RESUMO
Background: Mitogen-activated protein kinase kinase (MEK) is activated by mutated KRAS in >90% of pancreatic ductal adenocarcinoma (PDAC). MEK and focal adhesion kinase (FAK) are frequently co-activated in PDAC providing a rationale for combining trametinib, an oral allosteric MEK1/2 inhibitor, with GSK2256098, an oral FAK inhibitor. Methods: Advanced PDAC patients whose disease progressed after first line palliative chemotherapy were treated with GSK2256098 250 mg twice daily and trametinib 0.5 mg once daily orally. The primary endpoint was clinical benefit (CB; complete response, partial response, or stable disease ≥24 weeks). Twenty-four patients were planned to enroll using a 2-stage minimax design (P0=0.15, P1=0.40; alpha =0.05, power 0.86). The combination would be considered inactive if 2/12 or fewer patients achieved CB at the end of stage 1, and would be considered active if >7/24 response-evaluable patients achieved CB by the end of stage 2. Serial blood samples were collected for circulating tumor DNA (ctDNA) mutation profiling. Results: Sixteen patients were enrolled and 11 were response evaluable. Of those 11, 10 had progressive disease as best tumor response and one had stable disease for 4 months. No treatment related grade ≥3 adverse events (AEs) were observed. The median progression free survival (PFS) was 1.6 (95% CI: 1.5-1.8) months and the median overall survival (OS) was 3.6 (95% CI: 2.7-not reached) months. One response-inevaluable patient achieved clinical stability for 5 months with reduction in CA19-9 and ctDNA levels with a MAP2K1 treatment resistance mutation detected in ctDNA at clinical progression. Conclusions: The combination of GSK2256098 and trametinib was well tolerated but was not active in unselected advanced PDAC.
RESUMO
A cross-sectional study was conducted to determine the prevalence and characteristics of Escherichia coli, Staphylococcus aureus, Bacillus spp. and Salmonella spp. in "bara", "channa", condiments/spices and ready-to-eat "doubles" sold by vendors in the St. George and Caroni counties of Trinidad. Of 196 samples of each of "bara", "channa", condiments/spices and ready-to-eat "doubles" examined, E. coli was detected in 0 (0.0 per cent), 14 (7.1 per cent), 96 (49.0 per cent) and 67 (34.2 per cent), respectively; Staphylococci were isolated from 104 (53.1 per cent), 71 (36.2 per cent), 129 (65.8 per cent) and 123 (62.8 per cent) samples, respectively; and Bacillus spp. were recovered from 22 (11.2 per cent), 85 (43.4 per cent), 100 (51.0 per cent) and 88 (44.9 per cent) samples, respectively. Salmonella spp. were not isolated from any sample. Of the 177 isolates of E. coli recovered from all sources, 9 (5.1 per cent), 7 (4.0 per cent) and 47 (26.6 per cent) were mucoid, haemolytic and non-sorbitol fermenters (NSF), respectively, but none agglutinated with O157 antiserum. Of 427 staphylococcal isolates, 130 (30.4 per cent) were confirmed as S. aureus of which 20 (15.4 per cent) were haemolytic and 84 (64.6 per cent) pigmented, while 17 (20.7 per cent) of 82 strains of S. aureus tested produced enterotoxins. Ready-to-eat "doubles", a popular food in Trinidad, therefore pose a potential health risk to consumers due to the high level of contamination with bacteria.
