Long-term follow-up results of the multicenter phase II trial of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of standard tyrosine kinase inhibitor therapy.

BACKGROUND: This investigator-initiated trial provided the justification for the phase III GRID study resulting in worldwide regulatory approval of regorafenib as a third-line therapy for patients with metastatic gastrointestinal stromal tumors (GIST). We report the genotype analyses, long-term safety, and activity results from this initial trial of regorafenib in GIST. PATIENTS AND METHODS: The trial was conducted between February 2010 and January 2014, among adult patients with metastatic GIST, after failure of at least imatinib and sunitinib. Patients received regorafenib orally, 160 mg once daily, days 1-21 of a 28-day cycle. Clinical benefit rate (CBR), defined as complete or partial response (PR), or stable disease lasting ≥16 weeks per RECIST 1.1, progression-free survival (PFS), overall survival (OS), long-term safety data, and metabolic response by functional imaging were assessed. RESULTS: Thirty-three patients received at least one dose of regorafenib. The median follow-up was 41 months. CBR was documented in 25 of 33 patients [76%; 95% confidence interval (CI) 58% to 89%], including six PRs. The median PFS was 13.2 months (95% CI 9.2-18.3 months) including four patients who remained progression-free at study closure, each achieving clinical benefit for more than 3 years (range 36.8-43.5 months). The median OS was 25 months (95% CI 13.2-39.1 months). Patients whose tumors harbored a KIT exon 11 mutation demonstrated the longest median PFS (13.4 months), whereas patients with KIT/PDGFRA wild-type, non-SDH-deficient tumors experienced a median 1.6 months PFS (P < 0.0001). Long-term safety profile is consistent with previous reports; hand-foot skin reaction and hypertension were the most common reasons for dose reduction. Notably, regorafenib induced objective responses and durable benefit in SDH-deficient GIST. CONCLUSIONS: Long-term follow-up of patients with metastatic GIST treated with regorafenib suggests particular benefit among patients with primary KIT exon 11 mutations and those with SDH-deficient GIST. Dose modifications are frequently required to manage treatment-related toxicities. CLINICAL TRIAL NUMBER: NCT01068769.

Radiofrequency ablation in the management of liver metastases from breast cancer.

OBJECTIVE: Systemic chemotherapy remains the standard treatment for patients with breast cancer hepatic metastases. Resection of metastases has survival advantages in a small percentage of selected patients. Radiofrequency ablation has been used in small numbers of selected patients. This small series was undertaken to review our experience with radiofrequency ablation in the management of patients with breast cancer hepatic metastases. CONCLUSION: Radiofrequency ablation of breast cancer hepatic metastases is safe and may be used to control hepatic deposits in patients with stable or no extrahepatic disease.

Biological responses to PCB exposure in shorthorn sculpin from Saglek Bay, Labrador.

A local source of polychlorinated biphenyls (PCBs) in Saglek Bay, Labrador, has contaminated marine sediments and the coastal food web. As part of a larger assessment of ecological risks in the Bay, we evaluated biological responses to PCB concentrations in a northern fish species, the shorthorn sculpin (Myoxocephalus scorpius). Biological endpoints, including ethoxyresorufin-O-deethylase (EROD) activity in liver tissue, fish body condition, lipid content, and relative liver mass were examined in 35 sculpin collected during August-September 1999. Across a wide range of PCB concentrations (5.1-6920 ng/g wet weight (ww) in whole fish excluding liver), sculpin showed significant EROD induction (as much as 25-fold in the most exposed group). Responses varied directly with PCB concentrations but there was also an apparent threshold for induction at about 50 ng/g ww (whole fish excluding liver). A strong relationship between sculpin PCB concentrations and the concentrations of PCBs in the marine sediments of Saglek Bay suggests that concentrations above this threshold can arise from very low concentrations in sediments (2.3 ng/g dry weight). Other biological endpoints did not show significant responses to PCB concentrations, nor were they related to the observed EROD activity. Although PCDF compounds were present in trace amounts (primarily 2,3,4,7,8-PnCDF), mono-ortho and non-ortho substituted (coplanar) PCBs appeared to contribute the majority of the total dioxin toxic equivalent (TEQ) concentrations. Overall, the results indicate that biological responses occur in shorthorn sculpin with relatively low PCB concentrations (approximately 50 ng/g), which are not unrealistic for even mildly contaminated areas in northern Canada.

PCBs in sediments and the coastal food web near a local contaminant source in Saglek Bay, Labrador.

Polychlorinated biphenyls (PCBs) were measured in marine sediments and the coastal food web in Saglek Bay, Labrador, to investigate the influence of a local PCB source. Saglek Bay has been the site of a military radar station since the late 1950s and there was PCB-contaminated soil at a beach prior to cleanup in 1997-1999. PCB concentrations in marine sediments during 1997-1999 ranged from 0.24 to 62000 ng/g (dry weight) and decreased exponentially with distance from the contaminated beach. Given this gradient, spatial trends of PCBs in the food web were examined over four zones, according to distance from the contaminated beach: within 1.5 km--zone one, 1.5-4.5 km--zone two, 4.5-7.5 km--zone three, and greater than 7.5 km--zone four. PCB concentrations in a bottom-feeding fish (shorthorn sculpin, Myoxocephalus scorpius), decreased significantly from zone one to zone two, three, four, and distant Labrador reference sites. PCB concentrations in the eggs of a diving seabird (black guillemot, Cepphus grylle) were as high as 48000 ng/g during 1997-1999 and average concentrations in zones one and two were 84 and 13 times higher than in zone four. Marine invertebrates closely reflected the concentrations of PCBs in the associated sediment. In contrast to the benthic-based food web, anadromous arctic char (Salvelinus alpinus) showed no evidence of PCB accumulation from the contaminated sediments. Relatively high PCB concentrations were discovered in some great black-backed gulls (Larus marinus) and ringed seals (Phoca hispida) but appear to relate more to their high trophic level than sampling location. Those species that fed on or near the seabed and had limited foraging ranges were strongly influenced by the local contamination. Total PCB concentrations in the benthic-based food web were significantly higher than background levels for a distance of at least 7.5 km from the contaminated beach. This area is small in the context of widely distributed contamination from long-range transport but the area's high concentrations are comparable to levels associated with adverse effects elsewhere. Our findings should be useful to better assess the environmental impacts of PCB contamination at other coastal sites in the Arctic.

The refeeding syndrome: a review.

Refeeding syndrome has been used to describe those phenomena, such as severe hypophosphatemia and other metabolic complications, seen in malnourished patients receiving concentrated calories via total parenteral nutrition. The purpose of this review is to clarify and broaden this definition, as well as to make recommendations for its recognition and, more importantly, prevention.

A method of obtaining, processing, and analyzing human intestinal secretions for antibody content.

Human intestinal secretions can be readily obtained using a commercially available intestinal lavage solution. Although such secretions contained abundant protease activity, significant loss of immunoglobulins was prevented by the addition of a mixture of protease inhibitors. The total content of IgA, IgM, and IgG antibody in secretions was measured using sandwich ELISA. In the secretions of ten normal volunteers IgA was most abundant (197 micrograms/ml +/- 103 SD) followed by IgM (12.5 micrograms/ml +/- 6.8 SD) and IgG (0.24 micrograms/ml +/- 0.04 SD). The IgA in secretions was predominantly secretory IgA as shown by sucrose density centrifugation. The effect of intestinal secretions on the sensitivity of the antigen-specific ELISA was tested by adding murine myeloma IgA anti-TNP added to samples of human secretions. IgA anti-TNP activity could be detected as low as 1 ng/ml, and there was no evidence of interference with the ELISA by other constituents in the secretions. Using these methods an antigen-specific secretory IgA anti-cholera toxin B subunit response in the secretions of volunteers given an oral B subunit vaccine was readily demonstrated.

Protein binding of coherin and other small molecules by thin-layer gel chromatography.

The protein binding stoichiometry of small molecules is here determined on a nanomole scale by a simplified procedure utilizing chromatography on thin layers of cross-linked dextran gels. New data are presented on the thin layer chromatographic properties of representative ligands, including a-amino acids, peptides, dyes and fluorigenic reagents, in relation to their molecular weights, polar characteristics, gel water regain values and denaturants, providing criteria for the general application of this method to studies of ligand binding with large as well as small molecules. By this procedure coherin peptides, A1 and B1--4, respectively, bind to coherin C in the molar ratio, 2:1, with a binding constant of about 10(5) M-1. Coherin C is believed to act as a carrier peptide.

Mother-son folie a deux: a case report.

A case of folie a deux is presented in which the child is the dominant psychotic partner and his mother is the passive partner in whom a paranoid psychosis is induced. The conditions under which folie a deux may occur, the diagnosis, and the treatment of the disorder are discussed.

Bilateral central retinal artery occlusions in polyarteritis nodosa.

The third reported case of bilateral central retinal artery occlusion associated with polyarteritis nodosa is presented. An alternative etiology of the frequently observed association of polyarteritis nodosa with optic atrophy is suggested. A plan of therapy is recommended.