analysis including smoking history, lesion diameter, multiple resected lesions, and ringlike peripheral high iodine concentration, the only independent significant predictor of pulmonary metastasis was ringlike peripheral high iodine concentration (OR, 7.81 [95% CI, 2.28-29.60); p = .001). CONCLUSION. Ringlike peripheral high iodine concentration had excellent interobserver agreement and high specificity (albeit poor sensitivity) for differentiating pulmonary metastasis from primary lung cancer and was independently predictive of pulmonary metastasis. CLINICAL IMPACT. Ringlike peripheral high iodine concentration could help guide management of patients with known cancer and an indeterminate solitary nodule.

Distinct Prognostic Impact of PET Findings Based on Radiological Appearance in Clinical Stage IA Lung Adenocarcinoma.

INTRODUCTION: Although solid appearance on computed tomography and positive findings on positron emission tomography (PET) have been both associated with poor outcome in lung adenocarcinoma, the extent to which these findings overlap is unknown. This study aimed to determine the differences in prognostic significance of PET findings in part-solid nodules (PSNs) and solid nodules. MATERIALS AND METHODS: We retrospectively investigated 417 patients with clinical stage IA adenocarcinoma who underwent curative resection between 2010 and 2017. We compared disease-free survival (DFS), cumulative incidence of disease recurrence (CIR) and clinicopathological characters between PET-positive and negative groups among PSNs and solid nodules, respectively. We used 2.5 as a cut-off value of maximum standardized uptake value (SUV max). RESULTS: In PSNs (n = 235), PET-positive group (n = 59) showed more aggressive features in several clinicopathological variables, poorer DFS (P < .001) and higher CIR (P < .001) than PET-negative group (n = 176). In contrast, in solid nodules (n = 182), DFS (P = .521) and CIR (P = .311) were not significantly different between PET-positive (n = 128) and negative groups (n = 54). SUV max was proved to be the independent prognostic factor of DFS by multivariate analysis (HR, 1.155; 95% CI, 1.036-1.287) only in PSNs. CONCLUSION: These findings showed distinct impact on prognosis of PET findings between PSNs and solid nodules. PET-positive finding was more important prognostic factor in PSNs than in solid nodules among clinical stage IA lung adenocarcinoma.

Ex-vivo 1.5T MR Imaging versus CT in Estimating the Size of the Pathologically Invasive Component of Lung Adenocarcinoma Spectrum Lesions.

PURPOSE: The purpose of this study was to investigate whether ex-vivo MRI enables accurate estimation of the invasive component of lung adenocarcinoma. METHODS: We retrospectively reviewed 32 patients with lung adenocarcinoma who underwent lung lobectomy. The specimens underwent MRI at 1.5T. The boundary between the lesion and the normal lung was evaluated on a 5-point scale in each three MRI sequences, and a one-way analysis of variance and post-hoc tests were performed. The invasive component size was measured histopathologically. The maximum diameter of each solid component measured on CT and MR T1-weighted (T1W) images and the maximum size obtained from histopathologic images were compared using the Wilcoxon signed-rank test. Inter-reader agreement was evaluated using intraclass correlation coefficients (ICC). RESULTS: T1W images were determined to be optimal for the delineation of the lesions (P < 0.001). The histopathologic invasive area corresponded to the area where the T1W ex-vivo MR image showed a high signal intensity that was almost equal to the intravascular blood signal. The maximum diameter of the solid component on CT was overestimated compared with the maximum invasive size on histopathology (mean, 153%; P < 0.05), while that on MRI was evaluated mostly accurately without overestimation (mean, 108%; P = 0.48). The interobserver reliability of the measurements using CT and MRI was good (ICC = 0.71 on CT, 0.74 on MRI). CONCLUSION: Ex-vivo MRI was more accurate than conventional CT in delineating the invasive component of lung adenocarcinoma.

Machine learning-based gene alteration prediction model for primary lung cancer using cytologic images.

BACKGROUND: Understanding the gene alteration status of primary lung cancers is important for determining treatment strategies, but gene testing is both time-consuming and costly, limiting its application in clinical practice. Here, potential therapeutic targets were selected by predicting gene alterations in cytologic specimens before conventional gene testing. METHODS: This was a retrospective study to develop a cytologic image-based gene alteration prediction model for primary lung cancer. Photomicroscopic images of cytology samples were collected and image patches were generated for analyses. Cancer-positive (n = 106) and cancer-negative (n = 32) samples were used to develop a neural network model for selecting cancer-positive images. Cancer-positive cases were randomly assigned to training (n = 77) and validation (n = 26) data sets. Another neural network model was developed to classify cancer images of the training data set into 4 groups: anaplastic lymphoma kinase (ALK)-fusion, epidermal growth factor receptor (EGFR), or Kirsten rat sarcoma viral oncogene homologue (KRAS) mutated groups, and other (None group), and images of the validation data set were classified. A decision algorithm to predict gene alteration for cases with 3 probability ranks was developed. RESULTS: The accuracy and precision for selecting cancer-positive patches were 0.945 and 0.991, respectively. Predictive accuracy for the EGFR and KRAS groups in the validation data set was ~0.95, whereas that for the ALK and None groups was ~0.75 and ~ 0.80, respectively. Gene status was correctly predicted in the probability rank A cases. The model extracted characteristic conventional cytologic findings in images and a novel specific feature was discovered for the EGFR group. CONCLUSIONS: A gene alteration prediction model for lung cancers by machine learning based on cytologic images was successfully developed.

Relationship Between Pathologic T1 Categories and Pathologic Factors Affecting Prognosis in Pulmonary Adenocarcinoma.

Introduction: The eight TNM classification of lung tumors provides a more precise prediction of prognosis than previous classification systems, especially in T1 tumors, the invasion size of which are less than or equal to 3 cm. T1 is divided into T1a (6-10 mm), T1b (11-20 mm), and T1c (21-30 mm), but the relationship between pathologic T (pT)1 categories and other pathologic factors has not been thoroughly evaluated. Methods: Surgically resected pulmonary adenocarcinomas (N = 551) were extracted on the basis of computed tomography-based tumor size measurements, including 302 pT1a to c cases (pT1a: n = 98, pT1b: n = 156, and pT1c: n = 48). Pathologic factors, including a minor component of micropapillary or solid subtype, were analyzed by new T categories. Recurrence-free and disease-specific survivals (DSSs) were evaluated using univariable and multivariable analyses and Cox proportional hazards models. Results: Lymphatic invasion, vascular invasion, and nodal metastasis increased remarkably from pT1a to pT1c, step-wisely. Visceral pleural invasion was elevated from 7% (6-10 mm) to 33% (21-30 mm) along with an increase in invasion size. Recurrence-free survival (RFS) and DSS relevantly deteriorated from the group of pathologic stages 0, IA1, and IA2 to the group IA3 and IB. Multivariable analysis revealed that lymph node metastasis and solid components were independent prognostic factors for both RFS and DSS in pT1a to c cases. Conclusions: The new TNM classification precisely predicts prognosis. Tumor invasion size is closely associated with lymphatic and vascular invasion, nodal metastasis, and visceral pleural invasion. As a minor component, solid subtype was a potent adverse prognostic factor affecting both RFS and DSS after surgery in T1 categories.

Combination of epidermal growth factor receptor mutation and the presence of high-grade patterns is associated with recurrence in resected stage I lung adenocarcinoma.

OBJECTIVES: This study aimed to evaluate the prognostic impact of the combination of epidermal growth factor receptor (EGFR) mutation and the presence of high-grade patterns (solid or micropapillary component) in resected stage I lung adenocarcinoma. METHODS: Patients who underwent curative resection for pathological stage I lung adenocarcinoma and EGFR mutation analysis were included in this study. The impact of the combination of EGFR mutation and the presence of >5% high-grade patterns on recurrence-free survival (RFS) was retrospectively analysed using Cox proportional hazards model and propensity score-matched analysis. RESULTS: Among the included 721 patients, EGFR mutations were positive in 380 (52.7%). In the EGFR-mutated group, cases with high-grade patterns showed poorer RFS than those without (5-year RFS, 77.7% vs 92.5%, P < 0.001), whereas there were no significant prognostic differences in the EGFR wild-type group (5-year RFS, 89.8% vs 88.2%, P = 0.807). Multivariable analyses revealed that the combination of EGFR mutations and the presence of high-grade patterns was associated with poor RFS (hazard ratio = 1.655, P = 0.035). Furthermore, EGFR mutation was associated with poor RFS in the group with high-grade patterns (hazard ratio = 2.108, P = 0.008). After propensity score matching, EGFR-mutated cases with high-grade patterns showed poorer RFS (P = 0.028). CONCLUSIONS: The combination of EGFR mutation and the presence of high-grade patterns was associated with recurrence in resected stage I lung adenocarcinoma. Histological subtypes, including minor components, should be considered when evaluating the risk of recurrence in patients with EGFR-mutated lung adenocarcinoma.

Prognostic Stratification According to Size and Dominance of Radiologic Solid Component in Clinical Stage IA Lung Adenocarcinoma.

INTRODUCTION: Although several studies have investigated the prognostic significance of the radiographic appearance of stage IA lung adenocarcinoma, the prognostic impact of solid component size or consolidation-to-tumor ratio (CTR) of part-solid nodules (PSNs) still remains controversial. This study aimed to clarify the combined prognostic impact of the mentioned radiographic features of PSNs and compare it with that of pure solid nodules in the current TNM classification. METHODS: We retrospectively investigated 1014 patients with clinical stage IA (TNM eighth edition) adenocarcinoma who underwent curative resection. Overall survival (OS) and pathologic characteristics of pure solid nodules, solid-dominant PSNs (CTR > 0.5), and ground-glass opacity (GGO)-dominant PSNs (CTR ≤ 0.5) were compared according to T category. RESULTS: Patients with pure solid nodules (297 cases) had significantly shorter OS compared with those with PSNs (717 cases) (p < 0.001) but a marginal difference compared with those with solid-dominant PSNs (286 cases) (p = 0.051). No significant difference in OS was found according to T category in those with GGO-dominant PSNs (431 cases). Patients with cT1b and T1c solid-dominant PSNs had significantly worse prognosis compared with those with other PSNs and had comparable prognosis with those with cT1b pure solid nodules (p = 0.892). Higher frequency of nodal and lymphovascular involvement and pathologic upstaging was observed with T category progression in solid-dominant PSNs. CONCLUSIONS: An hierarchy of prognosis and pathologic malignant characteristics was observed according to T category in patients with solid-dominant PSNs but not in those with GGO-dominant PSNs, suggesting the importance of classifying PSNs on the basis of solid component size and CTR for accurate prognostic comparison with pure solid nodules.

Soluble PD-L1 works as a decoy in lung cancer immunotherapy via alternative polyadenylation.

Immune checkpoint therapy targeting the PD-1/PD-L1 axis is a potentially novel development in anticancer therapy and has been applied to clinical medicine. However, there are still some problems, including a relatively low response rate, innate mechanisms of resistance against immune checkpoint blockades, and the absence of reliable biomarkers to predict responsiveness. In this study of in vitro and in vivo models, we demonstrate that PD-L1-vInt4, a splicing variant of PD-L1, plays a role as a decoy in anti-PD-L1 antibody treatment. First, we showed that PD-L1-vInt4 was detectable in clinical samples and that it was possible to visualize the secreting variants with IHC. By overexpressing the PD-L1-secreted splicing variant on MC38 cells, we observed that an immune-suppressing effect was not induced by their secretion alone. We then demonstrated that PD-L1-vInt4 secretion resisted anti-PD-L1 antibody treatment, compared with WT PD-L1, which was explicable by the PD-L1-vInt4's decoying of the anti-PD-L1 antibody. The decoying function of PD-L1 splicing variants may be one of the reasons for cancers being resistant to anti-PD-L1 therapy. Measuring serum PD-L1 levels might be helpful in deciding the therapeutic strategy.

Positive bag lavage cytology during thoracoscopic surgery for lung cancer is a significant predictor of locoregional recurrence.

OBJECTIVES: Advances in thoracoscopic surgery have made skin incisions smaller, but there are concerns about cancer cell contamination during sample extraction. We performed retrieval bag lavage cytology (BLC) during thoracoscopic surgery to evaluate the risk of cancer dissemination and the prognostic influence of BLC status. METHODS: BLC was investigated in 893 patients who underwent thoracoscopic lobectomy or segmentectomy for lung cancer between 2013 and 2018. The clinicopathological features and prognosis were compared between the BLC-positive and BLC-negative groups. RESULTS: Forty-nine patients (5.5%) were positive for BLC. BLC correlated with pleural invasion (49.0% vs. 12.9%, P < 0.001); however, BLC was positive in 3.3% of cases without pleural invasion. Multivariate analysis revealed that tumor size, lymph node metastasis, lymphatic and pleural invasion were predictive factors for positive BLC. Prognosis was poorer in the BLC-positive group than in the BLC-negative group (5-year overall survival, 73.6% vs. 90.2%, P < 0.001); nevertheless, positive BLC was not an independent prognostic factor. The locoregional recurrence rate was higher among BLC-positive patients than among BLC-negative patients, whereas there was no significant difference in the distant recurrence rate. Positive BLC was associated with locoregional recurrence (hazard ratio 1.87, P = 0.044) and the correlation was stronger in stage I lung cancer. There were no cases of extraction bag breakage or port-site recurrence. CONCLUSIONS: BLC positivity was correlated with the risk of locoregional recurrence in patients with surgically resected lung cancer, although it was not an independent prognostic factor. Careful manipulation is essential for extracting specimens from the thoracic cavity.

A Reasonable Definition of Oligo-Recurrence in Non-Small-Cell Lung Cancer.

BACKGROUND: The concept of oligo-recurrence in non-small-cell lung cancer (NSCLC) has been suggested to describe the possibility of achieving long-term survival or even cure with local therapy for recurrence despite having recurrent disease. Oligo-recurrence involves a limited number of metachronous recurrences that can be treated with local therapy. However, the number of recurrences that constitutes an oligo-recurrence has varied among studies and remains to be defined. The aim of this study was to elucidate the number of recurrences that constitutes an oligo-recurrence in NSCLC. PATIENTS AND METHODS: We retrospectively reviewed 577 patients with NSCLC who had underwent complete resection and developed recurrence between 1990 and 2009, and these patients were evaluated. Patients were categorized according to the number of recurrences, and postrecurrence survival (PRS) was compared between groups. RESULTS: Altogether, 270 patients underwent local therapy for all recurrent lesions. In these patients, sex (female), histological type (adenocarcinoma), gene mutation status, recurrence-free interval <1 year, and presence of 1 or 2 recurrences were factors associated with prolonged PRS. Additionally, all patients who maintained a cancer-free status for at least 5 years after treatment for recurrence and were considered possibly cured, had 1 or 2 recurrences. CONCLUSION: Among patients receiving radical local therapy, the PRS was particularly longer among those with 1 or 2 recurrences, and these patients were able to aim for postrecurrence cure. Thus, a reasonable threshold to define oligo-recurrence in NSCLC is 1 or 2 recurrences that can be treated with local therapy.

Prognostic impact and distinctive characteristics of surgically resected anaplastic lymphoma kinase-rearranged lung adenocarcinoma.

OBJECTIVE: Anaplastic lymphoma kinase (ALK) rearrangement is a representative lung cancer with driver mutation because of the efficacy of ALK-tyrosine kinase inhibitors. ALK-tyrosine kinase inhibitors are extensively used for ALK-rearranged lung cancer, whereas the therapeutic benefit of surgery remains unclear. Thus, we aimed to assess the clinical benefit of surgery in ALK-rearranged lung cancer and to elucidate the oncologic characteristics of ALK-rearranged lung cancer through surgically resected cases. METHODS: We retrospectively evaluated 1925 lung adenocarcinoma cases surgically resected between 1996 and 2017 at our institute. Moreover, 75 ALK-rearranged and 75 non-ALK-rearranged cases were extracted using propensity score matching. The survival rates, prognostic factors, and post-recurrence state were assessed. RESULTS: Multivariable analysis revealed that ALK rearrangement was an independent prognostic factor for improved cancer-specific survival (hazard ratio, 0.2; 95% confidence interval, 0.05-0.88; P = .033). In the matched cohort, the 5-year cancer-specific survival rates after surgery in the ALK-rearranged and non-ALK-rearranged groups were 97% and 77%, respectively. The ALK-rearranged group had a significantly better cancer-specific survival than did the non-ALK-rearranged group (log-rank test; P = .003). With respect to post-recurrence state, oligo-recurrence was highly frequent in the ALK-rearranged group, and post-recurrence survival was significantly improved by administration of either ALK-tyrosine kinase inhibitors (log-rank test; P = .011) or local ablative therapies (log-rank test; P = .035). CONCLUSIONS: Surgically resected ALK-rearranged lung adenocarcinoma has excellent long-term outcome. Not only ALK-tyrosine kinase inhibitors but also a combination of local and systemic therapies may be important treatment strategies for ALK-rearranged lung adenocarcinoma even in the post-recurrence state.

Standard therapy-resistant small cell lung cancer showing dynamic transition of neuroendocrine fate during the cancer trajectory: A case report.

While small cell lung cancer (SCLC) has been treated as a single disease historically, recent studies have suggested that SCLC can be classified into molecular subtypes based on the expression of lineage transcription factors such as achaete-scute homolog 1 (ASCL1), neurogenic differentiation factor 1 (NEUROD1), POU domain class 2 transcription factor 3 (POU2F3) and transcriptional coactivator YAP1 (YAP1). These transcription factor-based subtypes may be specifically targeted in therapy, and recent studies have suggested that the SCLC subtypes represent different stages of dynamic evolution of SCLC rather than independent diseases. Nevertheless, evidence of shift in neuroendocrine differentiation during SCLC evolution has been lacking in the clinical setting. In the present study, a 60-year-old male was diagnosed with extensive SCLC. The tumor responded not to the standard SCLC regimen of carboplatin, etoposide and atezolizumab, but to the non-SCLC regimen of carboplatin, nab-paclitaxel and pembrolizumab. The patient succumbed 5 months after the initial diagnosis and a pathological autopsy was performed. The tumor was originally negative for all four transcription factors, ASCL1, NEUROD1, POU2F3 and YAP1, in the biopsy specimens at diagnosis. Loss of synaptophysin expression and emergence of Myc proto-oncogene protein and YAP1 expression was recorded in the autopsy specimens, suggesting the transition to a decreased neuroendocrine fate during the disease trajectory. This case provides clinical evidence of dynamic transition of neuroendocrine fate during SCLC evolution. In light of SCLC heterogeneity and plasticity, development of precision medicine is required.

Novel Histologic Classification of Small Tumor Cell Nests for Lung Adenocarcinoma With Prognostic and Etiological Significance: Small Solid Nests and Pure Micropapillary Nests.

Small tumor cell nests such as micropapillary nests are histologic poor prognostic markers for adenocarcinomas of various organs, including the lung. However, for the lung, the association of micropapillary patterns with smoking is controversial, which may be because of a vague definition of micropapillary patterns. This study clarifies the implications of small tumor cell nests by introducing a new dichotomic classification based on the glandular polarity of tumor cells: pure micropapillary nests (pMPs), preserving glandular polarity, and small solid nests (SSNs), lacking polarity. We examined the clinicopathologic factors in 436 resected adenocarcinomas, and analyzed the overall survival between groups classified by either the presence or absence of pMPs and SSNs. pMP was positively associated with nonsmoking-related features such as epidermal growth factor receptor mutations and thyroid transcription factor 1 expression. By contrast, SSN was positively associated with smoking-related features such as KRAS mutations and hepatocyte nuclear factor-4a expressions. Besides, pMP and SSN were significant and independent indicators of poor prognosis in all stages. SSN was an indicator in stage I too, whereas pMP was not. Furthermore, prognoses of the group with SSN were significantly worse than those of pMP-only group. In conclusion, the present study has revealed 2 completely different patterns of small tumor cell nests in lung adenocarcinoma, the nonsmoking-related pMPs, and the smoking-related SSNs, by considering glandular polarity. MPP should include only pMPs, and SSNs should be in a solid pattern. This novel classification might boast clinical significance as a potent poor prognostic marker as well as a factor reflecting etiological and genetic characters.

Microsecond-timescale MD simulation of EGFR minor mutation predicts the structural flexibility of EGFR kinase core that reflects EGFR inhibitor sensitivity.

Approximately 15-30% of patients with lung cancer harbor mutations in the EGFR gene. Major EGFR mutations (>90% of EGFR-mutated lung cancer) are highly sensitive to EGFR tyrosine kinase inhibitors (TKIs). Many uncommon EGFR mutations have been identified, but little is known regarding their characteristics, activation, and sensitivity to various EGFR-TKIs, including allosteric inhibitors. We encountered a case harboring an EGFR-L747P mutation, originally misdiagnosed with EGFR-del19 mutation using a routine diagnostic EGFR mutation test, which was resistant to EGFR-TKI gefitinib. Using this minor mutation and common EGFR-activating mutations, we performed the binding free energy calculations and microsecond-timescale molecular dynamic (MD) simulations, revealing that the L747P mutation considerably stabilizes the active conformation through a salt-bridge formation between K745 and E762. We further revealed why several EGFR inhibitors, including the allosteric inhibitor, were ineffective. Our computational structural analysis strategy would be beneficial for future drug development targeting the EGFR minor mutations.

Two Cases of Lower Lobe Pneumatoceles Following Upper Lobectomy.

Postoperative pneumatocele is a rare complication of lung surgery. Here we describe 2 cases of pneumatoceles arising from the unaltered bottom part of the lower lobe a month or more after upper lobectomy. Based on histopathologic findings, we speculated that (1) negative pressure created by the volumetric gap between the thoracic cavity and the remnant lung and (2) increased positive pressure by the check valve mechanism from kinking or flexion of the airway after an upward movement of the remnant lung play crucial roles in the pathogenesis of postoperative pneumatoceles.