Changes over time in the course of advanced pancreatic cancer treatment with systemic chemotherapy: a pooled analysis of five clinical trials from two decades of the German AIO study group.

BACKGROUND: Over the past two decades, our group has conducted five multicenter trials focusing on first-line systemic therapy for patients with advanced pancreatic cancer. The current pooled analysis was designed to evaluate prognosis over time and the impact of clinical characteristics on survival. PATIENTS AND METHODS: Individual patient data were derived from five prospective, controlled, multicenter trials conducted by the 'Arbeitsgemeinschaft Internistische Onkologie' (AIO): 'Gem/Cis', 'Ro96', 'RC57', 'ACCEPT' and 'RASH', which recruited patients between December 1997 and January 2017. RESULTS: Overall, 912 patients were included. The median overall survival (OS) for all assessable patients was 7.1 months. OS significantly improved over time, with a median OS of 8.6 months for patients treated from 2012 to 2017 compared with 7.0 months from 1997 to 2006 [hazard ratio (HR) 1.06; P < 0.004]. Eastern Cooperative Oncology Group performance status (HR 1.48; P < 0.001), use of second-line treatment (HR 1.51; P < 0.001), and Union for International Cancer Control (UICC) stage (III versus IV) (HR 1.34, P = 0.002) had a significant impact on OS. By contrast, no influence of age and gender on OS was detectable. Comparing combination therapy with single-agent chemotherapy did not demonstrate a survival benefit, nor did regimens containing epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) such as afatinib or erlotinib, compared with chemotherapy-only arms. Patients with early-onset pancreatic cancer (age at study entry of ≤50 years, n = 102) had a similar OS compared with those >50 years (7.1 versus 7.0 months; HR 1.13; P = 0.273). The use of a platinum-containing regimen was not associated with better outcomes in patients with early-onset pancreatic cancer. CONCLUSIONS: Within this selected group of patients treated within prospective clinical trials, survival has shown improvement over two decades. This effect is likely attributable to the availability of more effective combination therapies and treatment lines, rather than to any specific regimen, such as those containing EGFR-TKIs. In addition, concerning age and sex subgroups, the dataset did not provide evidence for distinct clinical behavior.

Spatial variability in photosynthetic and heterotrophic activity drives localized δ13C org fluctuations and carbonate precipitation in hypersaline microbial mats.

Modern laminated photosynthetic microbial mats are ideal environments to study how microbial activity creates and modifies carbon and sulfur isotopic signatures prior to lithification. Laminated microbial mats from a hypersaline lagoon (Guerrero Negro, Baja California, Mexico) maintained in a flume in a greenhouse at NASA Ames Research Center were sampled for δ(13) C of organic material and carbonate to assess the impact of carbon fixation (e.g., photosynthesis) and decomposition (e.g., bacterial respiration) on δ(13) C signatures. In the photic zone, the δ(13) C org signature records a complex relationship between the activities of cyanobacteria under variable conditions of CO2 limitation with a significant contribution from green sulfur bacteria using the reductive TCA cycle for carbon fixation. Carbonate is present in some layers of the mat, associated with high concentrations of bacteriochlorophyll e (characteristic of green sulfur bacteria) and exhibits δ(13) C signatures similar to DIC in the overlying water column (-2.0‰), with small but variable decreases consistent with localized heterotrophic activity from sulfate-reducing bacteria (SRB). Model results indicate respiration rates in the upper 12 mm of the mat alter in situ pH and HCO3- concentrations to create both phototrophic CO2 limitation and carbonate supersaturation, leading to local precipitation of carbonate minerals. The measured activity of SRB with depth suggests they variably contribute to decomposition in the mat dependent on organic substrate concentrations. Millimeter-scale variability in the δ(13) C org signature beneath the photic zone in the mat is a result of shifting dominance between cyanobacteria and green sulfur bacteria with the aggregate signature overprinted by heterotrophic reworking by SRB and methanogens. These observations highlight the impact of sedimentary microbial processes on δ(13) C org signatures; these processes need to be considered when attempting to relate observed isotopic signatures in ancient sedimentary strata to conditions in the overlying water column at the time of deposition and associated inferences about carbon cycling.

Identification of Desulfobacterales as primary hydrogenotrophs in a complex microbial mat community.

Hypersaline microbial mats have been shown to produce significant quantities of H2 under dark, anoxic conditions via cyanobacterial fermentation. This flux of a widely accessible microbial substrate has potential to significantly influence the ecology of the mat, and any consumption will affect the net efflux of H2 that might otherwise be captured as a resource. Here, we focus on H2 consumption in a microbial mat from Elkhorn Slough, California, USA, for which H2 production has been previously characterized. Active biologic H2 consumption in this mat is indicated by a significant time-dependent decrease in added H2 compared with a killed control. Inhibition of sulfate reduction, as indicated by a decrease in hydrogen sulfide production relative to controls, resulted in a significant increase in H2 efflux, suggesting that sulfate-reducing bacteria (SRB) are important hydrogenotrophs. Low methane efflux under these same conditions indicated that methanogens are likely not important hydrogenotrophs. Analyses of genes and transcripts that encode for rRNA or dissimilatory sulfite reductase, using both PCR-dependent and PCR-independent metatranscriptomic sequencing methods, demonstrated that Desulfobacterales are the dominant, active SRB in the upper, H2-producing layer of the mat (0-2 mm). This hypothesis was further supported by the identification of transcripts encoding hydrogenases derived from Desulfobacterales capable of H2 oxidation. Analysis of molecular data provided no evidence for the activity of hydrogenotrophic methanogens. The combined biogeochemical and molecular data strongly indicate that SRB belonging to the Desulfobacterales are the quantitatively important hydrogenotrophs in the Elkhorn Slough mat.

Phase I/II trial of capecitabine and oxaliplatin in combination with bevacizumab and imatinib in patients with metastatic colorectal cancer: AIO KRK 0205.

BACKGROUND: Combined inhibition of platelet-derived growth factor receptor beta signalling and vascular endothelial growth factor promotes vascular normalisation in preclinical models and may lead to increased delivery of chemotherapy to tumour tissue. This phase I/II trial assessed the safety and efficacy of capecitabine plus oxaliplatin (XELOX) plus bevacizumab and imatinib in the first-line treatment of patients with metastatic colorectal cancer. METHODS: Two dose levels (I/II) were defined: capecitabine 850/1000 mg m(-2) twice daily on days 1-14; oxaliplatin 100/130 mg m(-2) on day 1; bevacizumab 7.5 mg kg(-1) on day 1; imatinib 300 mg day(-1) on days 1-21 every 21 days. The primary study endpoint was safety. The phase II secondary endpoint was 6-month progression-free survival (PFS). RESULTS: Dose level I was chosen for phase II testing because, even though further dose escalation was permitted by the protocol, gastrointestinal toxicities were considered to be clinically significant. A total of 49 patients were evaluated. The 6-month PFS rate was 76%, median PFS was 10.6 months and median overall survival was 23.2 months. Haematological toxicities were generally mild. Sensory neuropathy and diarrhoea were the most common grade 3 toxicities. CONCLUSION: The combination of XELOX with bevacizumab and imatinib is tolerable and has promising efficacy.

Science potential from a Europa lander.

The prospect of a future soft landing on the surface of Europa is enticing, as it would create science opportunities that could not be achieved through flyby or orbital remote sensing, with direct relevance to Europa's potential habitability. Here, we summarize the science of a Europa lander concept, as developed by our NASA-commissioned Science Definition Team. The science concept concentrates on observations that can best be achieved by in situ examination of Europa from its surface. We discuss the suggested science objectives and investigations for a Europa lander mission, along with a model planning payload of instruments that could address these objectives. The highest priority is active sampling of Europa's non-ice material from at least two different depths (0.5-2 cm and 5-10 cm) to understand its detailed composition and chemistry and the specific nature of salts, any organic materials, and other contaminants. A secondary focus is geophysical prospecting of Europa, through seismology and magnetometry, to probe the satellite's ice shell and ocean. Finally, the surface geology can be characterized in situ at a human scale. A Europa lander could take advantage of the complex radiation environment of the satellite, landing where modeling suggests that radiation is about an order of magnitude less intense than in other regions. However, to choose a landing site that is safe and would yield the maximum science return, thorough reconnaissance of Europa would be required prior to selecting a scientifically optimized landing site.

A randomized multicenter phase II study comparing capecitabine with irinotecan or cisplatin in metastatic adenocarcinoma of the stomach or esophagogastric junction.

BACKGROUND: The combination of irinotecan with 5-fluorouracil demonstrates efficacy with tolerable safety in the first-line treatment of metastatic gastroesophageal cancer (mGC). This randomized phase II trial compared for the first time capecitabine with irinotecan or cisplatin in this setting. PATIENTS AND METHODS: Patients were randomly assigned to receive 3-week cycles of capecitabine 1000 mg/m(2), twice daily for 14 days, with on day 1 either irinotecan 250 mg/m(2) (XI) or cisplatin 80 mg/m(2) (XP). The primary end point was overall response rate (ORR) and secondary end points included progression-free survival (PFS), overall survival (OS) and safety. RESULTS: Of 118 patients recruited, 112 were eligible for safety analysis and 103 for efficacy analysis. In the XI and XP treatment arms, there were no marked differences in ORR, 37.7% versus 42.0%, and median PFS, 4.2 versus 4.8 months, although median OS was longer, 10.2 versus 7.9 months, respectively. Grade 3/4 toxicity was higher in the XP regimen for thrombocytes (18.2% versus 1.8%), nausea (23.6% versus12.3%) and vomiting (16.4% versus 1.8%) and in the XI arm for diarrhea (22.8% versus 7.3%). CONCLUSION: The comparable activity and safety of the XI and XP regimens establish XI as a relevant platinum-free first-line treatment choice for patients with mGC.

Short- and long-term olivine weathering in Svalbard: implications for Mars.

Liquid water is essential to life as we know it on Earth; therefore, the search for water on Mars is a critical component of the search for life. Olivine, a mineral identified as present on Mars, has been proposed as an indicator of the duration and characteristics of water because it dissolves quickly, particularly under low-pH conditions. The duration of olivine persistence relative to glass under conditions of aqueous alteration reflects the pH and temperature of the reacting fluids. In this paper, we investigate the utility of 3 methodologies to detect silicate weathering in a Mars analog environment (Sverrefjell volcano, Svalbard). CheMin, a miniature X-ray diffraction instrument developed for flight on NASA's upcoming Mars Science Laboratory, was deployed on Svalbard and was successful in detecting olivine and weathering products. The persistence of olivine and glass in Svalbard rocks was also investigated via laboratory observations of weathered hand samples as well as an in situ burial experiment. Observations of hand samples are consistent with the inference that olivine persists longer than glass at near-zero temperatures in the presence of solutions at pH approximately 7-9 on Svalbard, whereas in hydrothermally altered zones, glass has persisted longer than olivine in the presence of fluids at similar pH at approximately 50 degrees C. Analysis of the surfaces of olivine and glass samples, which were buried on Sverrefjell for 1 year and then retrieved, documented only minor incipient weathering, though these results suggest the importance of biological impacts. The 3 types of observations (CheMin, laboratory observations of hand samples, burial experiments) of weathering of olivine and glass at Svalbard show promise for interpretation of weathering on Mars. Furthermore, the weathering relationships observed on Svalbard are consistent with laboratory-measured dissolution rates, which suggests that relative mineral dissolution rates in the laboratory, in concert with field observations, can be used to yield valuable information regarding the pH and temperature of reacting martian fluids.

Capecitabine plus oxaliplatin (CapOx) versus capecitabine plus gemcitabine (CapGem) versus gemcitabine plus oxaliplatin (mGemOx): final results of a multicenter randomized phase II trial in advanced pancreatic cancer.

BACKGROUND: To compare the efficacy and safety of three different chemotherapy doublets in the treatment of advanced pancreatic cancer (PC). PATIENTS AND METHODS: At total of 190 patients were randomly assigned to receive capecitabine 1000 mg/m(2) twice daily on days 1-14 plus oxaliplatin 130 mg/m(2) on day 1 (CapOx), capecitabine 825 mg/m(2) twice daily on days 1-14 plus gemcitabine 1000 mg/m(2) on days 1 and 8 (CapGem) or gemcitabine 1000 mg/m(2) on days 1 and 8 plus oxaliplatin 130 mg/m(2) on day 8 (mGemOx). Treatment cycles were repeated every three weeks. The primary end point was progression-free survival (PFS) rate at 3 months; secondary end points included objective response rate, carbohydrate antigen 19-9 response, clinical benefit response, overall survival and toxicity. RESULTS: The PFS rate after 3 months was 51% in the CapOx arm, 64% in the CapGem arm and 60% in the mGemOx arm. Median PFS was estimated with 4.2 months, 5.7 months and 3.9 months, respectively (P = 0.67). Corresponding median survival times were: 8.1 months (CapOx), 9.0 months (CapGem) and 6.9 months (mGemOx) (P = 0.56). Grade 3/4 hematological toxicities were more frequent in the two Gem-containing arms; grade 3/4 non-hematological toxicity rates did not exceed 15% in any arm. CONCLUSION: CapOx, CapGem and mGemOx have similar clinical efficacy in advanced PC. Each regimen has a distinct but manageable tolerability profile.

Mathematical simulation of the diel O, S, and C biogeochemistry of a hypersaline microbial mat.

The creation of a mathematical simulation model of photosynthetic microbial mats is important to our understanding of key biogeochemical cycles that may have altered the atmospheres and lithospheres of early Earth. A model is presented here as a tool to integrate empirical results from research on hypersaline mats from Baja California Sur (BCS), Mexico into a computational system that can be used to simulate biospheric inputs of trace gases to the atmosphere. The first version of our model, presented here, calculates fluxes and cycling of O(2), sulfide, and dissolved inorganic carbon (DIC) via abiotic components and via four major microbial guilds: cyanobacteria (CYA), sulfate reducing bacteria (SRB), purple sulfur bacteria (PSB) and colorless sulfur bacteria (CSB). We used generalized Monod-type equations that incorporate substrate and energy limits upon maximum rates of metabolic processes such as photosynthesis and sulfate reduction. We ran a simulation using temperature and irradiance inputs from data collected from a microbial mat in Guerrero Negro in BCS (Mexico). Model O(2), sulfide, and DIC concentration profiles and fluxes compared well with data collected in the field mats. There were some model-predicted features of biogeochemical cycling not observed in our actual measurements. For instance, large influxes and effluxes of DIC across the MBGC mat boundary may reveal previously unrecognized, but real, in situ limits on rates of biogeochemical processes. Some of the short-term variation in field-collected mat O(2) was not predicted by MBGC. This suggests a need both for more model sensitivity to small environmental fluctuations for the incorporation of a photorespiration function into the model.

Hepatitis B surface antigen presentation and HLA-DRB1*- lessons from twins and peptide binding studies.

The aim of this study was to investigate the underlying mechanisms of the genetic association between certain HLA-DRB1* alleles and the immune response to HBsAg vaccination. Therefore, HBsAg peptide binding to HLA-DR molecules was measured in vitro by peptide binding ELISAs. Additionally, HBsAg-specific T cell reaction and cytokine profile of immune response were analysed ex vivo in ELISPOT assays and DR-restriction of T-cell proliferative responses was investigated with HBsAg specific T cell clones. In addition, we compared HBsAg specific T cell responses of 24 monozygotic and 3 dizygotic twin pairs after HBsAg vaccination. Our results showed that the peptide binding assays did not reflect antigen presentation in vivo. DR alleles associated with vaccination failure like DRB1*0301 and 0701 efficiently presented HBsAg peptides. In 11 of 24 investigated monozygotic twin pairs we observed pronounced differences in the recognition of HBsAg peptides. This study indicates that HLA-DR associations with HBsAg vaccination response are not caused by differences in peptide binding or by a shift in the Th1/Th2 profile. Our findings strongly argue for differences in the T cell recognition of peptide/MHC complexes as the critical event in T cell responsiveness to HBsAg.

Innovative drugs and strategies in the treatment of upper gastrointestinal tract carcinomas.

The results of the standard therapy of upper gastrointestinal tract cancer remain unsatisfactory, mainly because still the majority of cases are diagnosed at a late stage of disease, which implicates a poor prognosis. Innovative strategies focus on neoadjuvant chemotherapy in locally advanced gastric cancer and chemo- or radiochemotherapy in advanced oesophageal cancer. Results of phase II studies published so far have been promising. There is rising evidence that adjuvant radiochemotherapy in gastric cancer may be of benefit for curatively resected patients, whereas the results of trials including a systematic lymphadenectomy have to be awaited. New substances like the taxanes or irinotecan in the palliative setting did not prove to be superior to platinum-based standard chemotherapy protocols so far.

The role of microbial mats in the production of reduced gases on the early Earth.

The advent of oxygenic photosynthesis on Earth may have increased global biological productivity by a factor of 100-1,000 (ref. 1), profoundly affecting both geochemical and biological evolution. Much of this new productivity probably occurred in microbial mats, which incorporate a range of photosynthetic and anaerobic microorganisms in extremely close physical proximity. The potential contribution of these systems to global biogeochemical change would have depended on the nature of the interactions among these mat microorganisms. Here we report that in modern, cyanobacteria-dominated mats from hypersaline environments in Guerrero Negro, Mexico, photosynthetic microorganisms generate H2 and CO-gases that provide a basis for direct chemical interactions with neighbouring chemotrophic and heterotrophic microbes. We also observe an unexpected flux of CH4, which is probably related to H2-based alteration of the redox potential within the mats. These fluxes would have been most important during the nearly 2-billion-year period during which photosynthetic mats contributed substantially to biological productivity-and hence, to biogeochemistry-on Earth. In particular, the large fluxes of H2 that we observe could, with subsequent escape to space, represent a potentially important mechanism for oxidation of the primitive oceans and atmosphere.

Different transcriptional activity and in vitro TNF-alpha production in psoriasis patients carrying the TNF-alpha 238A promoter polymorphism.

Genes encoded on chromosome 6 within the major histocompatibility complex region are thought to play an important role in the pathogenesis of psoriasis. A potential candidate gene is tumor necrosis factor alpha. The tumor necrosis factor alpha promoter contains several polymorphisms including two G-->A transitions at position -308 and -238, which are the most common in Caucasian populations. The TNF238.2 (-238A) allele has been strongly associated with psoriasis. We have investigated the effect of the -238 and -308 variants on transcription of the tumor necrosis factor alpha gene in luciferase reporter gene assays. In addition, peripheral blood mononuclear cells of 47 patients with psoriasis and 43 controls were stimulated with different antigens and mitogens (streptococcal sonicate and superantigen, lipopolysaccharide, phorbol-12-myristate, phytohemagglutinin, CD3 antibodies) and tumor necrosis factor alpha production was measured in supernatants by enzyme-linked immunosorbent assay. The psoriasis-associated tumor necrosis factor alpha promoter allele TNF238.2 showed a significantly decreased transcriptional activity. Peripheral blood mononuclear cells carrying this allele produced significantly less tumor necrosis factor alpha after stimulation with T cell mitogens and streptococcal antigens in comparison to controls. The promoter allele TNF238.2 seems to influence tumor necrosis factor alpha production; a possible role in the pathogenesis of psoriasis has to be further evaluated.