Combined systemic inflammation score (SIS) correlates with prognosis in patients with advanced pancreatic cancer receiving palliative chemotherapy.

PURPOSE: The prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) remains dismal. New cytotoxic agents such as nab-paclitaxel and liposomal irinotecan (nal-Iri) have extended the armamentarium of therapeutic options in the last years. Nowadays, sequential therapeutic strategies with moderately toxic chemotherapeutic protocols can be administered to the patients. However, prognostic and predictive biomarkers are still missing to identify those patients, which profit most from a "continuum of care" concept rather than receiving intensive first-line protocols such as FOLFIRINOX. To this end, we retrospectively evaluated the impact of the systemic inflammation as one essential hallmark of cancer in patients with advanced PDAC treated with sequential systemic. METHODS: A cohort of 193 PDAC patients treated at our center from January 2005 to August 2011 were retrospectively evaluated for the following systemic inflammatory response (SIR) markers: neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR) C-reactive protein (CRP), and the modified Glasgow Prognostic Score (mGPS). SIR markers were correlated with clinico-pathological findings, response to chemotherapy and overall survival (OS) using Kaplan-Meier curves and Cox proportional models. RESULTS: All evaluated SIR markers were significantly associated with OS in patients with metastatic disease but not in patients with locally advanced PDAC. Interestingly, all SIR markers were only prognostic in patients not receiving antibiotics as surrogate marker for systemic bacterial infections. Based on the evaluated SIR markers, we propose a new Systemic Inflammation Score (SIS), which significantly correlated with reduced OS (HR: 3.418 (1.802-6.488, p < 0.001)) and the likelihood of receiving further-line systemic therapies (p = 0.028). CONCLUSION: Routinely assessed SIR biomarkers have potential to support therapeutic decision making in patients with metastatic PDAC.

Long-term outcome of patients with advanced pancreatic cancer treated with sequential chemotherapies before the era of modern combination therapy protocols.

INTRODUCTION: Patients (pts) with locally advanced (LAPC) or metastatic pancreatic ductal adenocarcinoma (mPDAC) have a dismal prognosis. Recently, new combination chemotherapies such as FOLFIRINOX and nab-paclitaxel/gemcitabine have demonstrated superiority over gemcitabine monotherapy. However, a substantial proportion of pts cannot tolerate these intensive front-line protocols. Moreover, the long-term superiority of multiagent protocols over less intensive strategies remains to be shown. To provide a benchmark for future studies, we analyzed the outcome of patients with LAPC or mPDAC treated at the West German Cancer Center before the FOLFIRINOX/nab-paclitaxel + gemcitabine era. METHODS: This retrospective analysis included 201 consecutive pts with LAPC and mPDAC treated between 2007 and 2011. Efficacy parameters were correlated with type of chemotherapy, number of treatment lines and clinicopathological parameters. RESULTS: Gemcitabine monotherapy was given as first-line therapy in 51.1%, whereas 48.9% received combination chemotherapies such as gemcitabine/oxaliplatin or FOLFOX. Patients received a median of two lines of treatment, with 54.8% receiving second-line and 37.9% receiving third- and further-line therapies. There was no significant difference between gemcitabine monotherapy and combination therapies. Despite moderate activity of first-line treatment, median overall survival for LAPC was 11.3 months and 8.7 months for mPDAC. Multivariate analysis identified age and number of treatment lines as prognostic markers. CONCLUSION: The long-term outcome of unselected pts with LAPC and mPDAC treated before the introduction of aggressive multiagent chemotherapy protocols compares favorably with the results of contemporary benchmark trials. This suggests a multifactorial benefit from interdisciplinary care provided over sequential treatment lines at high volume expert centers.

Lack of genetic structure among Eurasian populations of the tick Ixodesricinus contrasts with marked divergence from north-African populations.

Host-parasite interactions may select for significant novel mutations with major evolutionary consequences for both partners. In poor active dispersers such as ticks, their population structures are shaped by their host movements. Here, we use population genetics and phylogeography to investigate the evolutionary history of the most common tick in Europe, Ixodes ricinus, a vector of pathogenic agents causing diseases in humans and animals. Two mitochondrial and four nuclear genes were sequenced for 60 individuals collected on four geographical scales (local, regional, Eurasian and western Palearctic scales). The overall level of nucleotide diversity was low and the variability did not differ at the local, regional or Eurasian scales but increased two fold for the western Palearctic scale. Moreover, the phylogenetic trees indicated an absence of genetic structure among Eurasian ticks, contrasting with a strong differentiation of the north-African ticks which formed a divergent clade. The homogeneity in Eurasian ticks may be explained by gene flows due to passive dispersal of ticks by hosts within a continuous population and recent range expansion of I. ricinus as shown by the fit of the observed frequency distribution of numbers of mismatches between pairwise sequences with the demographic expansion model (Harpending raggedness index, P=0.74). The genetic divergence of the north-African populations could be explained by genetic drift in these small populations that are geographically isolated and/or selection pressures due to different ecological conditions (seasonal activity, pathogenic agents and hosts communities). The consequences of these results on the epidemiology of vector-borne diseases are discussed.

Molecular evolution within and between self-incompatibility specificities.

Genes under multiallelic balancing selection have sharply contrasted evolutionary dynamics across timescales, with much longer coalescence time among functionally distinct allelic lines but much shorter coalescence time among gene copies within allelic lines as compared with the genomic background. In this paper, we combine theoretical and empirical approaches to investigate patterns of molecular evolution within and between self-incompatibility (SI) specificities. We first use numerical simulations to investigate coalescence times within allelic lines in a subdivided population for a sporophytic SI system. We then report on a comprehensive analysis of nucleotide polymorphism among gene copies within five distinct allelic lines in the closely related Arabidopsis halleri and Arabidopsis lyrata. In line with our model predictions, we find that the observed level of polymorphism among gene copies was generally low but differed among allelic lines. The data provide compelling direct evidence for recombination and/or gene conversion not only within the two most recessive allelic lines but also between two closely related but distinct allelic lines, suggesting that recombination at the Arabidopsis SI locus is possible in the absence of large sequence divergence among haplotypes. We observed shared polymorphic sites between the two species in one allelic line and strikingly similar haplotypes in another allelic line. We discuss whether convergent evolution may have led to this pattern and suggest that these observations are consistent with ongoing or very recent introgression, as previously documented.