Early kinetics of C reactive protein for cancer-agnostic prediction of therapy response and mortality in patients treated with immune checkpoint inhibitors: a multicenter cohort study.

BACKGROUND: C reactive protein (CRP) kinetics have recently been suggested as predictive biomarkers for the efficacy of immune checkpoint inhibitor (ICI) therapy in selected cancer types. The aim of this study was to characterize early CRP kinetics as a tumor-agnostic biomarker for ICI treatment outcomes. METHODS: In this multicenter retrospective cohort study, two independent cohorts of patients with various cancer types undergoing palliative ICI treatment at Austrian academic centers served as the discovery (n=562) and validation cohort (n=474). Four different patterns of CRP kinetics in the first 3 months of ICI therapy were defined (CRP-flare responders, CRP-responders, CRP non-responders, patients with all-normal CRP). Objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were defined as coprimary endpoints. Univariable and multivariable logistic regression, landmark analysis and Cox regression including CRP kinetics as time-dependent variable were performed. RESULTS: The ORR in patients with all-normal CRP, CRP responders, CRP flare-responders and CRP non-responders was 41%, 38%, 31% and 12%, respectively. The median OS and PFS estimates were 24.5 months (95% CI 18.5 to not reached) and 8.2 months (95% CI 5.9 to 12.0) in patients with all-normal CRP, 16.1 months (95% CI 12.6 to 19-8) and 6.1 months (95% CI 4.9 to 7.2) in CRP-responders, 14.0 months (95% CI 8.5 to 19.4) and 5.7 months (95% CI 4.1 to 8.5) in CRP flare-responders and 8.1 months (95% CI 5.8 to 9.9) and 2.3 months (95% CI 2.2 to 2.8) in CRP non-responders (log-rank p for PFS and OS<0.001). These findings prevailed in multivariable analysis and could be fully confirmed in our validation cohort. Pooled subgroup analysis suggested a consistent predictive significance of early CRP kinetics for treatment efficacy and outcome independent of cancer type. CONCLUSION: Early CRP kinetics represent a tumor-agnostic predictor for treatment response, progression risk and mortality in patients with cancer undergoing ICI therapy.

The AST/ALT Ratio Is an Independent Prognostic Marker for Disease-free Survival in Stage II and III Colorectal Carcinoma.

BACKGROUND/AIM: The Aspartate aminotransaminase/Alanine aminotransaminase ratio (AST/ALT ratio) has been identified as a prognostic marker for several malignancies. In this study, we evaluated the prognostic value of the AST/ALT ratio in a large cohort of non-metastatic colorectal cancer patients (CRC). PATIENTS AND METHODS: A total of 536 patients with stage II and III CRC, as well as available AST/ALT ratio were included in this single-center retrospective analysis. Laboratory data were measured within two weeks before histological tumor diagnosis. Co-Primary endpoints for this analysis were disease-free survival (DFS) and overall survival (OS). RESULTS: In univariate cox regression DFS was significantly shorter in patients with an elevated AST/ALT ratio (HR=1.568, 95%CI=1.10-2.23, p=0.012). In multivariable analysis, the prognostic association between an elevated AST/ALT ratio and a poor survival prevailed statistically significant (HR=1.53, 95%C=1.05-2.22, p=0.026). No statistically significant association between the AST/ALT ratio and OS was observed (HR=1.4, 95% CI=0.89-2.22, p=0.14). CONCLUSION: In this study, the serum AST/ALT ratio emerged as a valid prognostic marker for DFS in non-metastatic colorectal cancer patients at stage II and III.

External validation of the prognostic relevance of the advanced lung cancer inflammation index (ALI) in pancreatic cancer patients.

BACKGROUND: The advanced lung cancer inflammation index (ALI) was first introduced for prognosis prediction in lung cancer patients and since then evaluated in several other malignancies. However, in pancreatic cancer (PC) the ALI and its prognostic utility were only investigated in a comparably small and specific cohort of locally advanced PC patients treated with chemoradiotherapy. METHODS: In our single-center cohort study, we included 429 patients with histologically verified PC who were treated between 2003 and 2015 at our academic institution. The ALI was defined as body mass index (BMI; kg/m2 ) × serum albumin levels (g/dL)/neutrophil-lymphocyte ratio (NLR) and we defined the optimal cutoff for biomarker dichotomization by ROC-analysis. Kaplan-Meier method as well as uni- and multivariate Cox regression Hazard proportional models were implemented to assess the prognostic potential of ALI in PC patients. We considered cancer-specific survival (CSS) as the primary endpoint of the study. RESULTS: The ALI showed a significant negative correlation with CA19-9 levels and C-reactive protein levels whereas we found an association with localized tumor stage and better performance status (P < .05 for all mentioned variables). As opposed to patients with a high ALI, decreased ALI was significantly associated with shorter CSS (HR = 0.606, 95% CI: 0.471-0.779, P = .001). Multivariate analysis demonstrated tumor grade, tumor stage, chemotherapy, C-reactive protein levels, and CA19-9 levels to independently predict for CSS (all P < .05). In contrast the ALI failed to independently predict for CSS in the performed multivariate models (HR = 0.878, 95% CI: 0.643-1.198, P = .411). CONCLUSION: In this large cohort of PC patients, the ALI did not complement existing clinicopathological factors for outcome determination.

Decreased Activity of Circulating Butyrylcholinesterase in Blood Is an Independent Prognostic Marker in Pancreatic Cancer Patients.

Introduction: The activity of butyrylcholinesterase (BChE) in blood reflects liver function and has recently been associated with systemic inflammatory response and tumor cachexia. As these conditions have been previously linked with pancreatic cancer (PC), the purpose of the present study was to evaluate the prognostic impact of plasma BChE in PC. Methods: Data from 574 consecutive PC patients, treated between 2004 and 2018 at a single academic center, was evaluated. The primary endpoint was cancer-specific survival (CSS), analyzed by Kaplan-Meier curve, and both univariate and multivariate Cox proportional models. Results: BChE activity negatively correlated with other liver parameters (bilirubin, gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and C-reactive protein (CRP)), and positively correlated with albumin levels, respectively (p < 0.01). In univariate analysis, a low plasma BChE activity was a factor of poor CSS (hazard ratio: 1.4, 95% confidence interval: 1.129-1.754, p = 0.002). In multivariate analysis, tumor stage, tumor grade, administration of chemotherapy, bilirubin levels and a low BChE activity (hazard ratio: 1.42, 95% confidence interval: 1.10-1.82; p = 0.006) were identified as independent prognostic factors. Conclusion: Decreased activity of BChE in blood plasma predicts shorter survival time in PC patients. Therefore, BChE might be helpful in additional stratification of patients into different prognostic risk groups.

The AST/ALT (De Ritis) ratio predicts clinical outcome in patients with pancreatic cancer treated with first-line nab-paclitaxel and gemcitabine: post hoc analysis of an Austrian multicenter, noninterventional study.

BACKGROUND: The pretreatment De Ritis ratio [aspartate transaminase (AST)/alanine transaminase (ALT)] has been shown to be an adverse prognostic marker in various cancer entities. However, its relevance to advanced pancreatic ductal adenocarcinoma (PDAC) has not yet been studied. In the present study we investigated the AST/ALT ratio as a possible predictor of treatment response and disease outcome in patients with advanced PDAC treated with first-line gemcitabine/nab-paclitaxel. METHODS: A post hoc analysis of a prospective, multicenter, noninterventional study was performed. A total of 202 patients with advanced PDAC treated with first-line gemcitabine/nab-paclitaxel for whom the AST/ALT ratio was measured were included in this analysis. RESULTS: Median and 1-year progression-free survival estimates were 4.8 months and 5.1%, respectively in patients with an AST/ALT ratio above the 75th percentile of its distribution, and 6.0 months and 18.7%, respectively in patients with an AST/ALT ratio less than or equal to this cutoff, respectively (log-rank p = 0.004). In univariable Cox regression, a doubling of the AST/ALT ratio was associated with a 1.4-fold higher relative risk of progression or death [hazard ratio = 1.38, 95% confidence interval (CI): 1.06-1.80, p = 0.017]. The prognostic association was also found in multivariable analysis adjusting for Eastern Cooperative Oncology Group performance status and lung metastases (hazard ratio per AST/ALT ratio doubling = 1.32, 95% CI: 1.00-1.75, p = 0.047). In treatment response analysis, a doubling of the AST/ALT ratio was associated with a 0.5-fold lower odds of objective response (odds ratio = 0.54, 95% CI: 0.31-0.94, p = 0.020). CONCLUSIONS: The pretreatment serum AST/ALT ratio predicts poor disease outcome and response rate in patients with advanced PDAC treated with gemcitabine/nab-paclitaxel and might represent a novel and inexpensive marker for individual risk assessment in the treatment of pancreatic cancer.

Deoxytrifluoromethylthiolation and Selenylation of Alcohols by Using Benzothiazolium Reagents.

Aliphatic compounds substituted with medicinally important trifluoromethylthio (SCF3 ) and trifluoromethylselenyl (SeCF3 ) groups were synthesized directly from alcohols by using the new benzothiazolium salts BT-SCF3 and BT-SeCF3 . These bench-stable fluorine-containing reagents are facile to use and can be prepared in two steps from non-fluorinated heteroaromatic starting materials. The metal-free deoxytrifluoromethylthiolation process using BT-SCF3 proceeds under mild conditions and the similarly efficient trifluoromethylselenylation reactions using BT-SeCF3 are, to the best of our knowledge, the first reported examples of this transformation.

Inflammatory biomarkers in metastatic colorectal cancer: prognostic and predictive role beyond the first line setting.

INTRODUCTION: Inflammatory biomarkers are useful prognostic tools in cancer patients. However, the prognostic and predictive value of inflammatory biomarkers beyond the 1st-line setting in metastatic colorectal cancer (mCRC) is unclear. RESULTS: In multivariate analysis 1 standard deviation increase in neutrophil-lymphocyte-ratio (NLR) was associated with an 8.5% absolute lower objective-response-rate (ORR) in 1st-line (p<0.0001), 3% lower ORR in 2nd-line (p< 0.0001), and 3% lower ORR in 3rd-line (p=0.24), respectively. Regarding progression free survival (PFS), an increase in the NLR was significantly associated with rising hazard-ratios (HR) over all treatment lines (HR=1.30, p= 0.021 1st-line); (HR=1.37, p<0.0001 2nd-line); (HR=1.44, p=0.042 3rd-line). The platelet-lymphocyte-ratio (PLR) was associated with 6-month PFS over all three treatment lines. Higher C-reactive-protein (CRP) predicted for worse PFS in the first two chemotherapy lines and in best supportive care (BSC). (HR=1.49 (p<0.0001 1st-line); HR=1.25 (p=0.007 2nd-line); HR=1.09 (95%CI 0.81-1.48, p=0.552 3rd-line and HR=1.43 (p= 0.002 in BSC)). METHODS: Two-hundred-fifty-eight patients with mCRC undergoing palliative chemo(immuno-)therapy were retrospectively included. Primary endpoints were 6-month PFS and ORR during 1st-line, 2nd-line, and 3rd-line treatment, and 6-month overall survival during BSC. CONCLUSION: This study shows that inflammatory biomarkers are useful predictors of disease outcome and treatment response over several treatment lines in mCRC patients.

Effectiveness of dentifrices with new formulations for the treatment of dentin hypersensitivity - A meta-analysis.

PURPOSE: This meta-analysis was conducted to evaluate if strontium-acetate- and arginine-containing dentifrices can significantly reduce dentin hypersensitivity (DH). METHODS: A systematic literature search was performed. The investigation period was from 2006 to 2015 with the search term "dentin hypersensitivity". Nine original articles were relevant. A network meta-analysis of combined z scores was performed. Pooled results from random effects models with their 95% confidence intervals are reported. RESULTS: The results from the random effects network meta-analysis show a significant improvement for the agents strontium acetate, arginine, and arginine with whitener, at all times for all stimuli, in comparison with the placebo. Strontium chloride is equivalent to the placebo. None of the dentifrices had a negative effect on DH. This meta-analysis showed that strontium-acetate- and arginine-containing dentifrices can significantly reduce DH. Calcium sodium silicate and potassium nitrate formulas show a tendency for pain relief. Because of the limited power of the available studies, a randomized study with several agents is recommended. CLINICAL SIGNIFICANCE: The aim of the treatment of dentin hypersensitivity (DH) is pain relief. Dentifrices with formulations of strontium acetate, of arginine or of arginine with whitener seem to have a good impact in the therapy of DH and can be recommended for daily use.

Patterns of venous thromboembolism risk in patients with localized colorectal cancer undergoing adjuvant chemotherapy or active surveillance: an observational cohort study.

BACKGROUND: Venous thromoboembolism (VTE) is a frequent and burdensome complication of metastatic colorectal cancer (CRC). However, the epidemiology of VTE in patients with localized CRC after surgery in curative intent is incompletely understood. In this single-center observational cohort study, we investigate patterns of VTE risk in localized CRC, and define its relationship with baseline risk factors, adjuvant chemotherapy and CRC recurrence. METHODS: Five-hundred-sixteen patients with stage II/III CRC were included retrospectively at the time of surgery, and followed until the occurrence of VTE, CRC recurrence, or death (median age = 65.1 years, stage II and III: n = 151 (29.5%), n = 361 (70.5%); adjCTX: n = 339 (65.7%)). RESULTS: During a median follow-up of 2.7 years, 15 VTEs (2.7%) and 116 recurrences (22.5%) occurred, and 46 patients (8.9%) died. Six-month, 1-year, and 5-year VTE risks were 1.6%, 2.0% and 3.2%, respectively. In competing risk time-to-VTE regression, adjCTX was not associated with an increased risk of VTE (Subdistribution hazard ratio = 0.98, 95% CI:0.33-2.88, p = 0.97). The occurrence of disease recurrence strongly increased the risk of VTE (Multi-state model: Transition hazard ratio (THR) = 13.03, 95% CI:4.39-38.74, p < 0.0001)). Conversely, the onset of VTE did not predict for recurrence (THR = 1.95, 95% CI: 0.62-6.16, p = 0.25). CONCLUSION: VTE risk is very low in localized CRC and does not appear to be increased by adjuvant chemotherapy. Thus, primary thromboprophylaxis is unlikely to result in clinical benefit in this population. The strongest determinant of VTE risk appears to be disease recurrence.

GAP promoter-based fed-batch production of highly bioactive core streptavidin by Pichia pastoris.

Streptavidin is a homotetrameric protein binding the vitamin biotin and peptide analogues with an extremely high affinity, which leads to a large variety of applications. The biotin-auxotrophic yeast Pichia pastoris has recently been identified as a suitable host for the expression of the streptavidin gene, allowing both high product concentrations and productivities. However, so far only methanol-based expression systems have been applied, bringing about increased oxygen demand, strong heat evolution and high requirements for process safety, causing increased cost. Moreover, common methanol-based processes lead to large proportions of biotin-blocked binding sites of streptavidin due to biotin-supplemented media. Targeting these problems, this paper provides strategies for the methanol-free production of highly bioactive core streptavidin by P. pastoris under control of the constitutive GAP promoter. Complex were superior to synthetic production media regarding the proportion of biotin-blocked streptavidin. The optimized, easily scalable fed-batch process led to a tetrameric product concentration of up to 4.16 ± 0.11 µM of biotin-free streptavidin and a productivity of 57.8 nM h(-1) based on constant glucose feeding and a successive shift of temperature and pH throughout the cultivation, surpassing the concentration in un-optimized conditions by a factor of 3.4. Parameter estimation indicates that the optimized conditions caused a strongly increased accumulation of product at diminishing specific growth rates (µ ≈ D < 0.01 h(-1) ), supporting the strategy of feeding. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:855-864, 2016.

Reduction in Radiation Exposure through a Stress Test Algorithm in an Emergency Department Observation Unit.

INTRODUCTION: Clinicians are urged to decrease radiation exposure from unnecessary medical procedures. Many emergency department (ED) patients placed in an observation unit (EDOU) do not require chest pain evaluation with a nuclear stress test (NucST). We sought to implement a simple ST algorithm that favors non-nuclear stress test (Non-NucST) options to evaluate the effect of the algorithm on the proportion of patients exposed to radiation by comparing use of NucST versus Non-NucST pre- and post-algorithm. METHODS: An ST algorithm was introduced favoring Non-NucST and limiting NucST to a subset of EDOU patients in October 2008. We analyzed aggregate data before (Jan-Sept 2008, period 1) and after (Jan-Sept 2009 and Jan-Sept 2010, periods 2 and 3 respectively) algorithm introduction. A random sample of 240 EDOU patients from each period was used to compare 30-day major adverse cardiac events (MACE). We calculated confidence intervals for proportions or the difference between two proportions. RESULTS: A total of 5,047 STs were performed from Jan-Sept 2008-2010. NucST in the EDOU decreased after algorithm introduction from period 1 to 2 (40.7%, 95% CI [38.3-43.1] vs. 22.1%, 95% CI [20.1-24.1]), and remained at 22.1%, 95% CI [20.3-24.0] in period 3. There was no difference in 30-day MACE rates before and after algorithm use (0.1% for period 1 and 3, 0% for period 2). CONCLUSION: Use of a simple ST algorithm that favors non-NucST options decreases the proportion of EDOU chest pain patients exposed to radiation exposure from ST almost 50% by limiting NucST to a subset of patients, without a change in 30-day MACE.

Constitutive production and efficient secretion of soluble full-length streptavidin by an Escherichia coli 'leaky mutant'.

Due to its various applications the protein streptavidin is a highly interesting target for heterologous production. This study focuses on different Escherichia coli-based constructs targeting a high-level expression and secretion of streptavidin to the medium. The effect of various promoters, variants of the target gene, leader sequences and host strains on expression and secretion into the culture broth was analyzed. Constitutive production of full-length streptavidin fused with the leader sequence of the bglA gene from Bacillus amyloliquefaciens by the periplasmic 'leaky mutant' E. coli JW1667-5 (Δlpp-752:kan) at 30°C generated the highest yield of the conditions tested, surpassing the extracellular concentration of a conventional T7-based expression system. Supplementation of the medium by the non-ionic surfactants Triton(®) X-100 and X-45 led to an improved secretion of the protein to the culture supernatant. Tetrameric concentrations of streptavidin of 2790±166nM were reached in shake flasks at a productivity of 49.6nMh(-1). Optimization of conditions led to a successful transfer to the bioreactor, yielding a maximal concentration of 2608±169nM and a productivity of 65.2nMh(-1) in fed-batch operation. The proportion of biotin-blocked binding sites of 8.3±4.3% indicated a highly bioactive product.

Drivers for the renaissance of coal.

Coal was central to the industrial revolution, but in the 20th century it increasingly was superseded by oil and gas. However, in recent years coal again has become the predominant source of global carbon emissions. We show that this trend of rapidly increasing coal-based emissions is not restricted to a few individual countries such as China. Rather, we are witnessing a global renaissance of coal majorly driven by poor, fast-growing countries that increasingly rely on coal to satisfy their growing energy demand. The low price of coal relative to gas and oil has played an important role in accelerating coal consumption since the end of the 1990s. In this article, we show that in the increasingly integrated global coal market the availability of a domestic coal resource does not have a statistically significant impact on the use of coal and related emissions. These findings have important implications for climate change mitigation: If future economic growth of poor countries is fueled mainly by coal, ambitious mitigation targets very likely will become infeasible. Building new coal power plant capacities will lead to lock-in effects for the next few decades. If that lock-in is to be avoided, international climate policy must find ways to offer viable alternatives to coal for developing countries.

The prevalence of tooth hypersensitivity following periodontal therapy with special reference to root scaling. A systematic review of the literature.

PURPOSE: To provide a current status of the art, answering the question whether a certain procedure of periodontal treatment is more reliable than another and where innovative developments could improve on the incidence of hypersensitivity by a systematic literature review. METHODS: Pubmed, Embase and Cochrane library were considered for the study. 2,656 articles of the PubMed search were found, from the beginning of 1945 until April 2011. 99 articles from PubMed were evaluated for this review. From Embase, 60 articles were selected and one was included in this review. From the Cochrane library, 182 were found, of which two contributed to the review. Included were all studies dealing with periodontal treatment followed by hypersensitivity and all studies dealing with the loss of attachment, followed by hypersensitivity. Excluded were any treatments of tooth hypersensitivity with pathogenesis not related to dentin exposure, genetically caused disorders, and fractures. Ultimately, 102 papers were evaluated, included and referred to in the review. RESULTS: The term "tooth hypersensitivity" is most often used. Common causes of loss of hard substance are listed and updated. Mechanical loss of hard tissue formed one group of etiological factors; gingival recession and loss of attachment another. Surgical interventions, scaling and root planing were considered and in most cases performed as combined procedures. The different methods were evaluated and critically discussed. There were no properly randomized studies in the literature. The weak point of all epidemiological studies is the lack of any objective measurement. With respect to periodontal therapy, further research and developmental work on medical devices is needed, as well as ongoing applied research with laser technologies, continuing education and training programs for professionals.

Deep level transient spectroscopy (DLTS) on colloidal-synthesized nanocrystal solids.

We demonstrate current-based, deep level transient spectroscopy (DLTS) on semiconductor nanocrystal solids to obtain quantitative information on deep-lying trap states, which play an important role in the electronic transport properties of these novel solids and impact optoelectronic device performance. Here, we apply this purely electrical measurement to an ethanedithiol-treated, PbS nanocrystal solid and find a deep trap with an activation energy of 0.40 eV and a density of NT = 1.7 × 10(17) cm(-3). We use these findings to draw and interpret band structure models to gain insight into charge transport in PbS nanocrystal solids and the operation of PbS nanocrystal-based solar cells.

Development of fed-batch strategies for the production of streptavidin by Streptomyces avidinii based on power input and oxygen supply studies.

Streptavidin is a tetrameric protein with an extremely high affinity to biotin and different biotin-like peptide-tags. This characteristic causes its widespread use in biotechnology. Streptavidin is produced by the fermentation of wild type Streptomyces avidinii or by recombinant Streptomyces lavendulae, Escherichia coli, and Bacillus subtilis strains. However, little is known about the influence of power input and oxygen supply as well as feeding strategies on the production of streptavidin by S. avidinii. This paper provides a systematic analysis of the effect of rotary frequency of the stirrer, leading to a plateau-like streptavidin formation behaviour between 400 and 700 min(-1). This plateau was characterized by specific power inputs between 79 and 107 W L(-1) and corresponding maximal product concentrations of 6.90 µM in 6 days. Lower as well as higher rotary frequencies were not beneficial. Subsequently, a linear fed-batch procedure could be established reproducibly yielding 39.20 µM streptavidin in 14 days, characterized by a constant productivity of 114 nM h(-1). Fed-batch procedures based on dissolved oxygen were less efficient. The linear feeding strategy presented in this paper led to the highest streptavidin concentration ever reported and exceeded the maximal product level given in the literature drastically by a factor of 8.5.

Multimodal early rehabilitation and predictors of outcome in survivors of severe traumatic brain injury.

BACKGROUND: To determine the effect of brain lesion pattern on early recovery after severe traumatic brain injury (TBI). METHODS: In a setting of a multimodal early rehabilitation unit at a level I trauma center, 135 consecutive survivors of severe TBI (mean age, 40 years, 25% women) were studied prospectively. Assessment of disability was performed weekly using an extended Barthel Index (eBI) ranging from -325 to +100 points. Clinical and brain morphologic variables were tested in multivariate logistic regression models to determine predictors of outcome. RESULTS: Imaging revealed cerebral contusion in 115 patients (85%) affecting the frontal (n = 80), temporal (n = 62), parieto-occipital (n = 17), brain stem (n = 13), and cerebellar (n = 5) regions. In addition, 80 patients (59%) showed diffuse brain edema, 75 (55%) subarachnoid, 37 (28%) subdural, and 18 (13%) epidural hemorrhage. After a mean stay of 72 +/- 51 days in the early rehabilitation unit, one patient died, 40 (30%) revealed good outcome (median eBI, +55), and a further 43 patients (32%) showed excellent outcomes (eBI, 90-100). Temporal (odds ratio 2.6; 95% confidence interval 1.1-6.5) and brain stem contusions (odds ratio 13.8; 95% confidence interval 3.0-64.1) were independent predictors of poor outcome. CONCLUSIONS: Temporal and brain stem contusions constitute independent risk factors for poor outcome in survivors of severe TBI. The results further suggest a high potential for multimodal early rehabilitation after severe TBI.