Cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric cancer: a phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO)

BACKGROUND: Cetuximab enhances the efficacy of chemotherapy in several cancer types. This trial assessed the activity of cetuximab and chemotherapy in advanced gastric cancer. METHODS: Patients with previously untreated, metastatic, gastric cancer received cetuximab 400 mg m(-2) at first infusion followed by weekly infusions of 250 mg m(-2) combined with FUFOX (oxaliplatin 50 mg m(-2), 5-FU 2000 mg m(-2), and DL-folinic acid 200 mg m(-2) d1, 8, 15 and 22 qd36). The primary endpoint was tumour response. RESULTS: Overall, 52 patients were enrolled. The most common grade 3/4 toxicities were diarrhoea (33%), and skin toxicity (24%). Efficacy was evaluable in 46 patients who showed a response rate of 65% (CI 95%: 50-79%) including four complete responses. Time to progression (TTP) was 7.6 months (CI 95%: 5.0-10.1 months) and overall survival (OS) was 9.5 months (CI 95%: 7.9-11.1 months). Epidermal growth factor receptor (EGFR) was detectable in 60% of tumours but showed no correlation with treatment outcome. A KRAS mutation was found in only 1 of 32 (3%) tumour samples analysed. CONCLUSION: Cetuximab plus FUFOX showed an interesting high response rate in metastatic gastric cancer. Cetuximab plus platinum-fluoropyrimidine chemotherapy is at present being investigated in a phase III randomised controlled trial

Competition of Escherichia coli DNA Polymerases I, II and III with DNA Pol IV in Stressed Cells

Escherichia coli has five DNA polymerases, one of which, the low-fidelity Pol IV or DinB, is required for stress-induced mutagenesis in the well-studied Lac frameshift-reversion assay. Although normally present at ∼200 molecules per cell, Pol IV is recruited to acts of DNA double-strand-break repair, and causes mutagenesis, only when at least two cellular stress responses are activated: the SOS DNA-damage response, which upregulates DinB ∼10-fold, and the RpoS-controlled general-stress response, which upregulates Pol IV about 2-fold. DNA Pol III was also implicated but its role in mutagenesis was unclear. We sought in vivo evidence on the presence and interactions of multiple DNA polymerases during stress-induced mutagenesis. Using multiply mutant strains, we provide evidence of competition of DNA Pols I, II and III with Pol IV, implying that they are all present at sites of stress-induced mutagenesis. Previous data indicate that Pol V is also present. We show that the interactions of Pols I, II and III with Pol IV result neither from, first, induction of the SOS response when particular DNA polymerases are removed, nor second, from proofreading of DNA Pol IV errors by the editing functions of Pol I or Pol III. Third, we provide evidence that Pol III itself does not assist with but rather inhibits Pol IV-dependent mutagenesis. The data support the remaining hypothesis that during the acts of DNA double-strand-break (DSB) repair, shown previously to underlie stress-induced mutagenesis in the Lac system, there is competition of DNA polymerases I, II and III with DNA Pol IV for action at the primer terminus. Up-regulation of Pol IV, and possibly other stress-response-controlled factor(s), tilt the competition in favor of error-prone Pol IV at the expense of more accurate polymerases, thus producing stress-induced mutations. This mutagenesis assay reveals the DNA polymerases operating in DSB repair during stress and also provides a sensitive indicator for DNA polymerase competition and choice in vivo

Radionuclide imaging of bone marrow disorders

Noninvasive imaging techniques have been used in the past for visualization the functional activity of the bone marrow compartment. Imaging with radiolabelled compounds may allow different bone marrow disorders to be distinguished. These imaging techniques, almost all of which use radionuclide-labelled tracers, such as 99mTc-nanocolloid, 99mTc-sulphur colloid, 111In-chloride, and radiolabelled white blood cells, have been used in nuclear medicine for several decades. With these techniques three separate compartments can be recognized including the reticuloendothelial system, the erythroid compartment and the myeloid compartment. Recent developments in research and the clinical use of PET tracers have made possible the analysis of additional properties such as cellular metabolism and proliferative activity, using 18F-FDG and 18F-FLT. These tracers may lead to better quantification and targeting of different cell systems in the bone marrow. In this review the imaging of different bone marrow targets with radionuclides including PET tracers in various bone marrow diseases are discussed

Metastatic epidural spinal cord compression: current concepts and treatment

Metastatic epidural spinal cord compression (MESCC) is a medical emergency complicating the course of 5–10% of patients with cancer [1]. When diagnosis and treatment is early with the patient ambulatory prognosis for continued ambulation is good [2]. If the patient is nonambulatory or paraplegic, prognosis for meaningful recovery of motor and bladder function is markedly decreased. In the last decade, significant advances in the understanding, management and treatment of metastatic epidural spinal cord compression have occurred.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45378/1/11060_2005_Article_BF01051052.pd

Winter distribution and haul-out behaviour of female Antarctic fur seals from South Georgia

Telemetry-based techniques have revealed the foraging patterns of many land breeding marine predators, especially during the summer breeding season. However, during the winter, when freed from the constraints of provisioning their young, such animals are more difficult to track. Using geolocation (Global Location Sensing, GLS) loggers and satellite tags (Platform Terminal Transmitters, PTTs) we successfully tracked 16 female Antarctic fur seals from South Georgia during the austral winter. The majority of females concentrated their winter foraging in the waters around the breeding beaches (90% of locations were within 510 km). However, as the winter progressed, two of the seals spent a number of months to the south, in and around the seasonal ice edge, and five seals migrated north and northwest from South Georgia. Four of these seals clearly crossed the Polar Front and two reached the Patagonian Shelf, apparently exploiting the continental shelf edge and the Subantarctic Front. Activity (saltwater immersion) data suggested that seals spent the majority of the winter months at sea but there were rare occasions when seals hauled out, either on land or on ice floes. We obtained data from two individuals that enabled us to compare the performance of PTT and GLS devices. For these seals the mean distance between GLS and PTT locations was 122 and 132 km. Although the recovery rates were low in this study, given improvements in attachment techniques, we have demonstrated that these micro-geolocation loggers provide an ideal tool with which to study the long-term dispersal of diving marine predators at larger scales. This is the first study to show that female fur seals from South Georgia remain at sea for almost the entirety of the non-breeding winter period. Using land-based observations it has been assumed that the fur seal population at South Georgia has little temporal overlap with the krill fishery that operates mostly during the winter months in this region. We have shown that a large proportion of the female fur seals that breed on South Georgia potentially remain in the vicinity of the island and are thus in direct competition with the region's fisheries activities

Multiple occurrences of king penguin (Aptenodytes patagonicus) sexual harassment by Antarctic fur seals (Arctocephalus gazella)

Supplementary material 1 (MPG 102966 kb) Online resource 1 Antarctic fur seal’s (Arctocephalus gazella) penis visible while coercing king penguin (Aptenodytes patagonicus). (W.A. Haddad)Supplementary material 2 (MPG 79504 kb) Online resource 2 King penguin (Aptenodytes patagonicus) tries to resist sexual coercion by Antarctic fur seal (Arctocephalus gazella). (W.A. Haddad)Supplementary material 3 (MPG 258500 kb) Online resource 3 Antarctic fur seal (Arctocephalus gazella) sexually coerces king penguin (Aptenodytes patagonicus). (W.A. Haddad)Sexual coercion is the use of force to achieve mating, while reproductive interference encompasses many forms of interspecific interactions during mating. We describe three new occurrences of the sexual coercion of king penguins (Aptenodytes patagonicus) by Antarctic fur seals (Arctocephalus gazella) on sub-Antarctic Marion Island. These recurrent observations follow a common pattern where the seal chases, captures and mounts the penguin, followed by copulation attempts. These observations are similar to a previously published observation from the same island and we suggest that this may be an emergent behaviour. Two hypotheses directed at possible drivers for these coercive actions are examined: it may be learned behaviour associated with some sort of reward or it may be an extreme case of reproductive interference that can be explained by the ‘mate deprivation hypothesis’, resulting from the continued growth of the A. gazella population on the island. Reporting of similar occurrences from a range of species may allow more robust inference towards the ultimate drivers of the behaviour.The Department of Science and Technology (DST), through the National Research Foundation (NRF) (South Africa).http://link.springer.com/journal/300hb2017Mammal Research InstituteZoology and Entomolog