The combination of soluble forms of PD-1 and PD-L1 as a predictive marker of PD-1 blockade in patients with advanced cancers: a multicenter retrospective study.

Introduction: The clinical relevance of soluble forms of programmed cell death-1 (sPD-1) and programmed cell death-ligand 1 (sPD-L1) remains unclear. We here investigated the relation between the efficacy of PD-1 blockade and pretreatment plasma levels of sPD-1 and sPD-L1 across a broad range of cancer types. Methods: We retrospectively analyzed clinical data from 171 patients with advanced solid tumors who received nivolumab or pembrolizumab monotherapy regardless of treatment line. The concentrations of sPD-1 and sPD-L1 were measured with a fully automated immunoassay (HISCL system). Results: The study subjects comprised patients with head and neck cancer (n = 50), urothelial cancer (n = 42), renal cell cancer (n = 37), gastric cancer (n = 20), esophageal cancer (n = 10), malignant pleural mesothelioma (n = 6), or microsatellite instability-high tumors (n = 6). High or low levels of sPD-1 or sPD-L1 were not significantly associated with progression-free survival (PFS) or overall survival (OS) for PD-1 blockade in the entire study population. Comparison of treatment outcomes according to combinations of high or low sPD-1 and sPD-L1 levels, however, revealed that patients with low sPD-1 and high sPD-L1 concentrations had a significantly poorer PFS (HR of 1.79 [95% CI, 1.13-2.83], p = 0.01) and a tendency toward poorer OS (HR of 1.70 [95% CI, 0.99-2.91], p = 0.05) compared with all other patients. Conclusion: Our findings suggest that the combination of low sPD-1 and high sPD-L1 levels is a potential negative biomarker for PD-1 blockade therapy.

Spermidine activates mitochondrial trifunctional protein and improves antitumor immunity in mice.

Spermidine (SPD) delays age-related pathologies in various organisms. SPD supplementation overcame the impaired immunotherapy against tumors in aged mice by increasing mitochondrial function and activating CD8+ T cells. Treatment of naïve CD8+ T cells with SPD acutely enhanced fatty acid oxidation. SPD conjugated to beads bound to the mitochondrial trifunctional protein (MTP). In the MTP complex, synthesized and purified from Escherichia coli, SPD bound to the α and ß subunits of MTP with strong affinity and allosterically enhanced their enzymatic activities. T cell-specific deletion of the MTP α subunit abolished enhancement of programmed cell death protein 1 (PD-1) blockade immunotherapy by SPD, indicating that MTP is required for SPD-dependent T cell activation.

Clinical features of nasal and sinonasal inverted papilloma associated with malignancy.

OBJECTIVE: Nasal and sinonasal inverted papilloma (IP) are rare benign tumors and have the potential to exhibit malignancy in approximately 10% of cases. This study aimed to analyze the clinical features of IP associated with malignancy. Furthermore, we reviewed our therapeutic strategy and the clinical course of malignant IP. METHODS: Overall, 70 patients with IP at our institution were retrospectively analyzed from April 2006 to December 2015; of these, six (9%) had associated malignancy. Data was collected on sex, age, presenting symptoms (nasal bleeding, rhinorrhea, facial or cheek pain, and nasal obstruction), bone destruction, and extent of disease on CT and MRI. Categorical data of patients with and without malignancy were compared using the chi-square test. A p value of <0.05 was considered statistically significant. Our therapeutic strategy for IP with malignancy, particularly the surgical procedure, i.e., the external incision or the endoscopic nasal approach, varied based on when the carcinoma was detected. In addition, we considered postoperative radiation therapy depending on histological examination. RESULTS: Nasal bleeding (p<0.001), pain (p=0.040), bone destruction (p<0.001), and extent of disease (p=0.026) on CT and MRI findings were significantly associated with malignancy. Carcinoma was diagnosed preoperatively in two (33%) and postoperatively in four patients (67%). We operated five patients (one case was not treated because of end-stage pancreatic cancer). Two patients underwent endoscopic sinus surgery (ESS) alone, two ESS plus Denker's method, and one ESS plus anterior craniotomy. Three patients underwent surgery only, and two patients received postoperative radiotherapy. The median follow-up period was 69.3 months. One patient died of the disease and the remaining patients are alive without recurrence. CONCLUSION: For IP patients exhibiting these clinical findings preoperatively, we should suspect complication with malignancy and plan a treatment. Even if postoperative histology does not confirm malignancy, we should ensure careful observation because of metachronous malignant transformation or the possibility to overlook small malignant lesions. Our result suggests that our strategy for malignant IP could be a reasonable option.

High-dose corticosteroids improve the prognosis of Bell's palsy compared with low-dose corticosteroids: A propensity score analysis.

OBJECTIVE: The aim of this study was to evaluate the effectiveness of high-dose corticosteroid (120mg prednisolone equivalent daily) in Bell's palsy compared with low-dose corticosteroid (60mg PSL equivalent). METHODS: A single-center retrospective observational study was performed. We included adult Bell's palsy patients who were treated within 7days after disease onset. We compared high- and low-dose corticosteroid for the non-recovery rate at 6 months after disease onset using inverse probability-weighted propensity score analysis (IPW-PS). RESULTS: A total of 368 Bell's palsy patients (281 in the high-dose and 87 in the low-dose group) were included. The non-recovery rate without IPW-PS was 13.8% in the low-dose and 8.2% in the high-dose group. After IPW-PS adjustment, the non-recovery rate was 13.1% in the low-dose and 7.8% in the high-dose group (difference=-5.28%, 95% confidence interval [CI] -12.7% to -2.1%, p=0.040). High-dose corticosteroid decreased the non-recovery rate in severe Bell's palsy patients with a Yanagihara score of 0-10 (difference=-16.1%, 95% CI -38.5% to -6.2%, p=0.012), but did not decrease in moderate Bell's palsy patients with a Yanagihara score of 12-18 (difference=-2.0%, 95% CI -11.0% to 7.0%, p=0.591). Subgroup analysis revealed that the efficacy of high-dose corticosteroids was higher when patients were treated within 3days after disease onset, but not when patients were treated at 4days or later after disease onset. CONCLUSIONS: Physicians would be better to treat severe Bell's palsy patients with high-dose corticosteroids when the patients are treated within 3days after disease onset.