A Randomized Phase 2/3 Study of Ensitrelvir, a Novel Oral SARS-CoV-2 3C-Like Protease Inhibitor, in Japanese Patients with Mild-to-Moderate COVID-19 or Asymptomatic SARS-CoV-2 Infection: Results of the Phase 2a Part

This multicenter, double-blind, phase 2a part of a phase 2/3 study assessed the efficacy and safety of ensitrelvir, a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3C-like protease inhibitor, in Japanese patients with mild-to-moderate coronavirus disease 2019 (COVID-19) or asymptomatic ARSCoV- 2 infection. Sixty-nine patients were randomized (1:1:1) to orally receive 5-day ensitrelvir fumaric acid (375 mg on day 1 followed by 125 mg daily, or 750 mg on day 1 followed by 250 mg daily) or placebo and followed up until day 28. The primary outcome was the change from baseline in the SARS-CoV-2 viral titer. A total of 16, 14, and 17 patients in the ensitrelvir 125 mg, ensitrelvir 250 mg, and placebo groups, respectively, were included in the intention-to-treat population (mean age: 38.0 to 40.4 years). On day 4, the change from baseline in SARS-CoV-2 viral titer (log10 50% tissue culture infectious dose/mL) in patients with positive viral titer and viral RNA at baseline was greater with ensitrelvir 125 mg (mean [standard deviation], –2.42 [1.42]; P = 0.0712) and 250 mg (–2.81 [1.21]; P = 0.0083) versus placebo (–1.54 [0.74]); ensitrelvir treatment reduced SARS-CoV-2 RNA by –1.4 to –1.5 log10 copies/ mL versus placebo. The viral titer and viral RNA were similar across groups on and after day 6. The median time to infectious viral clearance decreased by approximately 50 h with ensitrelvir treatment. All adverse events were mild to moderate. Ensitrelvir treatment demonstrated rapid SARS-CoV-2 clearance and was well tolerated (Japan Registry of Clinical Trials identifier: jRCT2031210350)

Assessment of Outcome of Hepatic Arterial Infusion Chemotherapy in Patients with Advanced Hepatocellular Carcinoma by the Combination of RECIST and Tumor Markers

To assess the outcome of stable disease (SD) patients with advanced hepatocellular carcinoma (HCC) by tumor markers after the first course of hepatic arterial infusion chemotherapy (HAIC). The study subjects were 156 HCC patients treated with HAIC and classified as Child Pugh A, with no extrahepatic metastasis, and no history of sorafenib treatment. In the study and validation cohorts, the AFP and DCP ratios of patients who were considered SD to the first course of HAIC were analyzed by AUROC for a prediction of response to the second course of HAIC. The imaging response to the first course of HAIC was classified as partial response (PR), SD and progressive disease (PD) in 29 (18.8%), 80 (51.9%), and 44 (28.6%) patients respectively. For SD patients, the α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) ratios of patients who were considered SD to the first course of HAIC were analyzed by the receiver operating characteristic curve for prediction of response to the second course of HAIC in the study cohorts. The area under the curve of AFP ratio was 0.743. The area under the curve of DCP ratio was 0.695. The cut-off values of AFP and DCP ratios were 1.3 and 1.0, respectively. In the validation cohort, the accuracy of the prediction of response in this validation cohort (71.4%) showed no significant difference compared to that in the study cohort (72.4%) (p = 1.0). The results suggested that patients with a high tumor marker ratio could be switched to alternative therapeutic regimens despite the SD response to HAIC

Photo- and Vapor-Controlled Luminescence of Rhombic Dicopper(I) Complexes Containing Dimethyl Sulfoxide

Halide-bridged rhombic dicopper­(I) complexes, [Cu₂­(μ-X)₂­(DMSO)₂­(PPh₃)₂] (X = I^–, Br^–; DMSO = dimethyl sulfoxide; PPh₃ = triphenylphosphine), were synthesized, the iodide complex of which exhibited interesting photochromic luminescence driven by photoirradiation and by exposure to DMSO vapor in the solid state. Single-crystal X-ray diffraction measurements revealed that the iodo and bromo complexes (abbreviated <b>Cu</b>_<b>2</b><b>I</b>_<b>2</b><b>-[O,O]</b> and <b>Cu</b>_<b>2</b><b>Br</b>_<b>2</b><b>-[O,O]</b>) were isomorphous, and that the two DMSO ligands were coordinated to the Cu­(I) ion via the O atom in both complexes. Both complexes exhibited bright blue phosphorescence at room temperature (λ_em = 435 nm, Φ_em = 0.19 and 0.14 for <b>Cu</b>_<b>2</b><b>I</b>_<b>2</b><b>-[O,O]</b> and <b>Cu</b>_<b>2</b><b>Br</b>_<b>2</b><b>-[O,O]</b>, respectively) with a relatively long emission lifetime (τ_em ∼ 200 μs at 77 K) derived from the mixed halide-to-ligand and metal-to-ligand charge transfer (³XLCT and ³MLCT) excited state. Under UV irradiation, the blue phosphorescence of <b>Cu</b>_<b>2</b><b>Br</b>_<b>2</b><b>-[O,O]</b> disappeared uneventfully and no new emission band appeared, whereas the blue phosphorescence of <b>Cu</b>_<b>2</b><b>I</b>_<b>2</b><b>-[O,O]</b> rapidly disappeared with simultaneous appearance of a new green emission band (λ_em = 500 nm). On further irradiation, the green emission of the iodide complex gradually changed to bright yellowish-green (λ_em = 540 nm); however, this change could be completely suppressed by lowering the temperature to 263 K or in the presence of saturated DMSO vapor. The initial blue phosphorescence of <b>Cu</b>_<b>2</b><b>I</b>_<b>2</b><b>-[O,O]</b> was recovered by exposure to DMSO vapor at 90 °C for a few hours. IR spectroscopy and theoretical calculations suggest that the DMSO ligand underwent linkage isomerization from O-coordination to S-coordination, and both the occurrence of linkage isomerization and the removal of DMSO result in contraction of the rhombic Cu₂­(μ-I)₂ core to make the Cu···Cu interaction more effective. In the contracted core, the triplet cluster-centered (³CC) emissive state is easily generated by thermal excitation of the ³XLCT and ³MLCT mixed transition state, resulting in the green to yellowish-green emission. In contrast, the Cu···Cu distance in <b>Cu</b>_<b>2</b><b>Br</b>_<b>2</b><b>-[O,O]</b> is considerably longer than that of <b>Cu</b>_<b>2</b><b>I</b>_<b>2</b><b>-[O,O]</b>, which destabilizes the ³CC emissive state, resulting in the nonemissive character

Photo- and Vapor-Controlled Luminescence of Rhombic Dicopper(I) Complexes Containing Dimethyl Sulfoxide

Halide-bridged rhombic dicopper­(I) complexes, [Cu₂­(μ-X)₂­(DMSO)₂­(PPh₃)₂] (X = I^–, Br^–; DMSO = dimethyl sulfoxide; PPh₃ = triphenylphosphine), were synthesized, the iodide complex of which exhibited interesting photochromic luminescence driven by photoirradiation and by exposure to DMSO vapor in the solid state. Single-crystal X-ray diffraction measurements revealed that the iodo and bromo complexes (abbreviated <b>Cu</b>_<b>2</b><b>I</b>_<b>2</b><b>-[O,O]</b> and <b>Cu</b>_<b>2</b><b>Br</b>_<b>2</b><b>-[O,O]</b>) were isomorphous, and that the two DMSO ligands were coordinated to the Cu­(I) ion via the O atom in both complexes. Both complexes exhibited bright blue phosphorescence at room temperature (λ_em = 435 nm, Φ_em = 0.19 and 0.14 for <b>Cu</b>_<b>2</b><b>I</b>_<b>2</b><b>-[O,O]</b> and <b>Cu</b>_<b>2</b><b>Br</b>_<b>2</b><b>-[O,O]</b>, respectively) with a relatively long emission lifetime (τ_em ∼ 200 μs at 77 K) derived from the mixed halide-to-ligand and metal-to-ligand charge transfer (³XLCT and ³MLCT) excited state. Under UV irradiation, the blue phosphorescence of <b>Cu</b>_<b>2</b><b>Br</b>_<b>2</b><b>-[O,O]</b> disappeared uneventfully and no new emission band appeared, whereas the blue phosphorescence of <b>Cu</b>_<b>2</b><b>I</b>_<b>2</b><b>-[O,O]</b> rapidly disappeared with simultaneous appearance of a new green emission band (λ_em = 500 nm). On further irradiation, the green emission of the iodide complex gradually changed to bright yellowish-green (λ_em = 540 nm); however, this change could be completely suppressed by lowering the temperature to 263 K or in the presence of saturated DMSO vapor. The initial blue phosphorescence of <b>Cu</b>_<b>2</b><b>I</b>_<b>2</b><b>-[O,O]</b> was recovered by exposure to DMSO vapor at 90 °C for a few hours. IR spectroscopy and theoretical calculations suggest that the DMSO ligand underwent linkage isomerization from O-coordination to S-coordination, and both the occurrence of linkage isomerization and the removal of DMSO result in contraction of the rhombic Cu₂­(μ-I)₂ core to make the Cu···Cu interaction more effective. In the contracted core, the triplet cluster-centered (³CC) emissive state is easily generated by thermal excitation of the ³XLCT and ³MLCT mixed transition state, resulting in the green to yellowish-green emission. In contrast, the Cu···Cu distance in <b>Cu</b>_<b>2</b><b>Br</b>_<b>2</b><b>-[O,O]</b> is considerably longer than that of <b>Cu</b>_<b>2</b><b>I</b>_<b>2</b><b>-[O,O]</b>, which destabilizes the ³CC emissive state, resulting in the nonemissive character

A First Case of Hepatic Angiosarcoma Treated with Recombinant Interleukin-2

A 60 year-old woman was admitted to our hospital because of management of multiple liver tumors. According to image findings and liver biopsy, she was diagnosed as having epithelioid hemangioendothelioma of the liver accompanied by metastases in the spleen, lungs and bones. Based on the spread of the liver tumors and the extensive systemic metastases, she was considered inoperable. Instead, she received hepatic arterial infusion therapy using recombinant interleukin-2. However, she died due to liver failure about two months after admission. Autopsy revealed that the liver tumor was angiosarcoma. It is difficult to differentiate angiosarcoma from epithelioid hemangioendothelioma based on the image findings and pathological findings of percutaneous liver biopsy. Many cases are diagnosed as angiosarcoma at autopsy. There is no established effective treatment for hepatic angiosarcoma, because the tumor stage at the time of diagnosis is often progressive. To date, immunotherapy with recombinant interleukin-2 has been reported to be effective clinically for cutaneous angiosarcoma, such as of the scalp and facial skin. To our knowledge, there have been no reported cases of hepatic angiosarcoma treated with recombinant interleukin-2. Our case is important should recombinant interleukin-2 be considered effective for hepatic angiosarcoma in the future