Insight into the significance of Foxp3 + tumor-infiltrating lymphocytes in squamous cell lung cancer.

PURPOSE: Although developing a better understanding of tumor-infiltrating Foxp3 + lymphocytes (Foxp3 + TILs) might provide essential knowledge to predict response to immunotherapy and prognosis, our current knowledge about Foxp3 + TILs is inadequate. This study investigated the prognostic significance of tumor-infiltrating Foxp3 + lymphocytes (Foxp3 + TILs) in squamous cell lung cancer (SQ-LC) objectively. METHODS: Among patients with SQ-LC surgically resected in our institution between 2011 and 2017, those with pathological stage IA3-IIIA were immunohistochemically studied to evaluate Foxp3 + TILs in their tumor stroma. The impact of Foxp3 + TILs on relapse-free survival (RFS) was analyzed with Kaplan-Meier survival analysis and multivariate analysis using a Cox proportional hazards model/Fine-Gray model. RESULTS: This study analyzed 100 patients. Multivariate analysis showed that a large number of Foxp3 + TILs in the stroma does not associate with a poor prognosis, rather that a large number of Foxp3 + TILs (≥ 64 cells) tend to be associated with a more favorable prognosis than a small number of Foxp3 + TILs (< 64 cells) (large vs small number: HR, 0.56; 95% CI, 0.17-1.83; P = 0.34). Exploratory analysis also showed that in the two populations divided by a difference in Foxp3 expression levels, similar trends to the main analysis were observed. CONCLUSION: Our results showed that a large number of Foxp3 + TILs in the stroma may not associate with a poor prognosis in SQ-LC. To use the seemingly complicated information of Foxp3 + TILs as biomarkers, better understanding the diversity and heterogeneity of Foxp3 + TILs and analyzing their subpopulations that increase in the TME may be needed.

Micropapillary and solid components as high-grade patterns in IASLC grading system of lung adenocarcinoma: Clinical implications and management.

OBJECTIVES: The grading system proposed by the International Association for the Study of Lung Cancer is based on a combination of predominant histologic subtypes and the proportion of high-grade components with a cutoff of 20%. We aimed to examine the clinical implications of the grading system beyond the discrimination of patient prognosis, while assessing the biological differences among high-grade subtypes. METHODS: We retrospectively reviewed 648 consecutive patients with resected lung adenocarcinomas and examined their clinicopathologic, genotypic, and immunophenotypic features and treatment outcomes. Besides the differences among grades, the clinical impact of different high-grade components: micropapillary (MIP) and solid (SOL) patterns, was individually evaluated. RESULTS: Survival outcomes were well-stratified according to the grading system. Grade 3 tumors exhibited aggressive clinicopathologic features, while being an independent prognostic factor in multivariable analysis. A small proportion (<20 %) of high-grade components in grade 2 had a negative prognostic impact. The prognostic difference bordering on the 20 % cutoff of the MIP proportion was validated; however, the proportion of SOL component did not affect prognosis. A survival benefit from adjuvant chemotherapy was observed in grade 3 tumors regardless of histologic subtype, but not in grade 1-2 tumors. The molecular and immunophenotypic features were different among grades, but still heterogeneous in grade 3, with MIP harboring frequent EGFR mutation and SOL exhibiting high PD-L1 expression. The treatment outcome after recurrence was worse in grade 3, but tumors with MIP pattern had an equivalent prognosis to that of grade 1-2 tumors, reflecting the high frequency of molecular targeted therapy. CONCLUSIONS: In addition to stratifying patient prognosis, the current grading system could discriminate clinical course, therapeutic effects of adjuvant chemotherapy, and molecular and immunophenotypic features. Further stratification based on biological heterogeneity in grade 3 remains necessary to enhance the role of the grading system in guiding patient management.

Insight into the significance of CD8+ tumor-infiltrating lymphocytes in squamous cell lung cancer.

BACKGROUND: Although there are great expectations regarding the use of tumor-infiltrating lymphocytes (TILs) to predict effects of immunotherapies and prognosis, knowledge about TILs remains insufficient for clinical application. METHODS: We objectively investigated the prognostic significance of tumor-infiltrating CD8 + lymphocytes (CD8 + TILs) in squamous cell lung cancer (SQ-LC). Among patients who underwent surgical resection of SQ-LC in 2011-2017, 100 patients with pathological stage IA3-III were immunohistochemically studied to evaluate CD8 + TILs in the tumor stroma and parenchyma. The impact of CD8 + TILs on relapse-free survival was analyzed using a Kaplan-Meier survival analysis and multivariate analyses using Fine-Gray and Cox proportional hazards models. RESULTS: The multivariate analysis showed that large and small numbers, but not intermediate numbers, of CD8 + TILs in the tumor stroma may be related to a more favorable prognosis (small vs. intermediate: HR, 0.64; 95% CI: 0.29-1.41, p = 0.27; large vs. intermediate: HR, 0.48; 95% CI: 0.21-1.09, p = 0.08). In contrast, a large number of CD8 + TILs in the tumor parenchyma was associated with a poor prognosis (HR, 2.60; 95% CI: 0.91-7.42, p = 0.075). An exploratory analysis showed a potentially strong association between an extremely large number of CD8 + TILs in the tumor parenchyma and a poor prognosis, even with a large number of CD8 + TILs in the tumor stroma. CONCLUSION: Our study provided partial but important information on the significance of CD8 + TILs in SQ-LC. To use CD8 + TILs as biomarkers, a better understanding of CD8 + TILs as well as other important components in the tumor microenvironment and the inflammatory phenotypes they form may be needed.

Prognostic implications of prostaglandin E-major urinary metabolite in resected non-small-cell lung cancer.

OBJECTIVES: Cyclooxygenase-2-derived prostaglandin E2 (PGE2) is highly involved in the promotion of cancer progression. The end product of this pathway, PGE-major urinary metabolite (PGE-MUM), is a stable metabolite of PGE2 that can be assessed non-invasively and repeatedly in urine samples. The aim of this study was to assess the dynamic changes in perioperative PGE-MUM levels and their prognostic significance in non-small-cell lung cancer (NSCLC). METHODS: Between December 2012 and March 2017, 211 patients who underwent complete resection for NSCLC were analysed prospectively. PGE-MUM levels in 2 spot urine samples taken 1 or 2 days preoperatively and 3-6 weeks postoperatively were measured using a radioimmunoassay kit. RESULTS: Elevated preoperative PGE-MUM levels were associated with tumour size, pleural invasion and advanced stage. Multivariable analysis revealed that age, pleural invasion, lymph node metastasis and postoperative PGE-MUM levels were independent prognostic factors. In matched pre- and postoperative urine samples obtained from patients who are eligible for adjuvant chemotherapy, an increase in PGE-MUM levels following resection was an independent prognostic factor (hazard ratio 3.017, P = 0.005). Adjuvant chemotherapy improved survival in patients with increased PGE-MUM levels after resection (5-year overall survival, 79.0 vs 50.4%, P = 0.027), whereas survival benefit was not observed in those with decreased PGE-MUM levels (5-year overall survival, 82.1 vs 82.3%, P = 0.442). CONCLUSIONS: Increased preoperative PGE-MUM levels can reflect tumour progression and postoperative PGE-MUM levels are a promising biomarker for survival after complete resection in patients with NSCLC. Perioperative changes in PGE-MUM levels may aid in determining the optimal eligibility for adjuvant chemotherapy.

Examination of the effectiveness of local therapy for oligo-recurrence of EGFR-mutated NSCLC.

BACKGROUND: The effectiveness of local therapy has been reported in patients with oligo-recurrence of non-small cell lung cancer (NSCLC), a metachronous recurrence with a limited number of recurrences, which can be treated with local therapy. Conversely, remarkable progress has been made in systemic therapy for NSCLC with the advent of molecular targeted therapy. In particular, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are very effective in the treatment of EGFR-mutated NSCLC. There is currently no consensus on treatment for oligo-recurrence of EGFR-mutated NSCLC. METHODS: From 2004 to 2014, 811 patients underwent complete resection for NSCLC at Kitasato University Hospital and, of these, 244 patients developed recurrence. Oligo-recurrence was defined as the presence of two or less recurrent lesions, and 34 patients presented with EGFR-mutated oligo-recurrence. RESULTS: We retrospectively examined and compared the effects of EGFR-TKIs with those of radical local therapy in patients with oligo-recurrent EGFR-mutated NSCLC. The five-year post-recurrence survival (PRS) rates of patients with EGFR-mutated oligo-recurrence who received radical local therapy (n = 23) and those who did not (n = 11) were 59.4 and 45.5%, respectively (p = 0.777). Multivariate analysis revealed no favorable prognostic factors associated with prolonged PRS, and radical local therapies did not improve PRS in patients with oligo-recurrence (p = 0.551). CONCLUSION: Radical local therapy did not affect PRS in patients with oligo-recurrent EGFR-mutated NSCLC. Even in cases of oligo-recurrence, the administration of local therapy in patients with EGFR-mutated NSCLC might be carefully considered.

Single-Cell Analysis Reveals Transcriptomic Features of Drug-Tolerant Persisters and Stromal Adaptation in a Patient-Derived EGFR-Mutated Lung Adenocarcinoma Xenograft Model.

INTRODUCTION: Targeted therapies require life-long treatment, as drug discontinuation invariably leads to tumor recurrence. Recurrence is mainly driven by minor subpopulations of drug-tolerant persister (DTP) cells that survive the cytotoxic drug effect. In lung cancer, DTP studies have mainly been conducted with cell line models. METHODS: We conducted an in vivo DTP study using a lung adenocarcinoma patient-derived xenograft tumor driven by an EGFR mutation. Daily treatment of tumor-bearing mice for 5 to 6 weeks with the EGFR inhibitor erlotinib markedly shrunk tumors and generated DTPs, which were analyzed by whole exome, bulk population transcriptome, and single-cell RNA sequencing. RESULTS: The DTP tumors maintained the genomic clonal architecture of untreated baseline (BL) tumors but had reduced proliferation. Single-cell RNA sequencing identified a rare (approximately 4%) subpopulation of BL cells (DTP-like) with transcriptomic similarity to DTP cells and intermediate activity of pathways that are up-regulated in DTPs. Furthermore, the predominant transforming growth factor-ß activated cancer-associated fibroblast (CAF) population in BL tumors was replaced by a CAF population enriched for IL6 production. In vitro experiments indicate that these populations interconvert depending on the levels of transforming growth factor-ß versus NF-κB signaling, which is modulated by tyrosine kinase inhibitor presence. The DTPs had signs of increased NF-κB and STAT3 signaling, which may promote their survival. CONCLUSIONS: The DTPs may arise from a specific preexisting subpopulation of cancer cells with partial activation of specific drug resistance pathways. Tyrosine kinase inhibitor treatment induces DTPs revealing greater activation of these pathways while converting the major preexisting CAF population into a new state that may further promote DTP survival.

Characterization of morphological alterations in micropapillary adenocarcinoma of the lung using an established cell line.

Micropapillary adenocarcinoma of the lung is a type of cancer associated with a poor prognosis and is characterized by the presence of tumor cells with a ring­like glandular structure floating within alveolar spaces. In the present study, the association between its morphological, biochemical and immunohistochemical characteristics, and malignancy was investigated using the KU­Lu­MPPt3 cell line established from a patient with MIP adenocarcinoma. Two subpopulations of KU­Lu­MPPt3 cells, namely adhesive (AD) and clumpy and suspended (CS) cells, were prepared and subjected to DNA microarray, reverse transcription­quantitative PCR, western blot and immunostaining analyses. Protein expression patterns were compared between the cell types and their derived tissues using immunostaining. The results revealed similar protein expression patterns between the tumor cells found in the alveolar spaces and CS cells, which exhibited morphological characteristic of MIP adenocarcinoma. Based on the results of DNA microarray analysis, the present study then focused on Akt and focal adhesion kinase (FAK), which were markedly activated in the KU­Lu­MPPt3 CS and AD cells, respectively. Following KU­Lu­MPPt3 CS cell plating onto collagen­coated culture dishes, some cells exhibited a transformation of their morphology into KU­Lu­MPPt3 AD­like cells within a few days, and their Akt and FAK activities were similar to those of the AD cells. Additionally, the inhibition of Akt and FAK activities with Akt and FAK inhibitors reduced KU­Lu­MPPt3 CS cell adhesion and proliferation. Thus, the aforementioned results indicated that the phosphorylation of FAK and Akt may play a crucial role in the regulation of KU­Lu­MPPt3 CS cell adhesion and proliferation, respectively. Furthermore, the malignant potential of MIP adenocarcinoma may be attributed to these morphological and biochemical alterations in the KU­Lu­MPPt3 cells.

Mechanism of Drug Tolerant Persister Cancer Cells: The Landscape and Clinical Implication for Therapy.

A minor population of cancer cells may evade cell death from chemotherapy and targeted therapy by entering a reversible slow proliferation state known as the drug tolerant persister (DTP) state. This DTP state can allow cancer cells to survive drug therapy long enough for additional mechanisms of acquired drug resistance to develop. Thus, cancer persistence is a major obstacle to curing cancers, where insight into the biology of DTP cells and therapeutic strategies targeting this mechanism can have considerable clinical implications. There is emerging evidence that DTP cells adapt to new environments through epigenomic modification, transcriptomic regulation, flexible energy metabolism, and interactions with the tumor microenvironment. Herein, we review and discuss the various proposed mechanisms of cancer persister cells and the molecular features underlying the DTP state, with insights into the potential therapeutic strategies to conquer DTP cells and prevent cancer recurrence or therapeutic failures.

Comparison between quantitative computed tomography, scintigraphy, and anatomical methods for prediction of postoperative FEV1 and DLCO: effects of chronic obstructive pulmonary disease status and resected lobes.

BACKGROUND: Postoperative assessment of pulmonary function is important for estimating the risk of thoracic surgery and long-term disability following pulmonary resection, including predicted postoperative (ppo) forced expiratory volume (FEV) in one second (ppoFEV1) and percent predicted lung diffusion capacity for carbon monoxide (ppo%DLCO) estimation. The ppo values were compared using four different estimation methods between chronic obstructive pulmonary disease (COPD) and non-COPD patients and according to the resected lobe. METHODS: This prospective study included 59 eligible patients requiring single lobectomy and succeeded in performing pulmonary function tests at 3 and 12 months after lobectomy. The ppoFEV1 and ppo%DLCO were compared with poFEV1 and po%DLCO obtained at 3 and 12 months after lobectomy. The ppo values were estimated using the four usual methods: the 19-segment anatomical technique (S), perfusion scintigraphy (Q), quantitative CT (CT), and quantitative CT with low attenuation volume (CTLAV) subtraction. RESULTS: For non-COPD and COPD patients, the smallest mean difference between ppo and po values was observed by S for FEV1 and %DLCO. Based on the resected lobe, the smallest mean difference was observed by (I) Q for right upper lobectomy (RUL) excluding %DLCO at 12 months by S, (II) S for left upper lobectomy (LUL), (III) CT and CTLAV for right lower lobectomy (RLL), and (IV) CT and CTLAV for left lower lobectomy (LLL) at 12 months. The ppo values calculated by S for RUL (FEV1 at 3 and 12 months and %DLCO at 3 months) and by all four methods for LLL (FEV1 and %DLCO at 3 months) were smaller than the po values. CONCLUSIONS: The S method is adequate for calculating ppoFEV1 and ppo%DLCO when patients are classified as non-COPD and COPD. However, S sometimes overestimates the ppoFEV1 and ppo%DLCO when patients are classified according to the resected lobe. The CTLAV method may be the method of choice instead of S for calculating ppoFEV1 and ppo%DLCO in patients who undergo lung lobectomy despite the presence or absence of airflow limitation.

Multiplex gene-panel testing for lung cancer patients.

The year 2019 was considered to be the first year of cancer genome medicine in Japan, with three gene-panel tests using next-generation sequencing (NGS) techniques being introduced into clinical practice. Among the three tests, the Oncomine CDx Target test was approved under the category of regular molecular testing for lung cancer, which meant that this test could be used to select patients for molecularly targeted drugs. Conversely, the other two tests, NCC OncoPanel and FoundationOne CDx, were assigned to be used under the National Cancer Genome Medicine Network, and implementation was restricted to patients for whom standard treatment was completed or expected to be completed. These NGS tests can detect a series of genetic alterations in individual tumors, which further promotes the development of therapeutic agents and elucidates molecular pathways. The NGS tests require appropriate tissue size and tumor cell content, which can be accessed only by pathologists. In this report, we review the current reimbursement schema in our national healthcare policy and the requirements of the specimens for NGS testing based on the recently published 'Guidance of Gene-panel Testing Using Next-Generation Sequencers for Lung Cancer', by the Japanese Society of Lung Cancer.

EGFR mutation genotyping and ALK status determination in liquid-based cytology samples of non-small cell lung cancer.

Personalised medicine for primary lung cancers (PLCs) requires molecular analysis of cancer tissue or cells. The primary objective of the present prospective study was to assess the concordance between epidermal growth factor receptor (EGFR) gene mutation detection and echinoderm microtubule-associated protein-like (EML) 4-anaplastic lymphoma kinase protein (ALK) expression using liquid-based cytology (LBC) samples and matched histology samples of PLC patients. A total of 117 patients who underwent surgical resection of non-small cell PLC were enrolled. Cytological specimens scratched from the resected PLC lesion were fixed in CytoRich Red. DNA extracted from LBC samples was examined for EGFR gene mutations. Anaplastic lymphoma kinase arrangement was analysed by immunostaining and fluorescence in situ hybridisation. Our patient cohort comprised 93 cases of adenocarcinoma, 16 squamous cell carcinoma, three adenosquamous carcinoma, two large cell neuroendocrine carcinoma, one pleomorphic carcinoma and two other cases. Sixty-six (58.4%) LBC samples harboured EGFR gene mutations. The overall concordance rate in EGFR gene mutation status, including minor mutations, between histologic and paired LBC specimens (N = 105) was 100%. The overall concordance rate of EGFR gene mutation status, including minor mutations and ALK status according to immunostains between histologic and paired LBC specimens, was 100% (105/105) and 100% (48/48), respectively. Genotyping and protein expression studies can be reliably performed using LBC samples prepared with CytoRich Red. Analysis of such samples may guide individual therapy in PLC patients.

Calculating the Tumor Nuclei Content for Comprehensive Cancer Panel Testing.

Comprehensive genetic panel testing generally requires that the analyzed tissues have a percent tumor nuclei (%TN) content of 20% or more to achieve assay performance comparable to the validated specifications. Pathologists play a crucial role in ensuring that the optimal results are achieved by accurately assigning %TN content of the available specimens and selecting the best material to submit for sequencing. This study addresses the issues in evaluating %TN, such as intraobserver variability, and examines whether focused training and feedback can improve pathologist performance. Nine referring institution pathologists (all board-certified and working at the core institute and the alignment hospitals under the National Cancer Genome scheme) evaluated 18 tumors that had been subjected to comprehensive genetic panel testing with the FoundationOne CDx assay. The %TN estimates provided by referring institution pathologists were compared with two standards: %TN assigned by the tumor sequencing institution's pathologist (a board-certified pathologist at Foundation Medicine, Inc.) and the computational %TN estimated from the mutant allele frequencies after sequencing was completed. The pathologists generally overestimated %TN in the first pretraining round of the evaluation, and the differences in the averaged %TN from the tumor sequencing institution and computational standards were statistically significant. However, the posttraining second-round results became significantly concordant with the standards. This study suggests that %TN content is empirically overestimated but the evaluation skill can be improved by providing a training and feedback program.

Ciliated muconodular papillary tumors of the lung: Cytologic features and diagnostic pitfalls in intraoperative examinations.

Ciliated muconodular papillary tumors (CMPTs) of the lung are rare, likely benign neoplastic lesions. Here we describe a case of a CMPT, focusing on its cytologic features, which to our knowledge have not been reported previously. Owing to dull back pain, a 69-year-old male non-smoker underwent CT, which revealed a 1.3 × 1.3-cm solid nodule in the peripheral field of the left lower lung lobe. A wedge resection of the nodule was performed, with the provisional diagnosis being primary lung cancer. Macroscopic examination of a resected specimen showed a 1.2-cm grayish nodule. Touch imprint smear cytology revealed ciliated columnar cells and mucous cells, as well as abundant extracellular mucin on inflammatory background of lymphocytes and histiocytes. Histologic examination revealed a nodular papillary tumor composed of ciliated columnar cells, mucous cells, and basal cells surrounded by a mucin pool. No nuclear atypia or mitotic figures were identified. The final diagnosis was CMPT. The postoperative course was uneventful, with no recurrence at 8 months after surgery. Although a CMPT is a rare lung tumor, it should be considered when cytological or histological examination of a solitary peripheral lung nodule shows non-atypical ciliated cells and mucous cells surrounded by mucin.

Relevance of Intraoperative Pleural Lavage Cytology and Histologic Subtype in Lung Adenocarcinoma.

BACKGROUND: The association between pleural lavage cytology (PLC) and histologic subtype remains unknown. In this study, we evaluated the effect of a micropapillary pattern (MPP) in lung adenocarcinomas on results of PLC. METHODS: We retrospectively reviewed 600 consecutive patients with surgically resected pulmonary adenocarcinomas and investigated the relationship between PLC status and clinicopathologic factors, including a histologically identified MPP component. RESULTS: PLC was positive in 25 patients (4.2%). Positive PLC was significantly associated with MPP (p = 0.0001), lymph node metastasis (p = 0.01), and pleural invasion (p < 0.0001) according to multivariate analysis. Furthermore, the presence of MPP reinforced the effect of some established predictive factors, such as large tumor size, lymph node metastasis, pleural invasion, and lymphovascular invasion, on positive PLC. Two factors-MPP and positive PLC-were associated with a higher incidence of occult N2 lymph node metastases. The prognosis of adenocarcinomas in patients with MPP or positive PLC was significantly worse than that of patients without these features. Furthermore, the survival of MPP and positive PLC group (MPP+ PLC+) was significantly worse than that of MPP and negative PLC group (MPP+ PLC-, p = 0.03). CONCLUSIONS: The presence of MPP in lung adenocarcinoma can be an independent predictor of positive PLC. These two factors have complementary and synergistic roles as prognostic factors. Detailed preoperative or intraoperative examination of histologic subtype and PLC findings may provide important information for prediction of tumor progression and decisions regarding the surgical procedure.

Feasible and promising modified trans-subxiphoid thoracoscopic extended thymectomy for patients with myasthenia gravis.

BACKGROUND: We have used a promising, minimally invasive thoracoscopic technique of extended thymectomy for patients with myasthenia gravis (MG). The aim of this study was to report our promising technique, a modified single-port trans-subxiphoid approach (MTXA) and to compare perioperative outcomes and effects on MG between our approach and sternotomy. METHODS: We retrospectively reviewed records of all patients undergoing extended thymectomy for MG and/or thymoma between January 1, 2010 and December 31, 2016. The patients were divided into the MTXA group and Sternotomy group. RESULTS: Of the 50 consecutive patients undergoing extended thymectomy for MG, finally, 13 patients undergoing our MTXA extended thymectomy technique were compared with 20 patients undergoing extended thymectomy via sternotomy. Intraoperative blood loss, postoperative length of stay, and C-reactive protein value on postoperative day 1 were significantly more favorable in the MTXA group than the Sternotomy group (P<0.0001, P=0.0040 and P=0.0073, respectively). Furthermore, no significant differences in the frequency of patients with improvement of their Quantitative Myasthenia Gravis score and/or MG-Activities of Daily Living scale, decrease in the serum level of acetylcholine receptor antibody, and dose reduction of oral prednisone were seen between the two groups. CONCLUSIONS: Our approach to extended thymectomy might be more favorable than sternotomy in patients with MG.

Lung metastases of a uterine tumor resembling ovarian sex-cord tumor: Report of a rare case.

Uterine tumor resembling an ovarian sex-cord tumor (UTROSCT) is a rare type of uterine neoplasm. We present an extremely rare case of lung metastases from a UTROSCT focusing on the cytologic features. A 69-year-old Japanese woman was admitted to our hospital for further examination and treatment for abnormal shadows in the right lung field. She had a history of total hysterectomy for UTROSCT. Moreover, she underwent wedge resection of the right middle lobe for lung metastasis of UTROSCT in 2011. Enhanced chest computed tomography scan revealed a solid nodule 8 mm in diameter in the right upper lobe and a well-demarcated 33-mm mass or nodule in the lower lobe. Under the diagnosis of metastatic tumors from UTROSCT, she underwent wedge resection of the right upper lobe and segmentectomy of the right S8. Cytologically, the stump smear from the resected tumors revealed round to short spindle-shaped neoplastic small cells arranged in sheets with poor cohesion and no cluster formation. The nuclei were irregular in shape, and the chromatin was finely granular, uniform, and increased. Mitotic figures were not observed. Necrosis was absent in the background. Histologically, the final diagnosis was UTROSCT group II. This is an unusual case of metastatic UTROSCT to the lung in which the cytologic features are described.

Molecular alterations in a new cell line (KU-Lu-MPPt3) established from a human lung adenocarcinoma with a micropapillary pattern.

PURPOSE: Lung adenocarcinomas with a micropapillary pattern (MPP) are characterized by more frequent and pronounced vascular invasion, higher incidence and more advanced lymph node involvement and poorer prognosis than papillary adenocarcinomas without an MPP. Here we established a new lung cancer cell line featuring micropapillary structure. METHODS: A 73-year-old never-smoker Japanese female, presenting with an abnormal chest shadow, was diagnosed with a clinical T2aN0M0 Stage IB lung adenocarcinoma and underwent left upper lobectomy with mediastinal lymph node dissection. Pathological study demonstrated a T2aN2M0 Stage IIIA micropapillary adenocarcinoma. Tumor cells were obtained from freshly resected lung material and used to establish the KU-Lu-MPPt3 cell line. RESULTS: The KU-Lu-MPPt3 cells featured adherent monolayers, adherent tufts, and suspended tufts without adhesion under the same culture conditions. The cells were positive for cytokeratin, epithelial cell-adhesion molecules, E-cadherin, mucin-1, thyroid transcription factor-1, vimentin, and anti-programmed death ligand 1. Xenograft tumors clearly demonstrated micropapillary structures. Sequencing and fragment analysis of the epidermal growth factor receptor in the primary tumor tissue and KU-Lu-MPPt3 cells revealed an in-frame deletion E746-A750 in exon 19. CONCLUSIONS: This cell line represents a new model system for molecular studies of lung adenocarcinoma which may be suitable for investigation of cancer spread and also for development of molecular-targeting and immunotherapies, both in vitro and in vivo.

Predictive clinical parameters for the response of nivolumab in pretreated advanced non-small-cell lung cancer.

BACKGROUND: Nivolumab offers a superior survival benefit over docetaxel in patients with advanced, previously treated non-small-cell lung cancer (NSCLC). An association between programmed cell death ligand-1 (PD-L1) expression and the efficacy of nivolumab has been reported in many studies. However, the association between the clinical parameters and efficacy of nivolumab remains unclear in advanced NSCLC patients. RESULTS: Among 124 patients, 108 (88%) were performance status (PS) 0 to 1. PD-L1 expression was assessed in 89 patients, with 51 (57%) patients having PD-L1 positive expression. In all patients, the objective response rate (ORR) in patients with elevated CRP levels (≥ 1 mg/dl) was significantly worse than those without elevated CRP levels (< 1 mg/dl) (8.3 vs 23.4%, p = 0.0180). The PS (≥ 2), smoking index (< 400), CRP levels (≥ 1 mg/dl) and LDH (≥ 245 IU/L) were significantly associated with a shorter PFS and OS in patients treated with nivolumab. Multivariate analyses showed that the PS (≥ 2), smoking index (< 400), CRP levels (≥ 1 mg/dl) and LDH (≥ 245 IU/L) and PD-L1 expression were significant factors associated with a longer PFS of nivolumab. MATERIALS AND METHODS: We retrospectively analyzed 124 patients who received nivolumab as a subsequent treatment. The patient characteristics, laboratory data at baseline (C-reactive protein [CRP] and lactate dehydrogenase [LDH]), PD-L1 expression, nivolumab response, progression-free survival (PFS), and overall survival (OS) were evaluated. CONCLUSIONS: Clinical parameters, such as PS, serum CRP, serum LDH, and smoking status, were significantly associated with the response duration and survival in patients treated with nivolumab.