Terufumi Kubo

Background: Chemo-immunotherapy is the standard first-line treatment for extensive-disease small-cell lung cancer (ED-SCLC), but biomarkers for benefit remain limited. Serum neuron-specific enolase (NSE) is a classical small-cell lung cancer (SCLC) biomarker, but its relationship with the tumor immune microenvironment remains unclear. This study aimed to evaluate the association of pretreatment serum NSE with clinical outcomes and intratumoral CD8-positive lymphocyte infiltration in patients with ED-SCLC. Methods: We retrospectively analyzed pathologically confirmed ED-SCLC patients who received first-line chemo-immunotherapy or chemotherapy. Pretreatment serum NSE was measured by electrochemiluminescence immunoassay (ECLIA). Progression-free survival (PFS) and overall survival (OS) were evaluated by NSE status. Tumor biopsy specimens were assessed for human leukocyte antigen (HLA) class I expression and CD8-positive lymphocyte infiltration. Cox models, treatment-by-NSE interaction analyses, log-transformed NSE analyses, and logistic regression for CD8 infiltration were performed. Results: A serum NSE threshold of 64.1 ng/mL stratified patients into low- and high-NSE groups. In the chemo-immunotherapy cohort, high NSE remained independently associated with shorter PFS after adjustment for performance status (PS), stage group, liver metastasis, and brain metastasis [hazard ratio (HR), 3.68; 95% confidence interval (CI): 1.39–9.76; P=0.009]. Treatment-by-NSE interaction was significant for PFS (HR, 4.52; 95% CI: 1.27–16.10; P=0.02). CD8-positive lymphocyte infiltration was more frequent in the low-NSE group. Low NSE was independently associated with CD8-positive lymphocyte infiltration after adjustment for HLA class I expression, PS, liver metastasis, and brain metastasis [odds ratio (OR), 11.68; 95% CI: 3.01–61.32; P=0.001]. Conclusions: Pretreatment serum NSE was associated with survival outcomes and CD8-positive lymphocyte infiltration in ED-SCLC. Serum NSE may serve as a clinically accessible prognostic marker and exploratory stratification biomarker for chemo-immunotherapy benefit, particularly for PFS.

Myxoid epithelioid sarcoma is a rare morphologic variant of epithelioid sarcoma characterized by abundant myxoid stroma and frequent loss of SMARCB1/INI1 expression. Orbital involvement is exceptionally uncommon. We report a case of a SMARCB1-deficient malignant orbital neoplasm with features overlapping myxoid epithelioid sarcoma in a 61-year-old man presenting with visual disturbance. Imaging studies revealed a 2.5-cm medial orbital mass without evidence of another primary lesion. The tumor was excised without prior biopsy. Histologically, the lesion was predominantly composed of abundant myxoid stroma containing scattered atypical epithelioid, signet ring-like, and spindle cells, with focal fascicular proliferation infiltrating skeletal muscle. Immunohistochemically, tumor cells were positive for pan-cytokeratin, EMA, vimentin, and CD34, while negative for S100, ΔNp63 (p40), p63, SS18-SSX, and TLE1. Complete loss of SMARCB1/INI1 expression was observed in tumor cells. The overall findings suggested a SMARCB1-deficient malignant neoplasm showing substantial morphologic and immunophenotypic overlap with myxoid epithelioid sarcoma. This case highlights the diagnostic challenges posed by SMARCB1-deficient tumors arising in unusual anatomical sites and expands the clinicopathological spectrum of myxoid epithelioid sarcoma-like neoplasms involving the orbit.

Immune checkpoint inhibitors (ICIs) can cause severe immune-related adverse events (irAEs), including life-threatening myositis and myocarditis. Characterizing the immunopathological features of these conditions is essential for improving clinical recognition and management. We report a case of a 76-year-old man with metastatic renal cell carcinoma who developed fatigue, elevated creatine kinase, and complete atrioventricular block after receiving nivolumab. Despite pacemaker implantation and plasmapheresis, the patient died of respiratory failure. Notably, serum tests were positive for anti-Kv1.4 and anti-titin antibodies, although typical myasthenia gravis features were absent. Autopsy revealed CD8-positive T-cell and CD163-positive macrophage infiltration in the myocardium and skeletal muscles, while also confirming a pathological complete response of the carcinoma. Spatial analysis using digital pathology demonstrated that Human leukocyte antigen (HLA) class I expression in cardiomyocytes was closely apposed to infiltrating CD8-positiveT cells in a patchy distribution. This observation suggests a potential local feedback loop where activated T cells may induce HLA class I upregulation in adjacent muscle fibers, sustaining focal inflammation. This case provides important insights into the complex pathophysiology of fatal irAEs and underscores the value of postmortem examination in irAEs.

Over the past decade, immune checkpoint inhibitors (ICIs) have moved from the research setting into routine clinical practice. Their use has expanded from single-agent therapy to combination regimens with cytotoxic chemotherapy, targeted agents, and radiotherapy, and more recently being incorporated into neoadjuvant treatment. Although ICIs have improved the outcomes of a subset of patients, this progress has been accompanied by the occurrence of immune-related adverse events (irAEs), which represent an important challenge in daily clinical care. Ongoing research continues to pursue more effective and durable antitumor immune responses. At the same time, enhanced immune activation is associated with an increased risk of unintended tissue injury, suggesting that irAEs are closely linked to the mechanisms underlying therapeutic immune activation. Therefore, the benefits and disadvantages of ICIs should be considered within the same biological framework. This review does not aim to provide a comprehensive catalog of irAEs; instead, we highlight several representative and clinically relevant topics and discuss them from a pathological perspective. By integrating clinicopathological observations across organ systems, we seek to illustrate how tissue-based findings can contribute to the understanding, recognition, and management of irAEs.

Background: Our previous study demonstrated that laundry detergents induce group 2 innate lymphoid cell‐driven eosinophilic airway inflammation by disrupting airway epithelial barriers and promoting IL‐33 release, and that detergent residues are present in nearly all household dust. However, their impact on allergen‐induced airway inflammation remains unclear. Methods: C57BL/6 background mice were intranasally primed four times with ovalbumin (OVA) or house dust mite (HDM) allergens in the presence or absence of a commercial laundry detergent. Following priming, mice were challenged with the same antigen for 3 consecutive days and sacrificed the day after the final challenge. Bronchoalveolar lavage fluid (BALF) and sera were analyzed by ELISA. Lungs were evaluated histologically and analyzed by qPCR. Results: Mice intranasally primed with antigen in the presence of detergent exhibited eosinophilic airway inflammation upon antigen challenge, accompanied by increased IL‐5 and IL‐13 levels in the BALF. Intranasal administration of detergent and antigen also stimulated antigen‐specific IgE production. These detergent‐ and allergen‐induced type 2 responses were significantly suppressed in Il33 ^−/− and Il13 ^−/− mice. Administration of an anti‐IL‐4 receptor α chain antibody during the challenge phase reduced eosinophil counts in the BALF and antigen‐specific IgE levels in the serum. By contrast, anti‐IL‐33 antibody treatment during the challenge phase did not affect eosinophilic airway inflammation or antigen‐specific IgE production. Conclusions: Laundry detergents promote sensitization to co‐inhaled allergens and exacerbate eosinophilic airway inflammation and antigen‐specific IgE responses via IL‐33 and IL‐13. These findings suggest that detergents can act as adjuvants that facilitate airway sensitization.

Placenta accreta spectrum (PAS) is a serious disease leading to complications and maternal death. The objective of the study was to characterize the placental villi and blood vessels of PAS villi histopathologically. We investigated 10 cases of PAS (five cases of placenta increta, two cases of placenta accreta, and three cases of placenta percreta) histologically. Immunohistochemical staining using anti-CD68 or anti-CD163 antibodies was performed to detect and count Hofbauer cells. Immunohistochemical staining with an anti-CD34 antibody was used to detect vascular endothelial cells, and the number and area of vessels were analyzed. The numbers of CD68-positive or CD163-positive Hofbauer cells were larger in PAS cases compared with control cases. The vascular area in villi was smaller in PAS cases compared with control cases. The number of blood vessels in villi was slightly higher in PAS cases than in control cases. The numbers of Hofbauer cells and vessels in villi were larger in PAS cases compared with control cases, whereas the area of vessels in villi was smaller in PAS cases compared with control cases. Although their biological meaning is elusive, these findings provide novel insights into the pathogenesis of PAS, particularly regarding the role of Hofbauer cells in immune-suppressive role and angiogenesis and the alterations in vascular structure and hemodynamics in the chorionic villi.

Immunoglobulin G4-related disease (IgG4-RD) is a chronic inflammatory condition of unknown etiology characterized by lymphocytic infiltration, fibrosis, and infiltration of IgG4-positive plasma cells. It affects various organs, including the pancreas and salivary glands. Immunological abnormalities are suspected to play a role in its pathogenesis, and there is an epidemiological link to allergic conditions and type 2 inflammation. This study focused on the expression of thymus and activation-regulated chemokine (TARC)/CCL17, which is involved in the migration of T helper 2 and/or regulatory T cells, in salivary gland tissues of patients with IgG4-RD. We analyzed 60 salivary gland biopsy samples obtained from patients at Sapporo Medical University Hospital between 2015 and 2020. Immunohistochemical analysis revealed TARC/CCL17 positivity in 87.2% of histologically confirmed IgG4-RD cases and negativity in 84.6% of histologically unconfirmed but clinically suspected IgG4-RD cases. There was a significant correlation between histologically confirmed IgG4-RD and TARC/CCL17 expression, suggesting its potential diagnostic utility and possible involvement in the pathogenesis of IgG4-RD.

Acral lentiginous melanoma (ALM) is the most common melanoma subtype in non-Caucasians. Despite advances in cancer immunotherapy, current immune checkpoint inhibitors remain unsatisfactory for ALM. Hence, we conducted comprehensive immune profiling using single-cell phenotyping with reactivity screening of the T cell receptors of tumor-infiltrating T lymphocytes (TILs) in ALM. Compared with cutaneous melanoma, ALM showed a lower frequency of tumor-reactive CD8 clusters and an enrichment of regulatory T cells with direct tumor recognition ability, suggesting a suppressive immune microenvironment in ALM. Tumor-reactive CD8 TILs showed heterogeneous expression of coinhibitory molecules, including KLRC1 (NKG2A), in subpopulations with therapeutic implications. Overall, our study provides a foundation for enhancing the efficacy of immunotherapy in ALM.

Immunotherapy using immune checkpoint inhibitors (ICIs) has shown superior efficacy compared with conventional chemotherapy in certain cancer types, establishing immunotherapy as the fourth standard treatment alongside surgical intervention, chemotherapy, and radiotherapy. In cancer immunotherapy employing ICIs, CD8‐positive cytotoxic T lymphocytes are recognized as the primary effector cells. For effective clinical outcomes, it is essential that the targeted cancer cells express HLA class I molecules to present antigenic peptides derived from the tumor. However, cancer cells utilize various mechanisms to downregulate or lose HLA class I molecules from their surface, resulting in evasion from immune surveillance. Correlations between prognosis and the integrity of HLA class I molecules expressed by cancer cells have been consistently found across different types of cancer. This paper provides an overview of the regulatory mechanisms of HLA class I molecules and their role in cancer immunotherapy, with a particular emphasis on the significance of utilizing pathological tissues to evaluate HLA class I molecules expressed in cancer cells.