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Esophageal squamous cell carcinoma (ESCC) as a common malignancy is prevalent in East Asia and in eastern and southern Africa. Although pembrolizumab, nivolumab and camrelizumab are respectively recommended as second-line treatment for advanced ESCC due to improved overall survival (OS), objective response rate (ORR) was modest. New effective treatments are needed. Hence, the study of camrelizumab plus apatinib (VEGFR2 inhibitor) as second-line treatment for advanced ESCC was performed. Methods This ongoing phase II trial (NCT03736863) in six sites in China enrolled pts aged 18-75 with unresectable locally advanced, locally recurrent, or metastatic ESCC that progressed or were intolerant after first-line chemotherapy, and an ECOG performance status of 0-1. Pts received 200 mg camrelizumab intravenously every 2 weeks and apatinib 250 mg orally once per day in 4-week cycles until disease progression, unacceptable adverse events (AEs) or withdrawal of consent. The primary endpoint was investigator-assessed ORR. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS) and OS. Results At data cutoff (Feb 28, 2021), 52 pts were enrolled, including 42 males and 50 with distant metastases, with the median age of 62 years. In the evaluable population of 39 pts, ORR without confirmation was 43.59% and DCR was 94.87%. The median duration of response was 6.9 months (95% CI 4.57–9.23). The median PFS was 6.8 month (95% CI 2.66–10.94). The 12-month overall survival was 52.2%. A total of 80.8% of pts had treatment-related AEs (TRAEs) with 46.2% of grade ≥ 3 TRAEs. The safety profile of camrelizumab and apatinib was consistent with other anti–PD-1 antibodies and angiogenesis inhibitors. Conclusion This is the first study that evaluates the combination anti–PD-1 antibody and anti-angiogenesis inhibitor as a second-line therapy for advanced ESCC. Camrelizumab plus apatinib showed encouraging clinical efficacy and acceptable safety. Further phase III randomized trials are warranted.

Although pufferfish of the family Tetraodontidae contain high levels of tetrodotoxin (TTX) mainly in the liver, some species of pufferfish, boxfish of the family Ostraciidae, and porcupinefish of the family Diodontidae do not. To clarify the mechanisms, uptake of TTX and saxitoxins (STXs) into liver tissue slices of pufferfish, boxfish and porcupinefish was examined. Liver tissue slices of the pufferfish (toxic species Takifugu rubripes and non-toxic species Lagocephalus spadiceus, L. cheesemanii and Sphoeroides pachygaster) incubated with 50 µM TTX accumulated TTX (0.99–1.55 µg TTX/mg protein) after 8 h, regardless of the toxicity of the species. In contrast, in liver tissue slices of boxfish (Ostracion immaculatus) and porcupinefish (Diodon holocanthus, D. liturosus, D. hystrix and Chilomycterus reticulatus), TTX content did not increase with incubation time, and was about 0.1 µg TTX/mg protein. When liver tissue slices were incubated with 50 µM STXs for 8 h, the STXs content was

Marine pufferfish of the Tetraodontidae family contain high levels of tetrodotoxin (TTX) in the liver and ovary. TTX is suggested to transfer from the liver to the ovary in female pufferfish during maturation. TTX in pufferfish eggs may act as a repellent against predators and as a sexual pheromone to attract male pufferfish. The toxification mechanism of the pufferfish ovary is poorly understood. Here we evaluated the chemical form of TTX and its related substances in the ovary of the panther pufferfish Takifugu pardalis by LC-ESI/MS. TTX and its analogs 4-epi-TTX, 4, 9-anhydroTTX, deoxyTTX, dideoxyTTX, and trideoxyTTX were detected in a low molecular weight fraction by Sephacryl S-400 column chromatography. The finding of an unknown TTX-related substance in a high molecular weight fraction from the Sephacryl S-400 column suggested the occurrence of toxin-binding protein in the ovary. The toxin-binding protein in the ovary was purified by ion-exchange HPLC, gel filtration HPLC, and SDS-PAGE. Amino acid sequencing and cDNA cloning revealed that the toxin-binding protein, TPOBP-10 (Takifugu pardalis ovary toxin-binding protein with a molecular mass of 10 kDa) was homologous with the predicted vitellogenin-1-like protein [Takifugu rubripes] subdomain, a von Willebrand factor type D domain. TPOBP-10 mRNA was highly expressed in the ovary and liver and less in other organs of female individuals based on RT-PCR. These findings reveal a novel function of the vitellogenin subdomain as binding with TTX-related substances, and its involvement in the toxification of the pufferfish ovary.