CD4⁺ T cells support the priming, expansion, and function of CD8⁺ T cells through dendritic cells. Precursor exhausted T cells (Tpex) maintain self-renewal and supply cytotoxic CD8⁺ T cells in the tumor microenvironment (TME), but the identity of their CD4⁺ T-cell partners remains unclear. Here, we perform scRNA-seq, scTCR-seq, and mass cytometry analysis on peripheral blood, tumor, and lymph nodes primarily from lung cancer patients and, in part, renal cell carcinoma. We identify an IL-7Rhigh CCR6⁺ Th1-like CD4⁺ T cell-population, named Th7R, that is numerically and spatially partnered with Tpex. Th7R cells express lymphotoxin-β and CXCL13, correlate with high endothelial venules, and co-localize with Tpex in tertiary lymphoid structures. Th7R cell abundance correlates with Tpex numbers in the TME and lymph nodes, and adoptive transfer of Th7R increases Tpex in a preclinical mouse model. Intratumoral Th7R and Tpex associate with improved response to neoadjuvant PD-1 blockade therapy. These results suggest that Th7R cells act as partners of Tpex to sustain antitumor T-cell immunity.

Glomus tumors are rare, benign mesenchymal neoplasms that account for less than 2

The immune system attempts to eliminate foreign substances, such as pathogens and viruses, that invade the body. As normal cells transform into cancerous cells, the immune system can eliminate these cells and suppress cancer onset. The immune system is regulated so that it does not become overactive or attack normal cells. When cancer cells transform from normal cells, they acquire various characteristics, and some cancer cells influence the regulatory function of the immune system to suppress it and escape immune attack. Therefore, treatments have been developed to eliminate the suppression of the immune system by cancer cells and to restore the immune system's ability to eliminate cancer cells. Immunotherapies include immune checkpoint inhibitors, cytokines, cancer vaccines, and effector cell therapies. Cytokine therapy activates the immune system by injecting substances produced by immune cells (such as interleukin 2 and interferon alpha) into the body, thereby increasing the ability of the immune system to attack cancer cells. Cancer vaccine therapy enhances the attack on cancer cells by injecting substances (antigens) that serve as markers for cancer cells into the body to make it easier for immune cells to detect the cancer. Depending on the type of antigen, cancer peptides, tumor cells, and dendritic cell vaccines are available. Effector cell therapy is a treatment method in which immune cells that directly attack cancer cells [CD8+ T cells, natural killer (NK) cells, etc.] are taken from the patient's body, expanded outside the body, activated, and returned to the body to attack cancer cells. To develop these treatments, it is essential to understand the cells and molecules related to immunity as well as the local tumor environment. In this article, we consider the factors related to antitumor immunity.

Abstract Solitary pulmonary papillomas (SPPs) are rare lung neoplasms. Histologically, SPP is classified into three subtypes, and mixed squamous and glandular papilloma (MP) is the rarest subtype. Although SPPs are considered benign tumors, there have been several reports on the synchronous malignant transformation in SPPs. An 82‐year‐old asymptomatic man was referred to our hospital for further examination of a 2.2 cm‐sized left lung tumor. Pathology of bronchoscopic specimens showed the possibility of pulmonary papilloma but did not reveal any malignancy. The patient complained of bloody sputum during the eighth month after the initial visit. The size of the lesion had increased to 4.3 cm. These data suggested the existence of malignancy, and the patient underwent an operation. Histologically, the tumor was composed of fibrovascular cores and papillomatous fronds lined by pseudostratified columnar cells and mucin‐filled goblet cells. Keratinizing squamous epithelium was also observed. Overall, the diagnosis of MP was obtained by fundamental histology. In addition, a solid part beneath mild atypical squamous epithelia, which was composed of malignant‐appearing squamous cells and spindle‐shaped atypical cells, was observed. The spindle portion was positive for cytokeratin AE1/AE3 and vimentin, and focally positive for alpha‐smooth muscle actin (αSMA). The final diagnosis was pulmonary pleomorphic carcinoma (PPC) arising in the MP. Only two cases have been reported for atypical spindle tumor cells that are found in MP or bronchiolar adenoma/ciliated muconodular papillary tumor (BA/CMPT), which has histologically similar features to MP. This is the second case report of PPC arising in MP.

Marfan syndrome is a genetic disorder in which impaired protein leads to connective tissue weakness. We herein report a case of unexpected tracheal stenosis that was diagnosed just before an operation for a recurrent right pneumothorax with Marfan syndrome. A 16-year-old boy with bilateral repeated pneumothoraces associated with Marfan syndrome came to our emergency room complaining of dyspnea. A chest radiograph showed recurrent right pneumothorax. An operation was planned due to prolonged air leakage even after chest tube drainage. On induction of general anesthesia for repairing pneumothorax, a sudden difficulty occurred during manual ventilation, and the blood oxygen saturation temporarily decreased to 50%. Therefore, emergent intubation with a single-lumen tube was applied, which led back to full saturation. Bronchoscopy revealed a tortuous and flattened trachea. An endobronchial blocker tube was applied due to difficulty in double-lumen tube insertion, and bullectomy was accomplished without any other unexpected events. Patients with Marfan syndrome may have asymptomatic tracheal stenosis due to structural abnormalities and latent tracheomalacia, and general anesthesia could be a trigger to develop the symptoms. Surgeons should bear this in mind, cooperate with anesthesiologists well, and prepare for emergent intubation when managing patients with Marfan syndrome in the perioperative settings.

Background The L-type amino acid transporter (LAT1) exhibits significantly increased expression within tumor cells across various neoplasms. However, the clinical significance of LAT1 expression in patients with pleural mesothelioma (PM) remains unclear. Methods Eighty patients diagnosed with PM between June 2007 and August 2022, were eligible for this study. LAT1, alanine-serine-cysteine transporter 2 (ASCT2), Ki-67, and VEGFR2 were evaluated by immunohistochemistry. Inflammatory and nutritional indices were also correlated with different variables, including neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), systemic immune-inflammation index (SII), prognostic nutritional index (PNI), advanced lung cancer inflammation index (ALI), and Glasgow prognostic score (GPS). Results LAT1 was highly expressed in 57.5% of patients with PM. Among the 80 patients included in this study, 65 (81.3%) received chemotherapy, either alone or followed by surgical resection, while 15 (18.7%) opted for best supportive care. The level of LAT1 significantly correlated with cell proliferation and ASCT2. Factors such as performance status, histology, LAT1 expression, PNI, ALI, and GPS were significant prognostic indicators for progression-free survival (PFS), while Ki-67, LAT1, NLR, SII, PNI, ALI, and GPS were identified as significant predictors for overall survival (OS). LAT1 expression emerged as an independent prognostic factor for predicting PFS and OS in all patients, as well as in the subgroup of 65 patients receiving chemotherapy. Notably, high LAT1 expression proved to be a significant predictor of outcome, particularly in the subgroup with high PLR and SII. Conclusion LAT1 was a significant predictor of outcomes in patients with PM and was more predictive of worse outcomes in patients with high inflammatory and low nutritional status.

Perioperative immune checkpoint inhibitors have been shown to improve prognosis in early-stage lung cancer. However, no biomarkers are known to indicate the requirement for treatment. This study aimed to identify T-cell clusters responsible for antitumor immunity in patients with early-stage lung cancer. Preoperative blood samples from 50 consecutive patients with lung cancer who were diagnosed as operable and underwent complete resection were analyzed by mass cytometry. Patients were divided into two groups: no recurrence at a minimum observation period of 851 days (median observation period: 1,031.5 days) and recurrence by the last observation date. Mass cytometry and single-cell RNA sequencing analysis of lymph nodes (LN) and tumor-infiltrating T cells were also performed. CCR4−CCR6+ Th7R showed discriminative ability between recurrence and non-recurrence patients with lung cancer. Patients with more than 3.04% Th7R showed significantly favorable disease-free survival. Th7R was a major component of CD4+ T cells in tumor microenvironments and LNs adjacent to lung cancer tissues and was the only cluster that decreased in peripheral blood after the removal of cancer tissues, suggesting that Th7R was primed and proliferated in tumor-draining LNs in the presence of cancer tissues. Th7R had the kinetics that antitumor T cells should have, as indicated by the cancer immunity cycle; thus, peripheral blood Th7R could represent the potency of tumor immunity by reflecting priming and proliferation in tumor-draining LNs and Th7R in the tumor microenvironment. Prediction using peripheral Th7R before surgery could allow the selection of patients who require perioperative drug therapy and optimize therapeutic interventions with clinical implications. Significance: Peripheral Th7R, a Th1-like CD4+ T-cell cluster reflecting priming status in draining LNs and immune status in the tumor microenvironment, predicts disease-free survival after complete resection and has significant clinical relevance in selecting appropriate therapeutic interventions in patients with early-stage lung cancer.

Fig. S1. Gating strategy of CyTOF analysis

Fig. S2. Kaplan-Meier analysis of disease-free survival (DFS) in patients with stage Ⅰ-Ⅱ disease (A), epidermal growth factor receptor (EGFR) wild-type disease, and EGFR mutations (B) using the threshold of preoperative %Th7R in peripheral blood obtained by receiver operating characteristic curve analysis. Significance was tested using the log-rank (Mantel-Cox) test. Hazard ratio (HR) and 95% confidence interval (CI) were obtained by log-rank test.

Table S1. List of antibodies used for CyTOF. Table S2. Differentially expressed genes between Th7R cluster and Th1 cluster in tumor-infiltrating lymphocytes.

Background and Objective:Theoretically, systematic lymph node dissection (SLND) in lung cancer surgery is a technique that leaves less cancer cells behind and is speculated to improve the prognosis, but its prognostic significance still remains controversial. In addition, the social environment surrounding lymph node dissection has changed with the advent of limited surgery for peripheral small-sized lung cancer and emergence of immune check inhibitor (ICI). Therefore, we reconsidered the role of lymph node dissection.Methods:By referring to past reports, we reviewed the process leading up to the establishment of SLND in lung cancer surgery. We compared five randomized prospective comparative studies on SLND and lymph node sampling (LNS) in lung cancer surgery.Key Content and Findings:Of the five randomized prospective comparative studies, two reported an improvement in overall survival (OS) with SLND, but the remaining three reported no significant difference in OS between SLND and LNS. One out of the five reports revealed a significant increase in complications with SLND. For peripheral non-small cell lung cancer (NSCLC) cases with tumor diameter ≤2 cm and consolidation-to-tumor ratio >0.5 segmentectomy was found to significantly improve the hazard ratio of OS, when compared to a lobectomy. However, the proportion of SLND and lobe-specific lymph node dissection (L-SLND) in each group seems to be unclear. In segmentectomy, the dissection of intersegmental lymph nodes tends to be lenient, and therefore it seems necessary to examine the significance of lymph node dissection in segmentectomy. ICIs are already showing excellent effects, and it may be necessary to examine how they will be affected by removal of regional lymph nodes where cancer-specific cytotoxic T lymphocytes (CTLs) are concentrated. SLND is essential for accurate staging, but ideally-in a host with no cancer cells in the lymph node or a host with cancer cells having a high sensitivity to ICI-it might be better to leave the regional lymph node.Conclusions:SLND may not be the right choice in all cases. A time may come when the extent of lymph node dissection is determined individually for each case. Future verification results are awaited.

Fig. S3. A: CD8+ T cells in peripheral blood collected before surgery were divided into four clusters according to CD62L and CD45RA expression and compared between no recurrence patients and recurrent patients: CD62LhighCD45RA+ naive, CD62LhighCD45RA- central memory (CM), CD62LlowCD45RA- effector memory (EM), and CD62LlowCD45RA+ effector memory with CD45RA expression (EMRA). B: Receiver operating characteristic curve (ROC) analysis was performed to determine if CD8+ T-cell clusters had the ability to discriminate between relapsed and non-relapsed patients. Then, Kaplan-Meier analysis of disease-free survival (DFS) was performed using the median value was used as a threshold because ROC analysis showed no significance. Significance was tested by log-rank (Mantel-Cox) test. Hazard ratio (HR) and 95% confidence interval (CI) were obtained by log-rank test.

We present the case of a 56-year-old male patient with paravertebral extramedullary hematopoiesis (EMH) secondary to myelodysplastic syndrome with ring sideroblasts and multilineage dysplasia. In a routine health checkup over 5 years prior, he presented with asymptomatic mild anemia and a posterior mediastinal mass. Pathological and cytomorphological findings of the resected paravertebral mass were similar to those of his bone marrow specimen, and included cellularity with erythroid hyperplasia, multilineage dysplastic changes, and the presence of ring sideroblasts. A concordant SF3B1 mutation was detected in both bone marrow and paravertebral mass samples, suggesting that the EMH cells were derived from the bone marrow.

Objective Cognitive dysfunction has a negative effect on cancer treatment; however, in a cancer setting, specific treatments can restore cognitive function. Such conditions are known as reversible dementia, with one of these being vitamin B12 (VB12) deficiency. However, there have been no reports of VB12 deficiency identified by preoperative evaluation in cancer patients. Method We studied a patient who was referred to the Department of Psycho-oncology on suspicion of cognitive decline prior to lung cancer surgery. Preoperative evaluation revealed VB12 deficiency. Results The patient was an 82-year-old woman diagnosed with lung cancer. She also presented with cognitive decline and, therefore, was referred to the Department of Psycho-oncology for preoperative evaluation. The patient scored 19 points on a Mini-Mental State Examination (MMSE), which is indicative of cognitive decline. As the onset of symptoms occurred several months previously and they were subacute, the possibility of reversible dementia was considered. Extensive examination revealed VB12 deficiency, and VB12 replacement therapy normalized the MMSE score to 25 points before surgery. Significance of the results When cognitive decline is observed in cancer patients, it is necessary to actively evaluate the serum levels of some B vitamins, including VB12.

AbstractBackground2‐deoxy‐2‐[fluorine‐18] fluoro‐d‐glucose (18F‐FDG) positron emission tomography (18F‐FDG‐PET) is a convenient modality to assess the metabolic activity within tumor cells. However, there is no consensus regarding the relationship between 18F‐FDG uptake and the immune environment in thymic epithelial tumors (TETs). We conducted a clinicopathological study to elucidate the relationship between 18F‐FDG uptake and programmed death ligands 1 and 2 (PD‐L1/PD‐L2) expression in patients with TETs. Methods: A total of 108 patients with histologically confirmed TETs classified as thymomas or thymic carcinomas who underwent surgical resection or biopsy or needle biopsy and 18F‐FDG PET before any treatment between August 2007 and March 2020 were enrolled in this study. Tumor specimens underwent immunohistochemical staining for PD‐L1, PD‐L2, GLUT1, HIF‐1α, VEGFR2, VEGF‐C, and β2 adrenergic receptor. Results: High uptakes of SUVmax, SUVmean, MTV, and TLG were identified in 28 (25.9%), 61 (56.5%), 55 (50.9%), and 55 (50.9%) of 108 patients, respectively. High uptake of SUVmax significantly correlated with PS (performance status) of 1–2, thymic carcinoma, and advanced stage, and SUVmax on 18F‐FDG uptake displayed a close association with PD‐L1 and PD‐L2 expressions, but not with MTV and TLG. Our analysis revealed that SUVmax was identified as being significant relationship for positive PD‐L1/PD‐L2 expression. GLUT1, HIF‐1α, and VEGFR2 were significantly associated with the expression of PD‐L1/PD‐L2 from the biological viewpoint.Conclusion18F‐FDG accumulation was closely associated with the expression of PD‐L1/PD‐L2, which, in turn, was correlated with glucose metabolism and hypoxia. PD‐L1/PD‐L2 could affect the glucose metabolism and hypoxia in thymic tumor cells.

Chyle leaks are attributed to damage to the thoracic duct itself or its tributaries during surgery. Chylothorax after lung cancer surgery can occur due to damaged thoracic duct tributaries; however, little is known of the mechanism involved. A 71-year-old female underwent a left upper lobectomy with hilar and mediastinal lymphadenectomy for a 1.8-cm primary squamous cell carcinoma, and developed a chylothorax a day later. Catheter lymphangiography revealed high-flow chyle leaks from a damaged thoracic duct tributary, known as a bronchomediastinal lymph trunk, due to a lymphatic reflex from the thoracic duct. Subsequently, catheter embolization of the tributary repaired the chylothorax. The potential for persistent chylothorax after lung cancer surgery and successful lymphatic intervention should be noted.

症例は71歳男性．47年前に左肺全摘，12年前に左膿胸に対して胸腔内洗浄を施行した．数年前より緩徐に進行する呼吸苦を認め来院した．縦隔偏位を伴う左慢性膿胸と診断し，胸腔ドレナージを施行するも培養よりメチシリン耐性コアグラーゼ陰性ブドウ球菌（MRCNS）が検出され，慢性膿胸に対して開窓術（第4-7肋骨切除）を施行した．胸腔内は易出血性の肉芽と器質化したフィブリン塊が占め，感染を伴ったChronic expanding hematoma（CEH）と診断した．CEHは被膜を含めた完全切除が最善とされるが，大量出血により致命的となる症例も報告されている．今回，我々は開窓術および内容除去に留め，周術期の管理を経て易出血性の肉芽の自然な脱落を促すことで局所の感染制御が可能であった1例を経験した．CEHの治療として侵襲の程度を考慮し，症例に応じた治療戦略が必要である．

71歳，男性．右下葉肺癌に対し下葉切除を行い退院．術後15日目に意識障害と呼吸不全により緊急搬送され，気管支鏡検査で下葉気管支断端の完全離開が認められた．一期的な瘻孔閉鎖は不可能と判断し，予め栄養サポートチーム（NST）の介入と理学療法を開始した上で開窓術を行った．術翌日から理学療法を再開し，NSTと逐一協議して経管栄養を実施した結果，開窓術後7日で人工呼吸器を離脱して歩行訓練が可能となった．2カ月で断端の閉鎖が確認され，4週間の局所陰圧閉鎖療法を追加することで遺残腔の完全な消失と創部の上皮化が得られた．開窓術後比較的短期間で瘻孔の閉鎖が得られた要因として周術期の栄養状態が概ね良好だったこと，残存する右上中葉の容積が大きく膿胸腔の清浄化と相まって胸腔が縮小して断端が覆われたこと，開窓術前からの各職種の積極的な介入が奏効したことが考えられた．局所陰圧閉鎖療法は遺残腔の縮小に有効であった．

81歳男性．胸部CTにて右第4肋骨に接する14 mm大および12 mm大の近接した結節影を指摘された．胸膜腫瘍を疑い，胸腔鏡下胸膜腫瘍切除＋胸腔内温熱化学灌流術（Cisplatin 80 mg/m2, 43℃・60分）を施行した．病理学的に限局性二相型悪性胸膜中皮腫と診断された．24ヵ月後の胸部CTで前回病巣の40 mm尾側の右第6肋骨に接して22 mm大の結節影が新たに出現した．胸膜中皮腫の孤立性再発と診断し胸腔鏡下胸膜腫瘍切除＋右下葉部分切除術を施行，病理学的に移行型悪性胸膜中皮腫と診断された．組織学的に初回手術時と類似しており，再発巣として矛盾はなかった．現在，再発なく経過観察中である．