FGFR2-amplified tumor clones are markedly heterogeneously distributed in carcinomas of the upper gastrointestinal tract.

BACKGROUND: FGFR2 is a therapy-relevant target in tumors of the upper gastrointestinal tract (GIT), and clinical trials are currently underway to test the efficacy of FGFR2 inhibitors. Tumor heterogeneity is one of the relevant causes of treatment failure. Almost nothing is known about the heterogeneous distribution of FGFR2-amplified clones in adenocarcinomas of the upper GIT. PATIENTS AND METHODS: To assess FGFR2 gene copy number alteration and intratumoral heterogeneity of upper GIT adenocarcinomas, we analyzed 893 patient-derived formalin-fixed paraffin-embedded tumor specimens, including primary operated and neoadjuvant-treated tumors (462 gastric carcinomas and 429 esophageal adenocarcinomas) as well as complementary lymph node and distant metastasis by fluorescence in situ hybridization. RESULTS: Twenty-six gastric tumors (5.6%) and 21 esophageal adenocarcinomas (4.9%) showed FGFR2 amplification. Overall, 93% of gastric carcinomas and 83% of esophageal carcinomas showed heterogeneous amplification. FGFR2 amplification was found in different histological growth patterns, including intestinal and diffuse type according to the Lauren classification. In the primary gastric carcinoma group, FGFR2 amplification was associated with poor prognosis (p = 0.005). CONCLUSION: Homogeneous FGFR2 amplification in tumors of the upper GIT is the exception. This has highly relevant implications in the nature of FGFR2 diagnostics (sufficient tumor cell number, determination of amplification at metastasis versus primary tumor, etc.) and on the response probability of appropriate inhibitors. It is relevant that the often poorly treatable and aggressive subtype of diffuse carcinomas (poorly cohesive carcinomas) also shows FGFR2 amplification and that an individualized therapy option with FGFR2 inhibitors could be an option in this group.

Determination of ED50 values for praziquantel in praziquantel-resistant and -susceptible Schistosoma mansoni isolates.

The dose of praziquantel required to kill 50% of adult worms in vivo (i.e. the ED50) was estimated for nine different isolates of Schistosoma mansoni in infected mice. Four of the isolates were selected because they had not knowingly been in contact with the drug (i.e. they were putatively praziquantel-susceptible). Five putatively praziquantel-resistant isolates were chosen because they had been selectively bred for drug-resistance in the laboratory and/or had previously been shown to be relatively resistant to praziquantel in the field. The work was performed in three laboratories in different countries using pre-agreed and comparable experimental protocols. All four praziquantel-susceptible isolates had ED50s estimated to be <100 mg/kg (mean=70+/-7 SD; median=68), while all five putatively praziquantel-resistant isolates had estimated ED50s >100 mg/kg (mean=209+/-48 SD; median=192). Thus, the five praziquantel-resistant isolates, including two that had been subjected to drug pressure during more than 20 passages in mice, had drug ED50s that were approximately three times as great as those of the praziquantel-susceptible isolates. Two of the five isolates in the putatively resistant group had previously been passaged 15 or more times in mice without administration of drug-pressure, but had ED50s consistent with the other three isolates in the group, indicating that the trait of praziquantel-resistance did not necessarily impair biological fitness during laboratory passage. The protocols used here to estimate the praziquantel ED50s of S. mansoni isolates should be useful for establishing and monitoring the drug susceptibility/resistance profiles of parasite isolates freshly obtained from endemic areas, particularly those in which increased usage of the drug is likely to occur.

Gene-associated markers provide tools for tackling illegal fishing and false eco-certification.

Illegal, Unreported and Unregulated fishing has had a major role in the overexploitation of global fish populations. In response, international regulations have been imposed and many fisheries have been 'eco-certified' by consumer organizations, but methods for independent control of catch certificates and eco-labels are urgently needed. Here we show that, by using gene-associated single nucleotide polymorphisms, individual marine fish can be assigned back to population of origin with unprecedented high levels of precision. By applying high differentiation single nucleotide polymorphism assays, in four commercial marine fish, on a pan-European scale, we find 93-100% of individuals could be correctly assigned to origin in policy-driven case studies. We show how case-targeted single nucleotide polymorphism assays can be created and forensically validated, using a centrally maintained and publicly available database. Our results demonstrate how application of gene-associated markers will likely revolutionize origin assignment and become highly valuable tools for fighting illegal fishing and mislabelling worldwide.