ALBERT

Description: Background: Constitutively activated receptor tyrosine kinase (TK) D816V KIT contributes to the pathogenesis of most ASM cases and exhibits resistance to imatinib. Midostaurine (MST, PKC412) is an inhibitor of the KIT TK and can block D816V KIT-transformed cell growth at an IC50 of 30–40nM. We report updated results of our ongoing phase II study of oral MST in ASM patients (pts). Methods: MS 100 mg bid was administered as continuous 28-day cycles until progression/intolerable toxicity. Lack of a major response (MR) or partial response (PR) per Valent criteria after 2 cycles resulted in pt discontinuation. To date, 15 pts have been enrolled, 9 with an associated MDS/MPD. Median age was 62 yrs (range 24–76), median # prior therapies was 1 (0–3). All 15 pts are evaluable for efficacy and safety. Responses were observed in 11/15 pts (73%). Best responses included 5 pts with a MR (all incomplete remissions), and 6 pts with a PR (5 good, 1 minor). Four pts were stopped after 2 cycles (2 stable disease, 2 progressive disease (PD)). The 5 MRs included resolution of hypoalbuminemia (n=3), increase in hemoglobin to 〉10 g/dL (n=1), and normalization of mild splenomegaly by CT (n=1). Additional MR findings in these pts included improvement in platelets to 〉100,000/mm3, and normalization of LFTs. Good PRs included reduction of ascites (n=2), 〉50% reduction in palpable hepatosplenomegaly (n=1), and 〉50% reduction in direct hyperbilirubinemia (n=2). In MR/PR pts, other findings included marked reduction in pleural effusion (n=2), reversion of weight loss, and improvement in cutaneous mastocytosis (MC) lesions. Among responders, the median duration of treatment was 10 cycles (4–18+). In 4 pts, the marrow MC burden decreased from the 50–60% to 10–15% range (stable in other responders). There was inconsistent reduction in the serum tryptase level among MR/PR pts. Safety: Nausea and/or vomiting (N/V) was the most frequent non-hematologic toxicity. Grade 1 tremor, grade 1–2 diarrhea, fatigue, and headache (HA) were less common. Possibly related hematologic toxicity consisted of worsening anemia in 2 pts (grade 3), and recurrent grade 3 thrombocytopenia despite dose reduction to 50 mg bid. Dose reduction occurred in 4 additional pts (N/V, n=2; HA, n=1; recurrent pleural effusion, n=1). Dose re-escalation to 100 mg bid was feasible in 3 of these 4 pts. Two pts had MST discontinued after 4 cycles (grade 3 fatigue, grade 2 N/V, n=1 each), and after cycles 8 and 15 for PD (n=2). Real-time allele-specific PCR has preliminarily detected D816V KIT in 9/15 (60%) pts. Further accrual is required to render any correlation between KIT mutation status and response. Preliminary pharmacokinetic analysis reveals that plasma concentrations of MST reached a maximal level of ∼3462 ng/mL on day 3, gradually decreased with time, and reached a stable level of ∼1368 ng/mL after cycle 1. This time dependent pattern is consistent with previous findings in AML pts. In conclusion, Midostaurine has sustained partial remitting activity in a high proportion of ASM pts.

Description: A detailed analysis of beak length to body size and mass measurements was carried out for the glacial squid Psychroteuthis glacialis, which is an endemic cephalopod species in the Southern Ocean. Beak lengths (lower rostral length) were measured from 211 specimens which had been sampled in the Atlantic sector of the Southern Ocean. The basic idea was to find some calibration model in order to inter- or extrapolate missing mantle length and/or wet body mass data by means of beak lengths. The relationships between beak length and mantle length/wet body mass bear essential information for future use in biomass estimates in Southern Ocean top predators, since beaks of P. glacialis occur frequently in the stomach contents of Antarctic seabirds, seals and toothed whales. Therefore, lower rostral lengths were plotted against both mantle length and wet body mass to determine the relationship between these variables. The relationships had limited scatter and very high coefficients of determination, showing that lower rostral length is a good predictor of the squid's mantle length and wet mass. A non-linear 3rd order polynomial regression of lower rostral length against mantle length was identified as the best fitted calibration model, explaining 93% (R 2) of the associated variance. The relationship between lower rostral length and wet body mass was empirically well fitted through regressing ln-transformed values of lower rostral length against wet body mass, explaining 95% (R 2) of the associated variance. The present investigation provides measurements for a wide size range of P. glacialis individuals compared to earlier studies, which were limited on very small data sets.

Description: The beaks of 10 cephalopod species were found in the diet of foraging and moulting king penguins (Aptenodytes patagonicus) from a breeding colony at Volunteer Beach, Falkland Islands during austral winter (September/October 1996). A total of 486 lower cephalopod beaks were collected, identified and measured (LRL: lower rostral length). Six cephalopod families occurred in the penguins’ diet with Onychoteuthidae being the most abundant (256 lower beaks) and represented by Moroteuthis ingens (168; LRL range 2.1–6.8 mm), Moroteuthis knipovitchi (79; LRL range 1.9–5.5 mm), and Kondakovia longimana (9; LRL range 2.1–7.4 mm). Other families were Ommastrephidae (135) with Martialia hyadesi (127; LRL range 2.6–8.7 mm), Illex argentinus (6; LRL range 5.0–6.0 mm), and Ommastrephes bartrami (2; LRL range 7.9–8.8 mm); Loliginidae with Loligo gahi (60; LRL range 0.8–2.1 mm); Gonatidae with Gonatus antarcticus (28; LRL range 1.3–3.3 mm); Neoteuthidae with Alluroteuthis antarcticus (4; LRL range 2.4–3.9 mm), and Histioteuthidae with Histioteuthis eltaninae (3; LRL range 3.3–3.4 mm). Allometric equations were used to relate lower rostral beak length with cephalopod body size and mass. M. ingens was the dominating cephalopod prey in terms of numbers (n=168), whereas M. hyadesi was most important in terms of biomass (64 682 g). The present study provides first information on the cephalopod prey of Falkland Islands king penguins. The data suggest that penguins take squid at coastal islands slope regions as well as in oceanic waters which demonstrates their ability to forage in a wide geographical area and to alternate between specific foraging sites. Possible competition with the commercial squid fishery off the Falkland Islands is discussed.