Efficacy and safety of ramucirumab plus carboplatin and paclitaxel in untreated metastatic thymic carcinoma: RELEVENT phase II trial (NCT03921671).

BACKGROUND: Thymic carcinoma (TC) is a rare tumor with aggressive behavior. Chemotherapy with carboplatin plus paclitaxel represents the treatment of choice for advanced disease. Antiangiogenic drugs, including ramucirumab, have shown activity in previously treated patients. RELEVENT trial was designed to evaluate the activity and safety of ramucirumab plus chemotherapy as first-line treatment in advanced TC. PATIENTS AND METHODS: This phase II trial was conducted within the Italian TYME network. Eligible patients had treatment naive advanced TC. They received ramucirumab, carboplatin and paclitaxel for 6 cycles, followed by ramucirumab maintenance until disease progression or intolerable toxicity. Primary endpoint was ORR according to RECIST v1.1 as assessed by the investigator. Secondary endpoints were PFS, OS and safety. Centralized radiologic review was performed. RESULTS: From 11/2018 to 06/2023, 52 patients were screened, 35 were enrolled. Median age was 60.8 years, 71.4% of patients were male and 85.7% had Masaoka-Koga stage IVB. ECOG PS was 0 in 68.5%, 1 in 31.4% patients. At the present analysis carried out some months later the interim analysis (earlier than expected) on 35 patients, ORR was 80.0% [95%CI 63.1-91.6]. At the centralized radiological review of 33/35 evaluable patients, ORR was 57.6% [95%CI 39.2-74.5]. After a median follow-up of 31.6 months, median PFS was 18.1 [95%CI 10.8-52.3] and median OS 43.8 [95%CI 31.9-NR] months. Thirty-two out of 35 patients (91.4%) experienced at least one treatment-related adverse event (AE), of which 48.6% were AE≥G3. CONCLUSIONS: In previously untreated advanced TC, the addition of ramucirumab to carboplatin and paclitaxel showed the highest activity compared to historical controls, with a manageable safety profile. Despite the small number of patients, given the rarity of the disease, the trial results support the consideration of this combination as first-line treatment in TC.

Bisphenol A content in fish caught in two different sites of the Tyrrhenian Sea (Italy).

Bisphenol A (BPA) is an endocrine disruptor (ED) that is abundant in the environment because of its extensive use in human-manufactured products. In this study, the BPA concentration was measured in the muscle and liver of five edible fish, characterized by different habitat and habits, caught in two different sites of the Tyrrhenian Sea (Italy). Our results show that: (i) fish livers are about 2.5 times more polluted than muscle; (ii) fish caught in the Gulf of Naples are more polluted than those from the Latium coasts, ranging from 1.2-fold more for White Bream to 6.6-fold for Grey Mullet; and (iii) the percentages of fish found to be BPA-polluted in the Gulf of Naples ranged from 73% (for Bass) to 90% (for Mullet), while the Latium fish range from 60% (for Bass) to 90% (for Mullet). These data indicate that consumers of fish caught in the Gulf of Naples are at a greater risk for BPA-induced endocrine pathologies compared to those who consume fish caught along the Latium coasts.

New glycosides from Capsicum annuum L. var. acuminatum. Isolation, structure determination, and biological activity.

Investigation of polar extracts from ripe fruits of Capsicum annuum L. var. acuminatum yielded three new glycosides, capsosides A (1) and B (2) and capsianoside VII (3), along with seven known compounds (4-10). The chemical structures were elucidated mainly by extensive nuclear magnetic resonance methods and mass spectrometry, and the biological activities of icariside E(5) (4) were tested by different assays. Icariside E(5), in contrast to capsaicin, neither induces an increase in the intracellular levels of reactive oxygen species nor affects the mitochondria permeability transition, and it does not signal through the vanilloid receptor type 1. Interestingly, this compound protects Jurkat cells from apoptosis induced by the oxidative stress mediated by serum withdrawal. These results suggest that icariside E(5) may have antioxidant properties that strengthen the importance of peppers in the Mediterranean diet.

New pyridinium alkaloids from a marine sponge of the genus Spongia with a human phospholipase A(2) inhibitor profile.

Four new bioactive pyridinium alkaloids, named spongidines A-D (5-8), have been isolated from a Vanuatu sponge of the genus Spongia, together with known petrosaspongiolides D (1) and G (2). Compounds 3 and 4 are 21-hydroxy derivatives of petrosaspongiolides K and P. Structure elucidation was accomplished through extensive 2D NMR experiments (COSY, ROESY, HMBC, HMQC) and IR, UV, and FABMS data. All compounds significantly inhibited human synovial phospholipase A(2) (PLA(2)) at 10 microM, with an IC(50) value of 5.8 microM for compound 4, which is the most potent inhibitor, with a higher selectivity toward this enzyme than the reference inhibitor manoalide. Pyridinium alkaloids (5-8) mainly inhibited human synovial PLA(2). Compound 8, which contains a sulfonic acid group, is the most interesting inhibitor.

Starfish saponins. 55. Isolation, structure elucidation, and biological activity of the steroid oligoglycosides from an Antarctic starfish of the family Asteriidae.

This paper reports an analysis of the chemical constituents from an Antarctic starfish of the family Asteriidae. Different steroid glycoside types are represented among its constituents, including the five hexaglycoside steroidal sulfates ("asterosaponins") asteriidosides A-E (1-5), differing in their oligosaccharide chain, and the two nonsulfated diglycosides asteriidoside F (6) and G (7), in which 6 is the 26-methyl analogue of 7. Also present are the two sulfated diglycosides asteriidoside H (8) and I (9) and one sulfated monoglycoside asteriidoside L (10). Eight of the compounds were tested against human nonsmall-cell lung carcinoma cells (NSCLC-L16) and found to be moderately cytotoxic.

Isolation, structure elucidation, and biological activity of the steroid oligoglycosides and polyhydroxysteroids from the Antarctic starfish Acodontaster conspicuus.

A total of 19 steroids, of which 13 steroidal oligoglycosides (nine new and four known) and six polyhydroxylated steroids (four new and two known), has been isolated from the Antarctic starfish Acodontaster conspicuus. The mixture is dominated by glycosides composed of steroidal aglycons having the hydroxyl groups typically disposed on one side of the tetracyclic nucleus, i.e., 3 beta,4 beta,6 alpha,8,15 beta-, with some having a sulfate at C-6, and differing in the side chains and/or in the disaccharide moieties that are usually attached at C-26, with some at C-28 and C-29. Those compounds are accompanied by minute amounts of glycosides with a delta 8(14)-double bond in the steroid, which is a structural feature not previously found among polyhydroxysteroids derived from starfish. Small amounts of six related unglycosidated polyhydroxysteroids and three higher-molecular-weight asterosaponins complete the composition of the mixture. The structures of the new compounds were determined by interpretation of their spectral data and by comparison with spectral data of known compounds. Eighteen of these compounds were evaluated for their ability to inhibit growth in Antarctic marine bacteria isolated from either the water column or the surfaces of benthic marine invertebrates. Of these compounds, 50% were active against at least one Antarctic marine bacterium. This suggests that these compounds may play an important role in deterring microbial fouling.

Isolation of 20 glycosides from the starfish Henricia downeyae, collected in the Gulf of Mexico.

Thirteen new (1-13) and seven known (14-20) steroid glycosides were isolated from Henricia downeyae, collected from the offshore waters of the northern Gulf of Mexico. Ethanolic extracts of these starfish caused growth inhibition in bacteria and fungi, potent antifouling activity against barnacle and bryozoan larvae, and feeding deterrent activity against a marine fish. The known compounds are typical glycosides found in several species of the family Echinasteridae, i.e., Echinaster sp. and Henricia laeviuscola. One of the new compounds belongs to this group, whereas the remaining 12 new compounds represent a novel series of steroid glycosides which have aglycons with structural similarities to the "asterosaponins". They possess a delta 9(11) 3 beta, 6 alpha-dihydroxysteroidal aglycon with 23-oxo or 22,23-epoxy functionalities and often a 20-hydroxyl group in the side chain. The sulfate is located at C-6 and the saccharide moiety at C-3, in contrast with the asterosaponins which have the sulfate at C-3 and the oligosaccaride moiety at C-6. All the new compounds contain a glucuronic acid unit, which is uncommon among steroid glycosides from echinoderms. The structures of the new compounds, isolated in amounts ranging from 3.4 to 0.9 mg, were determined by interpretation of their spectral data and by comparison with spectral data of known compounds.

Chemical and biological investigation of the polar constituents of the starfish Luidia clathrata, collected in the Gulf of Mexico.

Ten new [1-10] and three known [11-13] polyhydroxysteroids were isolated, along with four known asterosaponins [14-17], from the starfish Luidia clathrata, collected from the offshore waters of the northern Gulf of Mexico. The EtOH extracts of this starfish showed feeding-deterrent properties against marine fish, and inhibited the settlement of larvae of barnacles and bryozoans, as well as the growth of several bacteria. The structures of the new compounds were determined by interpretation of their nmr spectral data and by comparison with the spectral data of known compounds. The assignment of the configurations of the side-chain stereogenic centers of compounds 1 and 3-10 were based on the comparison of their nmr data with those of the stereoisomeric model compounds after derivatization with the chiral auxiliary MTPA reagent. Larval settlement assays conducted on ten isolated compounds revealed they are all potent inhibitors of settlement. Two of these isolated compounds inhibited the growth of several bacteria.

Starfish saponins, Part 53. A reinvestigation of the polar steroids from the starfish Oreaster reticulatus: isolation of sixteen steroidal oligoglycosides and six polyhydroxysteroids.

A reinvestigation of the starfish Oreaster reticulatus has led to the isolation of sixteen steroidal oligoglycosides and six polyhydroxysteroids. One steroidal monoglycoside has been identified as asterosaponin-1 [5], previously isolated from the same organism, and one pentaglycoside steroidal sulfate has been identified with the known ophidianoside F [1], previously isolated from starfish species of the family Ophidiasteridae. The novel pentaglycoside steroidal sulfates reticulatosides A [3] and B [4] represent the second examples of asterosaponins containing the 5 alpha-cholesta-9(11)-en-3 beta,6 alpha,20,22-tetraol aglycone. Of the remaining new steroidal oligoglycosides, the majority are characterized by the common (24S)-5 alpha-cholesta-3 beta,6 alpha,8,15 alpha,24-pentaol aglycone, with some having a sulfate group at C-6, and differing in the sugar moiety. Compounds 11, 12, 15, and 16 represent major departures from the more common structural features encountered in steroidal glycosides from starfish with the presence in 11 and 12 of a rare 5-O-methylgalactofuranosyl unit and in 15 and 16 of a 3-O-methyl-2-O-sulfate-xylopyranosyl unit. The latter was shown by nmr data combined with molecular dynamics calculations to exist in an 8:2 equilibrium mixture of the 1C4 and 4C1 conformations.

Four new dimeric peptide alkaloids, anchinopeptolides B-D, and cycloanchinopeptolide C, congeners of anchinopeptolide A, from the Mediterranean marine sponge Anchinoe tenacior.

Following the characterization of anchinopeptolide A[1], three new congeneric dimeric peptide alkaloids, named anchinopeptolides B [2], C[3], and D[4], have been isolated from the Mediterranean sponge Anchinoe tenacior. A fourth compound, cycloanchinopeptolide C[5], which is related to anchinopeptolide C[3] by a head-to-head intramolecular [2+2] cyclo-addition reaction, has also been isolated. The structures of these peptide alkaloids have been elucidated on the basis of spectral evidence. Anchinopeptolides bind to the somatostatin, human B2 bradykinin, and neuropeptide Y receptors.

Paniceins and related sesquiterpenoids from the Mediterranean sponge Reniera fulva.

Two novel sesquiterpenes, fulvanin 1 [1] and fulvanin 2 [2], have been isolated from the Mediterranean sponge Reniera fulva. Compound 2 is a sesquiterpenoid linked to a hydroquinone. Also found in Reniera fulva are four known paniceins, a group of aromatic sesquiterpenoids linked to a quinol, isolated previously from Halichondria panicea. The total assignments of 13C-nmr spectra of paniceins have been made with the aid of 2D1H-13C correlation techniques, confirming their structures. The paniceins were tested in the in vitro disease-oriented primary antitumor screen at NCI, Bethesda. Paniceins C and B3 showed cytotoxicity against NCI-H522 non-small lung cancer cells and CCRF-CEM leukemia cells, while panicein A hydroquinone revealed more selective cytotoxicity against the latter ones.

Starfish saponins, part 49. New cytotoxic steroidal glycosides from the starfish Fromia monilis.

Nine new cytotoxic steroidal glycosides 1-9 have been isolated from the starfish Fromia monilis collected off New Caledonia. Structures of these compounds, which include four mono-(1-4), two di-(5,6), and three glycosides (7-9), were elucidated through spectral interpretation. Monilosides G [7], H [8], and I [9] are the first tri-glycosides to be found among the group of glycosides of polyhydroxilated steroids from starfishes.