Oncological feasibility of segmentectomy for inner-located lung cancer.

Objective: Oncological feasibility of segmentectomy for internal non-small cell lung cancer (NSCLC) has not been assessed adequately. We assessed the oncological feasibility of segmentectomy for inner-located NSCLC by investigating surgical margins and patient prognosis after undergoing the procedure. Methods: Of the 3555 patients who underwent resection for lung cancer between 2013 and 2019 at our institution, 659 patients who underwent segmentectomy for clinical stage 0 to stage1A NSCLC were included in this study. Patients were separated into 2 groups according to whether the tumor was in the inner or outer third of the lung area. Clinical characteristics and prognoses were retrospectively compared between the groups. Results: Of the included 659 cases, 183 (27.8%) were inner-located, and 476 (72.2%) had outer-located NSCLC. The surgical margin was significantly shorter in the inner-located group than in the outer group (median, 16 vs 25 mm; P < .001). The 5-year recurrence-free survival and overall survival probabilities were 91.1%/91.8% (P = .530) and 94.1%/95.6% (P = .345) for inner/outer-located groups, respectively. Multivariate analysis showed that clinical stage IA2 or 3 (P = .043), lymphovascular invasion (P < .001), and surgical margins <20 mm (P = .017) were independent prognostic factors for recurrence-free survival. The location of the inner or outer tumors was not related to the prognosis. Conclusions: For clinical stage 0 to stage1A NSCLC, tumor location in the inner two-thirds of the lung was not associated with prognosis after segmentectomy. Because one of the independent prognostic factors is margin distance, segmentectomy for inner-located NSCLC would be oncologically acceptable when an adequate surgical margin is secured.

An algorithm-based technique for counting mitochondria in cells using immunohistochemical staining of formalin-fixed and paraffin-embedded sections.

PURPOSE: Visualizing mitochondria in cancer cells from human pathological specimens may improve our understanding of cancer biology. However, using immunohistochemistry to evaluate mitochondria remains difficult because almost all cells contain mitochondria and the number of mitochondria per cell may have important effects on mitochondrial function. Herein, we established an objective system (Mito-score) for evaluating mitochondria using machine-based processing of hue, saturation, and value color spaces. METHODS: The Mito-score was defined as the number of COX4 (mitochondrial inner membrane) immunohistochemistry-positive pixels divided by the number of nuclei per cell. The system was validated using four lung cancer cell lines, normal tissues, and lung cancer tissues (199 cases). RESULTS: The Mito-score correlated with MitoTracker, a fluorescent dye used to selectively label and visualize mitochondria within cells under a microscope (R2 = 0.68) and with the number of mitochondria counted using electron microscopy (R2 = 0.79). Histologically, the Mito-score of small cell carcinoma (57.25) was significantly lower than that of adenocarcinoma (147.5, p < 0.0001), squamous cell carcinoma (120.6, p = 0.0004), and large cell neuroendocrine carcinoma (111.8, p = 0.002). CONCLUSION: The Mito-score method enables the analysis of the mitochondrial status of human formalin-fixed paraffin-embedded specimens and may provide insights into the metabolic status of cancer.

Molecular subtypes of lung adenocarcinoma present distinct immune tumor microenvironments.

Overcoming resistance to immune checkpoint inhibitors is an important issue in patients with non-small-cell lung cancer (NSCLC). Transcriptome analysis shows that adenocarcinoma can be divided into three molecular subtypes: terminal respiratory unit (TRU), proximal proliferative (PP), and proximal inflammatory (PI), and squamous cell carcinoma (LUSQ) into four. However, the immunological characteristics of these subtypes are not fully understood. In this study, we investigated the immune landscape of NSCLC tissues in molecular subtypes using a multi-omics dataset, including tumor-infiltrating leukocytes (TILs) analyzed using flow cytometry, RNA sequences, whole exome sequences, metabolomic analysis, and clinicopathologic findings. In the PI subtype, the number of TILs increased and the immune response in the tumor microenvironment (TME) was activated, as indicated by high levels of tertiary lymphoid structures, and high cytotoxic marker levels. Patient prognosis was worse in the PP subtype than in other adenocarcinoma subtypes. Glucose transporter 1 (GLUT1) expression levels were upregulated and lactate accumulated in the TME of the PP subtype. This could lead to the formation of an immunosuppressive TME, including the inactivation of antigen-presenting cells. The TRU subtype had low biological malignancy and "cold" tumor-immune phenotypes. Squamous cell carcinoma (LUSQ) did not show distinct immunological characteristics in its respective subtypes. Elucidation of the immune characteristics of molecular subtypes could lead to the development of personalized immune therapy for lung cancer. Immune checkpoint inhibitors could be an effective treatment for the PI subtype. Glycolysis is a potential target for converting an immunosuppressive TME into an antitumorigenic TME in the PP subtype.

Advances in cancer DNA methylation analysis with methPLIER: use of non-negative matrix factorization and knowledge-based constraints to enhance biological interpretability.

DNA methylation is an epigenetic modification that results in dynamic changes during ontogenesis and cell differentiation. DNA methylation patterns regulate gene expression and have been widely researched. While tools for DNA methylation analysis have been developed, most of them have focused on intergroup comparative analysis within a dataset; therefore, it is difficult to conduct cross-dataset studies, such as rare disease studies or cross-institutional studies. This study describes a novel method for DNA methylation analysis, namely, methPLIER, which enables interdataset comparative analyses. methPLIER combines Pathway Level Information Extractor (PLIER), which is a non-negative matrix factorization (NMF) method, with regularization by a knowledge matrix and transfer learning. methPLIER can be used to perform intersample and interdataset comparative analysis based on latent feature matrices, which are obtained via matrix factorization of large-scale data, and factor-loading matrices, which are obtained through matrix factorization of the data to be analyzed. We used methPLIER to analyze a lung cancer dataset and confirmed that the data decomposition reflected sample characteristics for recurrence-free survival. Moreover, methPLIER can analyze data obtained via different preprocessing methods, thereby reducing distributional bias among datasets due to preprocessing. Furthermore, methPLIER can be employed for comparative analyses of methylation data obtained from different platforms, thereby reducing bias in data distribution due to platform differences. methPLIER is expected to facilitate cross-sectional DNA methylation data analysis and enhance DNA methylation data resources.

Passive Smoking-Induced Mutagenesis as a Promoter of Lung Carcinogenesis.

INTRODUCTION: The International Agency for Research on Cancer has classified passive smoking (PS) or secondhand smoke exposure as a group 1 carcinogen linked to lung cancer. However, in contrast to active smoking, the mutagenic properties of PS remain unclear. METHODS: A consecutive cohort of 564 lung adenocarcinoma samples from female never-smokers, who provided detailed information about their exposure to PS during adolescence and in their thirties through a questionnaire, was prepared. Of these, all 291 cases for whom frozen tumor tissues were available were subjected to whole exome sequencing to estimate tumor mutational burden, and the top 84 cases who were exposed daily, or not, to PS during adolescence, in their thirties or in both periods, were further subjected to whole genome sequencing. RESULTS: A modest yet statistically significant increase in tumor mutational burden was observed in the group exposed to PS compared with the group not exposed to PS (median values = 1.44 versus 1.29 per megabase, respectively; p = 0.020). Instead of inducing driver oncogene mutations, PS-induced substantial subclonal mutations exhibiting APOBEC-type signatures, including SMAD4 and ADGRG6 hotspot mutations. A polymorphic APOBEC3A/3B allele-specific to the Asian population that leads to up-regulated expression of APOBEC3A accentuated the mutational load in individuals exposed daily to PS during adolescence. CONCLUSIONS: This study reveals that PS-induced mutagenesis can promote lung carcinogenesis. The APOBEC3A/3B polymorphism may serve as a biomarker for identifying passive nonsmoking individuals at high risk of developing lung cancer.

Neutrophil-to-lymphocyte ratio is a prognostic factor reflecting immune condition of tumor microenvironment in squamous cell lung cancer.

Inflammatory factors in the peripheral blood, such as the C-reactive protein level and neutrophil-to-lymphocyte ratio (NLR), are prognostic markers in multiple types of cancer, including non-small cell lung cancer (NSCLC). However, the association between inflammatory factors and prognosis based on histological types has not been adequately reported. In addition, the relationship between these factors and the immune condition of the tumor microenvironment (TME) is unclear. In this single center, retrospective study, we first investigated the relationship between preoperative inflammatory markers and clinical outcomes in 176 patients with NSCLC who underwent surgery. Lung adenocarcinoma (LUAD) showed no significant prognostic marker, whereas for lung squamous cell carcinoma (LUSC), a multivariate analysis showed that a high NLR was significantly associated with postoperative recurrence. In LUSC patients, the median time of postoperative recurrence-free survival in patients with a low NLR was longer than that in patients with a high NLR. We then compared the tumor-infiltrating lymphocyte (TIL) profile with inflammatory markers in peripheral blood and found that the NLR was negatively correlated with the frequencies of T cells and B cells in LUSC tissues. Thus, the NLR is a useful predictive biomarker for postoperative recurrence and may reflect the immune condition of the TME in LUSC.

What Are the Complication Rates and Factors Associated With Total Femur Replacement After Tumor Resection? Findings From the Japanese Musculoskeletal Oncology Group.

BACKGROUND: Patients undergoing massive tumor resection and total femur replacement (TFR) face a substantial risk of hip dislocation and infection, often resulting in multiple implant revisions or hip disarticulation. These complications can impact their independence and prognosis. Additionally, their shorter life expectancy is influenced by challenges in achieving local radical resection and controlling metastases. Identifying suitable candidates for TFR is vital, necessitating investigations into dislocation, infection, implant failure rates, local recurrence, overall survival, and associated factors. QUESTIONS/PURPOSES: (1) What is the postsurgical complication (hip dislocation and infection) rate and factors associated with postsurgical complications in patients who underwent TFR after tumor resection? (2) What is the local recurrence rate, implant failure rate, overall survival rate, and factors associated with local recurrence and implant failure? METHODS: We retrospectively evaluated 42 patients (median [range] age 47 years [10 to 79 years]) who underwent TFR and tumor resection at the time of the same surgical procedure between 1990 and 2020 at 12 registered institutions that specialized in tumor treatment in Japan. A total of 55% (23) of the patients were men, and 79% (33) had bone sarcoma. The median (range) follow-up period was 36.5 months (2 to 327 months). Of the 42 patients, 12% (5) were lost to follow-up before 2 years without meeting a study endpoint (postsurgical complications, revision, or amputation), and another 19% (8) died before 2 years with implants intact, leaving 69% (29) of the original group who had either follow-up of at least 2 years or met a study endpoint before the minimum surveillance duration. Another 10% (4) had a minimum of 2 years of follow-up but had not been seen in the past 5 years. Infection was defined as deep-seated infection involving soft tissues, bones, joints, and the area around the implant. We did not consider superficial infections. Implant failure was defined when a patient underwent reimplantation or amputation. The complication and implant failure rates were assessed by the cumulative incidence function method, considering competing events. The Kaplan-Meier method was used to estimate the overall survival rate. RESULTS: The 1-month, 6-month, 1-year, and 2-year dislocation rates were 5%, 12%, 14%, and 14%, respectively. The 1-month, 6-month, 1-year, and 2-year infection rates were 5%, 7%, 10%, and 15%, respectively. Multivariable analyses for hip dislocation and infection revealed that resection of the abductor muscles and large tumor size were positively associated with hip dislocation. The 6-month, 1-year, and 2-year local recurrence rates were 5%, 15%, and 15%, respectively. The 6-month, 1-year, 2-year, and 5-year implant failure rates were 5% (95% confidence interval 1% to 15%), 7% (95% CI 2% to 18%), 16% (95% CI 6% to 29%), and 16% (95% CI 6% to 29%), respectively. Multivariable analyses of local recurrence and implant failure that led to reimplantation or amputation revealed that a positive surgical margin was positively associated with local recurrence. The 1-year, 2-year, and 5-year overall patient survival rates were 95% (95% CI 87% to 102%), 77% (95% CI 64% to 91%), and 64% (95% CI 48% to 81%), respectively. CONCLUSION: Hip dislocation, infection, and local recurrence were frequently observed in patients who received massive tumor resection and TFR in our study, eventually leading to reimplantation or amputation. Preserving the abductor muscles and resecting the tumor with a wide margin can prevent postoperative dislocation and local recurrence. Future research should focus on patient selection criteria, prevention of hip dislocation, and innovative treatments. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Impact of 18F-FDG PET on TNM Staging and Prognosis in Thymic Epithelial Tumors.

BACKGROUND: Preoperative fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG PET) of thymic epithelial tumors (TETs) is well known for identifying malignant-grade TETs; however, its predictive power for determining locally advanced tumors, lymph node (LN) metastasis, and prognosis remains unknown. PATIENTS AND METHODS: We retrospectively evaluated patients with resectable TETs who were preoperatively assessed using 18F-FDG PET from January 2012 to January 2023. The receiver operating characteristic curve was used to evaluate the cutoff value of the maximum standardized uptake value (SUVmax) to predict advanced-stage disease. Recurrence/progression-free survival (RFS/PFS) was analyzed using the Kaplan-Meier method. The staging was classified according to the tumor-node-metastasis system. RESULTS: Our study included 177 patients; 145 (81.9%) had pathological early-stage TET (stage I or II), and 32 (19.1%) had advanced stage (stage III or IV). The area under the curve value for predicting the advanced stage was 0.903, and the cutoff value was 5.6 (sensitivity 81.3%, specificity 84.8%). SUVmax > 5.6 was associated with worse prognosis for RFS/PFS. LN metastasis was preoperatively detected by FDG uptake in 30.8% of patients with pathological LN positivity, whereas LN metastasis was not pathologically detected in patients with SUVmax < 5.9. In patients with advanced-stage TETs, LN recurrence was more frequent in patients who were preoperatively detected by 18F-FDG PET than those who were not (75.0% versus 7.1%). CONCLUSIONS: 18F-FDG PET is a potentially valuable tool for predicting advanced stage and poor prognosis of recurrence in patients with TETs. SUVmax can help thoracic surgeons to guide them in selecting appropriate therapeutic strategies for TETs.

Tumor microenvironment-mediated immune profiles and efficacy of anti-PD-L1 antibody plus chemotherapy stratified by DLL3 expression in small-cell lung cancer.

BACKGROUND: Delta-like ligand 3 (DLL3) is a therapeutic target in small-cell lung cancer (SCLC). However, how DLL3 expression status affects the tumor microenvironment (TME) and clinical outcomes in SCLC remains unclear. METHODS: This retrospective study included patients with postoperative limited-stage (LS)-SCLC and extensive-stage (ES)-SCLC treated with platinum and etoposide (PE) plus anti-programmed cell death ligand 1 (PD-L1) antibody. We investigated the relationship of DLL3 expression with TME, mutation status, tumor neoantigens, and immunochemotherapy. RESULTS: In the LS-SCLC cohort (n = 59), whole-exome sequencing revealed that DLL3High cases had significantly more neoantigens (P = 0.004) and a significantly higher rate of the signature SBS4 associated with smoking (P = 0.02) than DLL3Low cases. Transcriptome analysis in the LS-SCLC cohort revealed that DLL3High cases had significantly suppressed immune-related pathways and dendritic cell (DC) function. SCLC with DLL3High had significantly lower proportions of T cells, macrophages, and DCs than those with DLL3Low. In the ES-SCLC cohort (n = 30), the progression-free survival associated with PE plus anti-PD-L1 antibody was significantly worse in DLL3High cases than in DLL3Low cases (4.7 vs. 7.4 months, P = 0.01). CONCLUSIONS: Although SCLC with DLL3High had a higher neoantigen load, these tumors were resistant to immunochemotherapy due to suppressed tumor immunity by inhibiting antigen-presenting functions.

An ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress.

Activation of the KRAS oncogene is a source of replication stress, but how this stress is generated and how it is tolerated by cancer cells remain poorly understood. Here we show that induction of KRASG12V expression in untransformed cells triggers H3K27me3 and HP1-associated chromatin compaction in an RNA transcription dependent manner, resulting in replication fork slowing and cell death. Furthermore, elevated ATR expression is necessary and sufficient for tolerance of KRASG12V-induced replication stress to expand replication stress-tolerant cells (RSTCs). PrimPol is phosphorylated at Ser255, a potential Chk1 substrate site, under KRASG12V-induced replication stress and promotes repriming to maintain fork progression and cell survival in an ATR/Chk1-dependent manner. However, ssDNA gaps are generated at heterochromatin by PrimPol-dependent repriming, leading to genomic instability. These results reveal a role of ATR-PrimPol in enabling precancerous cells to survive KRAS-induced replication stress and expand clonally with accumulation of genomic instability.

Prognostic role of preoperative fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography with an image-based harmonization technique: A multicenter retrospective study.

Objectives: Despite the prognostic impacts of preoperative fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography examination, fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography-based prognosis prediction has not been used clinically because of the disparity in data between institutions. By applying an image-based harmonized approach, we evaluated the prognostic roles of fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography parameters in clinical stage I non-small cell lung cancer. Methods: We retrospectively examined 495 patients with clinical stage I non-small cell lung cancer who underwent fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography examinations before pulmonary resection between 2013 and 2014 at 4 institutions. Three different harmonization techniques were applied, and an image-based harmonization, which showed the best-fit results, was used in the further analyses to evaluate the prognostic roles of fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography parameters. Results: Cutoff values of image-based harmonized fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography parameters, maximum standardized uptake, metabolic tumor volume, and total lesion glycolysis were determined using receiver operating characteristic curves that distinguish pathologic high invasiveness of tumors. Among these parameters, only the maximum standardized uptake was an independent prognostic factor in recurrence-free and overall survivals in univariate and multivariate analyses. High image-based maximum standardized uptake value was associated with squamous histology or lung adenocarcinomas with higher pathologic grades. In subgroup analyses defined by ground-glass opacity status and histology or by clinical stages, the prognostic impact of image-based maximum standardized uptake value was always the highest compared with other fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography parameters. Conclusions: The image-based fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography harmonization was the best fit, and the image-based maximum standardized uptake was the most important prognostic marker in all patients and in subgroups defined by ground-glass opacity status and histology in surgically resected clinical stage I non-small cell lung cancers.

Dynamics of recurrence after curative resection of nonsmall cell lung cancer.

BACKGROUND AND OBJECTIVES: This study examined the trend of hazards for postoperative recurrence of lung cancer according to pathologic stages. METHODS: We reviewed the records of 1987 patients who underwent resection for lung cancer between 2007 and 2012. Postoperative recurrence and development of second primary lung cancer were analyzed to evaluate the trend of hazard rate. RESULTS: Recurrence-free survival (RFS) probabilities at 5 postoperative years in patients with stage I/II/III disease were 87.8%/54.7%,/33.4%, respectively. The hazard rate of RFS was consistently low (<0.005) for stage I patients for 5 years after surgery. The hazard rate of RFS for stage II patients showed a peak of 0.016 at 12.4 months after surgery, and that for stage III patients had a higher peak of 0.029 at 13.7 months after surgery, after which they showed a gradual decrease. The hazard rate for the development of second primary lung cancer exceeded that of recurrence of first primary lung cancer after 72 months postoperatively. CONCLUSIONS: Short-interval postoperative surveillance might be unnecessary for stage I patients but should be considered in stage II/III patients. Screening of second primary lung cancer rather than surveillance of recurrence might be beneficial after more than 6 years postoperatively.

Tumor-infiltrating Leukocyte Profiling Defines Three Immune Subtypes of NSCLC with Distinct Signaling Pathways and Genetic Alterations.

Resistance to immune checkpoint blockade remains challenging in patients with non-small cell lung cancer (NSCLC). Tumor-infiltrating leukocyte (TIL) quantity, composition, and activation status profoundly influence responsiveness to cancer immunotherapy. This study examined the immune landscape in the NSCLC tumor microenvironment by analyzing TIL profiles of 281 fresh resected NSCLC tissues. Unsupervised clustering based on numbers and percentages of 30 TIL types classified adenocarcinoma (LUAD) and squamous cell carcinoma (LUSQ) into the cold, myeloid cell-dominant, and CD8+ T cell-dominant subtypes. These were significantly correlated with patient prognosis; the myeloid cell subtype had worse outcomes than the others. Integrated genomic and transcriptomic analyses, including RNA sequencing, whole-exome sequencing, T-cell receptor repertoire, and metabolomics of tumor tissue, revealed that immune reaction-related signaling pathways were inactivated, while the glycolysis and K-ras signaling pathways activated in LUAD and LUSQ myeloid cell subtypes. Cases with ALK and ROS1 fusion genes were enriched in the LUAD myeloid subtype, and the frequency of TERT copy-number variations was higher in LUSQ myeloid subtype than in the others. These classifications of NSCLC based on TIL status may be useful for developing personalized immune therapies for NSCLC. Significance: The precise TIL profiling classified NSCLC into novel three immune subtypes that correlates with patient outcome, identifying subtype-specific molecular pathways and genomic alterations that should play important roles in constructing subtype-specific immune tumor microenvironments. These classifications of NSCLC based on TIL status are useful for developing personalized immune therapies for NSCLC.

Utility of the endobronchial Watanabe spigot for intractable cancer-related pneumothorax: a retrospective observational study.

BACKGROUND: The use of endobronchial Watanabe spigots for intractable secondary pneumothorax in patients with cancer has not been adequate. This study aimed to investigate the use of endobronchial Watanabe spigots for intractable pneumothorax in patients with malignant tumors. METHODS: Consecutive patients with malignant tumors who underwent occlusion with an endobronchial Watanabe spigot for intractable pneumothorax associated with perioperative treatment or drug therapy at our institution between January 2014 and February 2022 were reviewed. RESULTS: Of the 32 cases in which an endobronchial Watanabe spigot was used, six were excluded; we thus evaluated 26 cases in which the chest tube was removed. Chest tubes were removed in 19 cases (73.1%) and could not be removed and required surgical treatment under general anesthesia in seven patients (26.9%), of which four (14.8%) underwent open-window thoracostomy. Half of the patients were treated with both an endobronchial Watanabe spigot and pleurodesis. Although thin-slice chest computed tomography revealed a fistula in 15 patients, the chest tube was removed in 11 (57.9%) patients. A significant difference was only observed in patients with a history of heavy smoking. CONCLUSIONS: The chest tube removal rate was comparable to those reported in previous studies. An endobronchial Watanabe spigot may be a useful treatment option for intractable cancer-related pneumothorax.

Role of fluorine-18-fluorodeoxyglucose positron emission tomography in selecting candidates for a minimally invasive approach for thymic epithelial tumour resection.

OBJECTIVES: We evaluated the potential of preoperative fluorine-18-fluorodeoxyglucose positron emission tomography to predict invasive thymic epithelial tumours in patients with computed tomography-defined clinical stage I thymic epithelial tumours ≤5 cm in size who are generally considered to be candidates for minimally invasive approaches. METHODS: From January 2012 to July 2022, we retrospectively analysed patients who exhibited tumour-node-metastasis (TNM) clinical stage I thymic epithelial tumours with lesion sizes ≤5 cm as determined by computed tomography. All patients underwent fluorine-18-fluorodeoxyglucose positron emission tomography preoperatively. We analysed the association of maximum standardized uptake values with both the World Health Organization histological classification and the TNM staging classification. RESULTS: A total of 107 patients with thymic epithelial tumours (thymomas, 91; thymic carcinomas, 14; carcinoids, 2) were evaluated. Nine patients (8.4%) were pathologically upstaged: TNM pathological stage II in 3 (2.8%), III in 4 (3.7%) and IV in 2 (1.9%). Among these 9 upstaged patients, 5 had thymic carcinoma with stage III/IV, 3 had type B2/B3 thymoma with stage II/III and 1 had type B1 thymoma with stage II. Maximum standardized uptake values were a predictive factor that distinguished pathological stage >I thymic epithelial tumours from pathological stage I [best cut-off value, 4.2; area under the curve = 0.820] and thymic carcinomas from other thymic tumours (best cut-off value, 4.5; area under the curve = 0.882). CONCLUSIONS: Thoracic surgeons should carefully determine the surgical approach for high fluorodeoxyglucose-uptake thymic epithelial tumours and keep in mind the issues associated with thymic carcinoma and potential combined resections of neighbouring structures.

Identification of inflamed-phenotype of small cell lung cancer leading to the efficacy of anti-PD-L1 antibody and chemotherapy.

BACKGROUND: Platinum etoposide plus anti-programmed cell death ligand-1 (PD-L1) antibody therapy is the standard of care for extensive-stage small cell lung cancer (ES-SCLC). However, patient characteristics associated with the efficacy of the combination therapy in SCLC are unclear. METHODS: We retrospectively reviewed post-surgical limited-stage (LS)-SCLC and ES-SCLC patients treated with atezolizumab plus carboplatin and etoposide (ACE). The association between SCLC subtypes based on transcriptomic data and pathological findings, including CD8-positive tumor-infiltrating lymphocyte (TIL) status, was investigated in the LS-SCLC cohort. The association between the efficacy of ACE therapy, pathological subtypes, and TIL status was evaluated in the ES-SCLC cohort. RESULTS: The LS-SCLC cohort (N = 48) was classified into four SCLC subtypes (ASCL1 + NEUROD1 [SCLC-A + N, N = 17], POU2F3 [SCLC-P, N = 15], YAP1 [SCLC-Y, N = 10], and inflamed [SCLC-I, N = 6]) based on transcriptomic data. SCLC-I showed enriched immune-related pathways, the highest immune score (CD8A expression and T-cell-inflamed gene expression profiles), and epithelial-mesenchymal transition (EMT), in transcriptional subtypes. Immunohistochemical staining (IHC) showed that SCLC-I had the highest density of CD8-positive TILs in transcriptional subtypes. In the ES-SCLC cohort, the efficacy of ACE therapy did not differ according to pathological subtypes. The progression-free survival (PFS) of TILHigh patients was significantly longer than that of TILLow patients (PFS: 7.3 months vs. 4.0 months, p < 0.001). CONCLUSION: Tumors with a high density of TILs, which represent the most immunogenic SCLC subtype (SCLC-I), based on transcriptomic data could benefit from ACE therapy.

Clinicopathological characteristics and molecular analysis of lung cancer associated with ciliated muconodular papillary tumor/bronchiolar adenoma.

Ciliated muconodular papillary tumor/bronchiolar adenoma (CMPT/BA) is a recently introduced benign lung tumor. It remains unclear whether CMPT/BA is associated with a specific type of lung cancer (LC). We studied the clinicopathological characteristics and genetic profiles of the coexisting primary LC and CMPT/BA (LCCM) cases. We identified eight LCCM (0.4%) from the resected Stage 0-III primary LC (n = 1945). The LCCM cohort was male-dominant (n = 8), elderly (median 72 years old), and most were smokers (n = 6). In addition to the adenocarcinoma (n = 8), we detected two squamous cell carcinomas and one small cell carcinoma-in some cases, multiple cancer. The target sequence/whole exome sequence (WES) revealed no shared mutations between CMPT/BA and LC. One exceptional case was invasive mucinous adenocarcinoma harboring an HRAS mutation (I46N, c.137T>A), but it was likely to be a single nucleotide polymorphism based on variant allele frequency (VAF). Other driver mutations in LC included EGFR (InDel, n = 2), BRAF(V600E) (n = 1), KRAS (n = 2), GNAS (n = 1), and TP53 (n = 2). BRAF(V600E) was the most frequent mutation in CMPT/BA (60%). In contrast, LC showed no specific trend in driver gene mutations. In conclusion, our study revealed differences in the gene mutation profiles of CMPT/BA and LC in coexisting cases, suggesting mostly independent clonal tumorigenesis of CMPT/BA from LC.

A case of vasculogenic mesenchymal tumor in the mediastinum: whole-exome sequencing reveals origin from pre-existing germ cell tumor.

Vasculogenic mesenchymal tumor (VMT), a primitive mesenchymal neoplasm enriched by various-sized atypical vessels, is a new entity that develops in mediastinal germ cell tumors (GCTs) with yolk sac tumor (YST) components after chemotherapy. Notably, patients with VMT in the residual GCT have increased risk of developing sarcomas or hematopoietic malignancies. Here, we report a late-teenage male patient with residual teratoma and high-grade VMT after chemotherapy for a mediastinal mixed GCT, including YST. Whole-exome sequencing revealed biallelic inactivation of TP53 and extensive copy number alterations that suggested whole-genome doubling. The biopsy tissue of the mixed GCT before chemotherapy exhibited overlapping genetic alterations to those in the VMT. Immunohistochemical analyses of the VMT showed that the abnormal vessels were positive for cytokeratin, glypican 3, EZH2, and IMP3. The findings that VMT inherits the genetic alterations of pre-existing mixed GCT and exhibits a partly YST-like immunophenotype might contribute to its clinical aggressiveness.