Protein secretion in cancer cells defines tumor survival and progression by orchestrating the microenvironment. Studies suggest the occurrence of active secretion of cytosolic proteins in liver cancer and their involvement in tumorigenesis. Here, we investigated the identification of extended-synaptotagmin 1 (E-Syt1), an endoplasmic reticulum (ER)-bound protein, as a key mediator for cytosolic protein secretion at the ER–plasma membrane (PM) contact sites. Cytosolic proteins interacted with E-Syt1 on the ER, and then localized spatially inside SEC22B⁺vesicles of liver cancer cells. Consequently, SEC22B on the vesicle tethered to the PM via Q-SNAREs (SNAP23, SNX3, and SNX4) for their secretion. Furthermore, inhibiting the interaction of protein kinase Cδ (PKCδ), a liver cancer-specific secretory cytosolic protein, with E-Syt1 by a PKCδ antibody, decreased in both PKCδ secretion and tumorigenicity. Results reveal the role of ER–PM contact sites in cytosolic protein secretion and provide a basis for ER-targeting therapy for liver cancer.

症例は73歳男性．左頸部C3～4皮膚分節に帯状疱疹を発症し皮疹は痂皮化したが，その翌日から同側第V，VII，VIII脳神経障害と同側C4～Th1髄節支配筋の脱力が出現した．アシクロビルの静注，ステロイドパルス療法，プレドニゾロンの内服治療後に全症状は消失した．当症例では皮疹を認めた皮膚分節より広範囲な神経障害を認めた点が特徴的であった．その機序として，脳脊髄液を介した波及，同時多発的な無疹性帯状疱疹，上位頸髄神経と脳神経の神経交通枝を介した経神経的な炎症波及が想定された．帯状疱疹の神経障害の多様性は髄膜炎，無疹性帯状疱疹の証明の困難さ，神経交通枝の存在の個体差に起因している可能性がある．

Background: Cold agglutinin-associated hemolysis (CAH) occurs in diverse clinical con-texts, including primary cold agglutinin disease (pCAD) and Waldenström macroglobu-linemia-associated cold agglutinin syndrome (WM-CAS). The differentiation of these enti-ties is often challenging, particularly in MYD88 L265P-negative cases. Since studies that examined the effects of chemoimmunotherapy (CIT) frequently predated routine molecular testing, it remains unclear whether the disease classification has an impact on treatment responses and durability. Methods: We retrospectively analyzed patients with pCAD, WM-CAS, and WM without CAS (WM-only) treated at a single center between April 2010 and November 2025. Diagnoses followed the revised fifth edition of the WHO Classifica-tion of Haematolymphoid Tumours. Clinicopathological features and outcomes were compared. Treatment responses were assessed using CAD-specific criteria based on he-moglobin and hemolysis markers. Time to next treatment (TTNT) and overall survival (OS) were analyzed using Kaplan-Meier methods. Results: Ten patients had CAH (5 pCAD, 5 WM-CAS) and 29 had WM-only. CAH cases showed higher lactate dehydrogenase and total bilirubin levels, whereas WM-only cases had higher serum IgM levels and greater bone marrow involvement. Rituximab-based CIT predominated as the first-line therapy for both pCAD and WM-CAS. Overall response rates were 100% in pCAD and 80% in WM-CAS, with similar kinetics. TTNT did not significantly differ between pCAD and WM-CAS. Elevated FDP was more frequent in CAH, while no overt thrombotic events or grade ≥3 infections were observed. Conclusions: Rituximab-based CIT effectively con-trolled CAH in both pCAD and WM-CAS, with similar durability. When hemolysis is the dominant clinical issue and the disease classification is unclear, tumor-directed therapy represents a treatment strategy.