Immunostimulatory oncolytic activity of coxsackievirus A11 in human malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an aggressive solid cancer with a poor prognosis, whereas coxsackievirus A11 (CVA11) is a potential oncolytic virus for cancer treatment. We here investigated the oncolytic activity of CVA11 with human MPM cell lines. CVA11 infection was cytotoxic in all six MPM cell lines examined and showed no or minimal cytotoxicity toward normal human normal cell lines. MPM cells with a higher surface level of intercellular adhesion molecule-1 (ICAM-1) expression tended to be more susceptible to CVA11-induced cytotoxicity, and a neutralizing antibody to ICAM-1 attenuated such cytotoxicity. CVA11 infection activated signaling by Akt and extracellular signal-regulated kinase (ERK) pathways, and inhibitors of such signaling also abrogated CVA11-mediated cytotoxicity. Furthermore, CVA11 infection-triggered multiple modes of tumor cell death including apoptosis, pyroptosis, and necroptosis, and such death was accompanied by the release or exposure of the proinflammatory cytokine interleukin-1ß and damage-associated molecular patterns such as calreticulin, high-mobility group box-1, annexin A1, and heat shock protein 70, which are hallmarks of immunogenic cell death. Notably, in vivo treatment of human MPM xenografts with intratumoral CVA11 injection resulted in significant suppression of tumor growth in SCID mice, and all mice infected with CVA11 showed no significant change in body weight. Our findings collectively suggest that the oncolytic activity of CVA11 for MPM is dependent on ICAM-1 as a virus receptor, as well as on Akt and ERK signaling, and that oncolytic virotherapy with CVA11 is a promising treatment modality with immunostimulatory activity for human MPM.

Middle-term natural course after acute pancreatitis associated with pancreas divisum.

Invasive treatment might be taken into consideration at the time of initial acute pancreatitis in patients with pancreas divisum who do not complain of abdominal pain to prevent progression to chronic pancreatitis.

Diagnosis of Food Protein-Induced Enteropathy Based on Gastrointestinal Mucosal Pathology before and after Elimination Diet Therapy: A Case Report.

We describe the case of a 1-year-old girl with food protein-induced enteropathy (FPE) that was difficult to diagnose. She was referred to our hospital with a 3-month history of diarrhea, vomiting, and weight loss. Although her diarrhea improved after a few days of fasting, oral intake of elemental diets, formula milk, or rice porridge resulted in repeated relapses. The serum IgE level was 1028 IU/mL, and radioallergosorbent tests were positive for milk, casein, alpha-lactalbumin, and other allergens. A histopathology of the duodenal mucosa revealed loss of mucosal villous structure, crypt hyperplasia, crypt apoptosis, and lymphocyte and eosinophil infiltration (<20 eos/hpf) into the lamina propria. After prednisolone (PSL) therapy and the complete removal of cows' milk and chicken eggs from her diet, the patient's diarrhea disappeared. Five months after discontinuing oral PSL and complete removal of cows' milk and chicken eggs, the duodenum exhibited normal mucosal villous structure and well-differentiated ducts. No abnormalities were observed in the egg rechallenge; however, diarrhea recurred after the cows' milk rechallenge. Thus, histopathologic examination of the gastrointestinal mucosa is useful for diagnosing FPE similar to oral food challenges, and re-evaluation after elimination diet therapy may be beneficial to rule out other diseases.

Transient hypoglycorrhachia with paroxysmal abnormal eye movement in early infancy.

Paroxysmal abnormal eye movement in early infancy is one of the initial symptoms of glucose transporter 1 deficiency syndrome (GLUT1DS). We describe four early infants with transient hypoglycorrhachia presenting with abnormal eye movements. Their symptoms disappeared after the introduction of a ketogenic diet (KD), and their development was normal. Since no variants in SLC2A1 were detected, the CSF-to-blood glucose ratios (C/B) were re-examined, and within normal range. None of the four patients displayed recurrent symptoms after withdrawal from the KD. Because long-term KD has potential adverse effects and could affect the quality of life of patients and their families, re-examination of CSF glucose during late infancy should be considered in the case of absence of the SLC2A1 pathogenic variant.

Cytotoxic chemotherapeutic agents and the EGFR-TKI osimertinib induce calreticulin exposure in non-small cell lung cancer.

OBJECTIVES: Synergistic anticancer efficacy of combination treatment with immune checkpoint inhibitors (ICIs) and platinum-based chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) may be attributable in part to the phenomenon of immunogenic cell death (ICD), which is characterized by the release of damage-associated molecular patterns (DAMPs) from dying tumor cells. The ability of cytotoxic chemotherapeutic agents and molecularly targeted drugs such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) to induce DAMPs during the treatment of NSCLC has remained unclear, however. MATERIALS AND METHODS: We investigated the ability of seven cytotoxic chemotherapeutic agents and the third-generation EGFR-TKI osimertinib to induce translocation of the DAMP calreticulin to the cell surface in multiple NSCLC cell lines. The plasma concentration of soluble CRT in advanced NSCLC patients treated with cytotoxic chemotherapy or osimertinib was measured. RESULTS: Antimetabolites and microtubule inhibitors induced expression of CRT at the cell surface (ecto-CRT) to a greater extent than did platinum agents in six NSCLC cell lines, exhibiting higher up-regulation of phosphorylation of eukaryotic initiation factor-2α (eIF2α). Ecto-CRT expression was positively correlated with apoptosis induction in NSCLC cells treated with these various chemotherapeutic agents. The drug-induced up-regulation of ecto-CRT in NSCLC cells was attenuated by the pan-caspase inhibitor Z-VAD-FMK. Osimertinib similarly increased ecto-CRT expression in association with apoptosis induction in five EGFR-mutated NSCLC cell lines. Furthermore, the plasma concentration of soluble CRT in 16 NSCLC patients treated with single-agent pemetrexed or docetaxel and in nine EGFR-mutated NSCLC patients treated with osimertinib was increased after treatment onset. CONCLUSION: Our findings indicate that antimetabolites, microtubule inhibitors, and osimertinib are effective inducers both of CRT exposure in NSCLC cell lines and of soluble CRT release in patients with advanced NSCLC, suggesting that these agents might prove effective for promotion of antitumor immunity in combination immunotherapy.