Small‐for‐size syndrome (SFSS) has a poor prognosis due to excessive shear stress and sinusoidal microcirculatory disturbances in the acute phase after living‐donor liver transplantation (LDLT). Multilineage‐differentiating stress enduring (Muse) cells are reparative stem cells found in various tissues and currently under clinical trials. These cells selectively home to damaged sites via the sphingosine‐1‐phosphate (S1P)–S1P receptor 2 system and repair damaged tissue by pleiotropic effects, including tissue protection and damaged/apoptotic cell replacement by differentiating into tissue‐constituent cells. The effects of intravenously administered human bone marrow‐Muse cells and ‐mesenchymal stem cells (MSCs) (4 × 10⁵) on liver sinusoidal endothelial cells (LSECs) were examined in a rat SFSS model without immunosuppression. Compared with MSCs, Muse cells intensively homed to the grafted liver, distributed to the sinusoids and vessels, and delivered improved blood chemistry and Ki‐67(+) proliferative hepatocytes and ‐LSECs within 3 days. Tissue clearing and three‐dimensional imaging by multiphoton laser confocal microscopy revealed maintenance of the sinusoid continuity, organization, and surface area, as well as decreased sinusoid interruption in the Muse group. Small‐interfering RNA‐induced knockdown of hepatocyte growth factor and vascular endothelial growth factor‐A impaired the protective effect of Muse cells on LSECs. Intravenous injection of Muse cells might be a feasible approach for LDLT with less recipient burden.

Acute esophageal necrosis is defined as necrosis of the esophageal mucosa causing diffuse black pigmentation of the esophagus, the so-called black esophagus from its endoscopic findings. The prevalence is only 0.001~0.2%, while its mortality rate is up to 32%. However, most of the cases are fatal by comorbidities. A 67-year-old female with diabetes mellitus was transported to the emergency room with hematemesis and disordered consciousness. She had suffered from nausea and epigastralgia for 2 days. The patient’s general status was shock evidenced by vital signs, and she did not respond to rehydration. After intubation, emergency endoscopic examination revealed black pigmentation of the esophageal mucosa, and the condition was diagnosed as acute esophageal necrosis. Antibiotics and plasmapheresis had been started, and the patient gradually stabilized. One week after the admission, esophagus perforation was suspected from the significant increase of the right pleural effusion and free air at the esophagus wall and the mediastinum on CT scan. Emergency thoracoscopy revealed an edematous esophagus which was colored black. Esophagectomy with esophagostomy and enterostomy was performed. On resected specimen, mucosal necrosis was found only on the squamous epithelium, with three perforating areas in the middle to lower thoracic esophagus. No signs of inflammation or ischemia were found on the gastric mucosa of the esophagogastric junction. After the operation, the patient recovered generally well, except for the severe stenosis of the cervical esophagus. Cervical esophagectomy, tracheotomy, and anterior thoracic route reconstruction with free jejunum interposition and gastric tube were performed 9 months after the first surgery. No postoperative complications occurred; on the 37th day after the operation, the patient was eating well and was transferred to continue swallowing rehabilitation. It is important to detect the esophagus perforation and mediastinitis early and thereby not to miss the chance of surgical intervention to save the patient’s life. Surgery should be minimized, and reconstruction should be considered next. If the cervical esophagus is also affected, reconstruction surgery should be performed by removing cervical esophagus and anastomosing it to the hypopharynx using a gastric tube and free jejunum interposition as needed.

Necroptosis is a pivotal process in cancer biology; however, the clinical significance of necroptosis in esophageal squamous cell carcinoma (ESCC) has remained unknown. Therefore, in this study, we aimed to verify the potential involvement of necroptosis in the clinical outcome, chemotherapeutic resistance, and tumor microenvironment of ESCC. Mixed lineage kinase domain-like protein (MLKL) and phosphorylated MLKL (pMLKL) were immunohistochemically examined in 88 surgically resected specimens following neoadjuvant chemotherapy (NAC) and 53 pre-therapeutic biopsy specimens, respectively. Tumor-infiltrating lymphocytes (TILs) were also evaluated by immunolocalizing CD3, CD8, and forkhead box protein 3 (FOXP3) in the residual tumors after NAC. High pMLKL status in the post-NAC resected specimens was significantly correlated with worse prognosis in ESCC patients. Multivariate analysis demonstrated that a high pMLKL status was an independent prognostic factor. In pre-NAC biopsy specimens, a high pMLKL status was significantly associated with a lower therapeutic efficacy. CD8+ TILs were significantly lower in the high-pMLKL group. FOXP3+ TILs were significantly higher in both high-MLKL and high-pMLKL groups. We first demonstrated pMLKL status as an independent prognostic factor in ESCC patients. Our study revealed the possible involvement of necroptosis in the immunosuppressive microenvironment, resulting in the attenuated therapeutic efficacy of NAC and eventual adverse clinical outcomes in ESCC.

The tumor microenvironment is considered to play a pivotal role in various human malignancies. Neuroendocrine and non-neuroendocrine neoplasms are considered to have different tumor microenvironments. However, owing to differences in the systemic and/or local immune statuses, tumor microenvironments in different patients may be difficult to compare. Mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs), although rare, could be useful for exploring the effects of neuroendocrine differentiation on the tumor microenvironment, because both neuroendocrine and non-neuroendocrine components are present in the same tumor. Here, we examined 33 cases of histologically confirmed MiNENs and evaluated the influence of neuroendocrine differentiation on the tumor microenvironment by comparing tumor-infiltrating lymphocytes, tumor-associated macrophages, and other relevant factors in the two components the same tumor. The immunoreactivity of those examined above was evaluated quantitatively. The values of vasohibin-1-positive density (p < 0.0001) and immunoreactivity (p < 0.0001) (representing the neoangiogenesis status) were significantly higher in neuroendocrine as compared to non-neuroendocrine areas of the same tumors. In addition, the Foxp3/CD8 (p = 0.0717) and the PD-1/CD8 ratios (p = 0.0176) (representing tumor immunity suppression) tend to increase in neuroendocrine carcinomas. Immunoreactivity of CD163, a marker of M2-like macrophages, was also higher in the neuroendocrine areas. Our findings indicate that neuroendocrine and non-neuroendocrine tumors differ from each other with respect to the characteristics of both tumor cells and the tumor microenvironment.