Efficacy and Safety of Salvage-line Nivolumab Monotherapy for Advanced Esophageal Squamous Cell Carcinoma: Comparison of 240 mg Versus 480 mg Doses.

BACKGROUND: Nivolumab monotherapy is the standard second-line treatment for advanced esophageal squamous cell carcinoma (ESCC) after failure of platinum-based chemotherapy without anti-PD-1 antibody. Fixed dosing with 240 mg every 2 weeks was approved initially, followed by fixed dosing with 480 mg every 4 weeks based on pharmacokinetics data. However, information on the comparative efficacy and safety of the two doses remains limited. METHODS: We compared progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and the incidence of adverse events (AEs) between the two doses in 117 patients who received second-line (n = 85) or later-line (n = 32) nivolumab monotherapy at our institution between January 2016 and December 2021. RESULTS: In the second-line group, patient characteristics for the 240 mg and 480 mg groups were as follows (240 mg vs. 480 mg): performance status (PS) 0/1/2 was 34/61/5% vs. 54/42/4%, and prior fluoropyrimidine plus platinum therapy (FP) was 81.3% vs. 42.3%. In the later-line group, the characteristics were: PS 0/1/2 was 28/60/12% vs. 14/86/0%, and prior FP was 60.0% vs. 42.8%. ORR was 11.9 vs. 24.0% in the second-line group (p = 0.19) and 0 vs. 14.3% in the later-line group (p = 0.22). Median PFS was 1.7 vs. 4.1 months on second-line (hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.35-1.01, p = 0.056) and 1.4 vs. 1.8 months on later-line (HR 0.58, 95% CI 0.23-1.46, p = 0.25); AEs of any grade were observed in 58.3 vs. 69.7%, respectively. CONCLUSIONS: The efficacy and safety of the two doses of nivolumab monotherapy were comparable in patients with advanced ESCC.

Transnasal photoimmunotherapy with cetuximab sarotalocan sodium: Outcomes on the local recurrence of nasopharyngeal squamous cell carcinoma.

Photoimmunotherapy for head and neck cancer (HNC-PIT) is a newly developed locoregional treatment targeting the epidermal growth factor. This treatment consists in administering cetuximab sarotalocan sodium that conjugates cetuximab with the dye IRdye700DX, which is activated by near-infrared ray illumination at 690 nm. HNC-PIT has been conditionally approved in Japan in September 2020 for the treatment of unresectable locally advanced or unresectable locoregionally recurrent HNC. However, its outcomes on the local recurrence of the nasopharyngeal squamous cell carcinoma (NPSCC) remain undetermined. In this report, we assessed the effects of HNC-PIT assisted by transnasal endoscopy on the local recurrence of NPSCC. A 77-year-old male presented with a local recurrence of NPSCC. The initial diagnosis revealed a squamous cell carcinoma, T2N2M0 stage III, positive for Epstein-Barr virus-encoded small RNA by in situ hybridization, which was treated with concurrent chemoradiotherapy (CRT). However, local recurrence was detected 14 months after CRT. We performed HNC-PIT under transnasal endoscopy. Seven months have passed since the HNC-PIT treatment, and the patient is alive without delayed adverse events and evidence of recurrence. Local recurrence of NPSCC, which is difficult to treat with minimally invasive surgery, is considered a potential candidate for HNC-PIT.

Safety and short-term efficacy of preoperative FOLFOX therapy in patients with resectable esophageal squamous cell carcinoma who are ineligible for cisplatin.

BACKGROUND: The standard preoperative treatment for resectable locally advanced esophageal squamous cell carcinoma (LAESCC) in Japan is docetaxel, cisplatin (CDDP), and 5-fluorouracil. However, patients with renal or cardiac dysfunction and elderly patients are ineligible for a CDDP-containing regimen because of toxicities. Oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) therapy has less renal toxicity than CDDP-containing regimens and does not require hydration. However, there are limited data on preoperative FOLFOX therapy in these patients. METHODS: This retrospective study analyzed patients with resectable LAESCC who were aged ≥ 75 years or had renal or cardiac dysfunction and received preoperative FOLFOX between 2019 and 2021. FOLFOX was administered every 2 weeks for 3 or 4 cycles and was followed by surgery. Adverse events associated with chemotherapy, the complete resection (R0) rate, relative dose intensity (RDI), and histopathological response were evaluated. RESULTS: Thirty-five patients were eligible. Median age was 77 (range 65-89) years; 68.6% were aged ≥ 75 years, 74.3% had renal dysfunction, and 17.1% had cardiac dysfunction. The RDI was 70.2% and 87.1% for bolus and continuous intravenous 5-fluorouracil, respectively and 85.2% for oxaliplatin. The most common grade ≥ 3 adverse events were neutropenia (60.0%) and leucopenia (28.6%). Two patients (5.7%) had febrile neutropenia and grade 3 pneumonia. Thirty-one patients underwent surgery. The R0 resection rate was 87.1%, and there was no histopathological evidence of residual tumor in 16.1%. There were no treatment-related deaths. CONCLUSIONS: Preoperative FOLFOX had a manageable safety profile and showed favorable short-term efficacy in patients with resectable LAESCC who were ineligible for CDDP-containing treatment.

Direct enhancement of intercomponent interactions in polyrotaxane and its pronounced effects on glass state properties.

Strong interactions between the host cyclodextrin and the threading guest polymer were introduced by selective modifications to the polymer of a polybutadine-based polyrotaxane. The changes in the intercomponent interactions influenced the mobility of the threading polymer that was confined in the glassy host framework, resulting in different mechanical properties.

Effects of using cane and vestibular rehabilitation on the walking function in elderly patients with dizziness.

OBJECTIVE: Adults over the age of 65 years with balance disorders are at about twice the risk of falls, compared with those without balance disorders. Falls contribute to about 74% of the proximal femoral fractures commonly seen in the elderly. Since balance disorders are more prevalent in older adults than in younger adults, it is important to deal with balance disorders in older adults to prevent falls and the resulting deterioration in their ADL (activity of daily living). In this study, we investigated the effects of vestibular rehabilitation (VR) and cane use on improving gait and balance in patients aged over 65 years with balance disorder. METHODS: Patients aged over 65 years presenting to the Department of Otolaryngology at St. Marianna University School of Medicine between July 1 and November 1, 2018, with symptoms of dizziness for ≥ 3 months and a Japanese translation of the Dizziness Handicap Inventory score of ≥ 26 were included in the study. We quantitatively analyzed their gait before and after VR, and with and without the use of a cane. RESULTS: A total of 21 patients participated in the study (14 women; mean age 73.9 ± 6.9 years). Before VR, using a cane made no difference to step length or walking speed. After VR, using a cane increased step length from 50.5 cm (95% confidence interval [CI], 47.4-53.7 cm) to 52.0 cm (95% CI, 48.9-55.1 cm) (p = 0.039). There was no change in walking speed. A comparison of walking assessment results while using a cane before and after VR showed that step length increased from 49.9 cm (95% CI, 46.6-53.2 cm) to 52.0 cm (95% CI, 48.9-55.1 cm) (p = 0.005), and walking speed increased from 90.5 cm/s (95% CI, 82.7-98.4 cm/s) to 96.1 cm/s (95% CI, 88.3-103.9 cm/s) (p = 0.005). CONCLUSIONS: Walking speed and step length with the use of a cane significantly improved following VR. VR and cane use may act synergistically to improve walking.

Prolonged Glass Transition due to Topological Constraints in Polyrotaxanes.

Topological constraints in polyrotaxanes significantly affected their glass transition dynamics. The effects of the constraints were systematically studied using a series of different coverage glass-forming polyrotaxanes consisting of a common polymer and threaded ring molecule of varying ratios. Although their ratios were similar and hence exhibited similar Tg values by differential thermal analysis, mechanical relaxation was considerably prolonged with increasing coverage. The relaxation became a two-step process: a faster step at a common temperature near the Tg and another which was prolonged by the coverage increase. Relaxation dynamics analysis revealed that segment motions, which are cooperative translations of different components, freeze at considerably higher temperatures than the Tg with increasing coverage. This suggests that although the rings are released from conventional interactions at the Tg, their cooperative translational motions are significantly constrained by the threading polymers with increasing coverage.

A Proinflammatory Effect of the ß-Glucan from Pleurotus cornucopiae Mushroom on Macrophage Action.

PCPS from P. citrinopileatus mushroom extract is a ß-1,6-glucan possessing a proinflammatory effect on innate immune cells. The PCPS stimulated THP-1 macrophages to secrete significant levels of TNF. Moreover, the mRNA expressions of TNF and IL-1ß were significantly enhanced by PCPS treatment. However, the PCPS did not induce to express both IL-12 and IL-10 mRNA in the macrophages. Next, the P. cornucopiae extract (containing mainly PCPS) treatment against mice showed significant increases in TNF and IL-1ß mRNA expressions in the peritoneal macrophages of them. In this study, the expression levels of IFNγ mRNA in the spleen were almost the same between the extract- (PCPS-) treated group and control group. However, the expression of IL-4 mRNA showed a lower level in the extract-treated group than that in the control. Our results suggested that the PCPS could induce proinflammatory action in the immune response. In addition, the proinflammatory effect of the PCPS on THP-1 was enhanced by 5'-GMP-Na, while it was reduced by vitamin D2. These two compounds are majorly contained in the P. citrinopileatus mushroom. Therefore, these results suggested that the P. citrinopileatus mushroom might contain other immune regulative compounds, such as vitamin D2, as well as PCPS.

Pleurotus citrinopileatus polysaccharide induces activation of human dendritic cells through multiple pathways.

Many edible mushrooms have become attractive as "health foods" and as source materials for immunomodulators. To increase our insight in the immune-modulatory properties of a polysaccharide of the oyster mushroom Pleurotus citrinopileatus, PCPS, we analyzed its effects on the function of human dendritic cells (DCs). We showed that PCPS induces upregulation of the surface maturation markers CD80, CD86 and HLA-DR on DCs, indicating its potential to induce DC maturation. In addition, PCPS stimulates DCs to secrete the pro-inflammatory cytokines TNF, IL-1ß, IL-6 and IL-12, as well as the anti-inflammatory cytokine IL-10, and induces enhanced mRNA levels of the chemokines CCL2, CCL3, CCL8, CXCL9, CXCL10, and LTA. The secretion of TNF and IL-12 by PCPS-activated DCs could significantly be decreased by an anti-Dectin-1 antibody, as well as by a Syk kinase and a Raf-1 inhibitor, indicating that PCPS induces Dectin-1 signaling at least partly through the Syk- and the Raf-1-dependent pathways in DCs. Structural analysis of PCPS suggests that this polysaccharide is a ß-1,3-branched ß-1,6-glucan, which is in line with its capacity to activate Dectin-1. We showed that PCPS can induce TLR2 and TLR4, but not TLR3, signaling using TLR-HEK293 reporter cell lines. In human DCs, the effect of PCPS was additively increased by TLR4 activation, and synergistically enhanced by stimulation of TLR2, suggesting that interaction of PCPS with these TLRs contributes to the observed DC modulation. In conclusion, PCPS has the capacity to activate human DCs via multiple pathways.

[Test for urokinase-type plasminogen activator inhibitor of edible plants in vitro].

OBJECTIVE: To study the effect of anti-progression activity of edible plants using urokinase as the biomarker. METHODS: Based on the assay of urokinase activity with peptide of Glu-Gly-Arg as the reaction substrate, extract of 25 fruits and 37 vegetables and water extract of tea were reacted against urokinase activity after Spectrozyme UK [carbobenzyl-1-gamma-Glu(alpha-t-BuO)-Gly-Arg-rho-nitroanilide. 2C2H5OH] was added and the residual urokinase activity was measured by the microplate photometer. RESULTS: About half of the fruit and vegetable samples showed urokinase inhibitory activity (UIA) at 20% or more and among them lemon, kiwi-fruit, peas, spinach and pumpkin showed effects over 80%, while garlic, radish, Japanese butterbur, garland chrysanthemum, celery, plum, pineapple and grape ranged between 50% and 79%. Average UIA of 51 kinds of tea was 83.2% and among them 28 kinds showed UIA over 90% and other 20 kinds of tea ranged from 70% to 89%. Green tea showed inhibitory effects on urokinase activity more powerful than black tea and Oolong tea. On the other hand, vegetable showed various UIA with different ways of processing. Comparing the effects of various solvents, garlic extracted with methanol, spinach with ethyl acetate, and pumpkin and radish with water showed highest UIA. CONCLUSION: Popular fruits, vegetables and tea in daily life could inhibit urokinase activity and may be helpful in the prevention of malignant tumor formation.

Effects of diet composition on mutagenic activity in urine.

The effects of dietary habits on mutagenic activity in urine were investigated using the umu test based on the use of the genetically engineered bacteria Salmonella typhimurium TA 1535 pSK1002. Genotoxic effects in sample urine were detected by measuring the activation of the SOS response in the bacteria and recording the beta- galactosidase activity. Human subjects consisted of smokers and non-smokers. Urine from subjects who consumed fish showed the highest mutagenic activity, followed by the urine samples from subjects who ate pork or beef. Chicken induced a low level of mutagenic activity. When the subjects ate fried or roasted animal foods, the urine samples gave higher mutagenicity than the urine samples from the subject who consumed non-fried or non-roasted animal foods. When the subject ate vegetables along with a diet rich in animal foods, the activity in urine decreased. Herbs and spices gave the same tendency toward decline as vegetables. Non-smoker urine shower mutagenic activity than samples from smokers.