Pretreatment Screening Research Articles

Expression and significance of long non-coding RNA metastasis associated in lung denocarcinoma transcript 1 in the process of hyperoxia-induced lung injury in preterm infants

Objective To explore the protective effect of long non-coding RNA (lncRNA) metastasis associated in lung denocarcinoma transcript 1 (MALAT1) involved in hyperoxia-induced lung injury in preterm infants. Methods This study had downloaded chip data set GSE25286 (Mouse GEO Genome 430 2.0 Array) from gene expression database gene expression omnibus (GEO), according to the state of hyperoxia exposure, the MALAT1 mRNA expression in rats normal lung tissues and hyperoxic lung tissues was compared at day 14th and 29th.In chip data set GSE43830(Human Exon 1.0 ST Arrays) from GEO, the expression of multiple genes[cell division cycle 6(CDC6), death effector domain containing 2(DEDD2), and Cyclin B1(CCNB1)] in WI38 cells (lung fibroblasts) was compared before and after MALAT1 was knockout.At the same time, the peripheral blood samples of premature infants were collected to verify.Totally 40 premature infants were hospitalized in the department of neonatology in our hospital from Jan 2015 to Dec 2016, the peripheral blood samples of 40 premature infants were collected.RNA was extracted and Real time-PCR was performed after reverse transcription, clinical data of these 40 cases were retrospectively analyzed. Results (1) By using Affymetrix Expression console and Affymetrix Transcriptome analysis console software source files of the chip of pretreatment and difference expression gene screening, the expression of lncRNA MALAT1 gene in lung tissues of hyperoxia lung injury mice significantly upregulated[fold change(FC)=2.33, P=0.001]. (2) After MALAT1 in WI38 cell was knockout, MALAT1 expression was significantly reduced(FC=-15.6, P=0.000), the expression of CDC6(FC=-2.37, P=0.001) and CCNB1(FC=-2.16, P=0.002) were down regulated, DEDD2 expression was up regulated(FC=2.46, P=0.000). (3) The results of peripheral blood samples from preterm infants showed that the expression of MALAT1 was significantly increased in preterm infants with hyperoxia-induced lung injury(0.375 5±0.081 9, t=4.634, P=0.015), compared with normal preterm infants(0.273 4±0.067 3). Conclusion Through inhibiting cell apoptosis, lncRNA MALAT1 can protect preterm infants with hyperoxia-induced lung injury, it may provide a new strategy for prevention and treatment of hyperoxia-induced lung injury in premature infants. Key words: Long noncoding RNA; Neonates; Lung injury; Metastasis associated in lung denocarcinoma transcript 1; Hyperoxia

Research of moldy tea identification based on RF-RFE-Softmax model and hyperspectra

To provide consumers with high-quality and safe tea, an accurate, fast and effective method of discriminating moldy tea based on hyperspectral technology was put forward. Moldy tea with three different degrees was studied in this paper. Hyperspectral images of all samples were firstly acquired by the hyperspectral imaging system, and then the spectral data was extracted from the images. Savitzky-Golay and SNV-Detrending were respectively used to pretreat the spectral data. After that, the random forest-recursive feature elimination and the principal component analysis were adopted for feature selection and feature extraction. By combining different pretreatment and feature screening methods, the softmax model optimised by the gradient descent algorithm was established to identify the tea with different moldy degrees. Comparing the classification accuracy and cost function value of all models, the softmax model based on Savitzky-Golay and SNV-Detrending preprocessing and random forest-recursive feature elimination feature selection performed best, which achieved the identification accuracy of 100% for the training set and 98.5% for the test set. Therefore, it is feasible to identify moldy tea with different degrees by using RF-RFE-softmax model and hyperspectral technology.

Pharmacogenetics and Metabolism from Science to Implementation in Clinical Practice: The Example of Dihydropyrimidine Dehydrogenase

Fluoropyrimidines are widely used in the treatment of solid tumors and remain the backbone of many combination chemotherapy regimens. Despite their clinical benefit, they are associated with frequent gastrointestinal and hematological toxicities, which often lead to treatment discontinuation. Fluoropyrimidines undergo complex anabolic and catabolic biotransformation. Enzymes involved in this pathway include dihydropyrimidine dehydrogenase (DPD), which breaks down 5-FU and its prodrugs. Candidate gene approaches have demonstrated associations between 5-FU treatment outcomes and germline polymorphisms in DPD. The aim of this review is to report and discuss the latest results on fluoropyrimidine pharmacogenetics. Literature from PubMed databases and bibliography from retrieved publications have been analyzed according to terms such DPD, DPYD, fluoropyrimdines, polymorphisms, toxicity, pharmacogenetics. To date, many sequence variations have been identified within DPYD gene, although the majority of these have no functional consequences on enzymatic activity. Nowadays, there is a general agreement on the clinical significance of the importance of DPD deficiency in patients who suffer from severe, life-threatening drug toxicity although preemptive testing is not applied to all patients. Considering the published literature, clinicians are strongly encouraged to consider testing for DPD poor metabolizer variants as a rational pre-treatment screening for patients candidate to a fluoropyrimidine-based regimens, in order to prevent toxicities and personalise treatments.

HLA-A*24:02 as a common risk factor for antiepileptic drug-induced cutaneous adverse reactions.

Objective:To investigate the involvement of human leukocyte antigen (HLA) loci in aromatic antiepileptic drug–induced cutaneous adverse reactions.Methods:A case-control study was performed to detect HLA loci involved in aromatic antiepileptic drug–induced Stevens-Johnson syndrome in a southern Han Chinese population. Between January 1, 2006, and December 31, 2015, 91 cases of Stevens-Johnson syndrome induced by aromatic antiepileptic drugs and 322 matched drug-tolerant controls were enrolled from 8 centers. Important genotypes were replicated in cases with maculopapular eruption and in the meta-analyses of data from other populations. Sequence-based typing determined the HLA-A, HLA-B, HLA-C, and HLA-DRB1 genotypes.Results:HLA-B*15:02 was confirmed as strongly associated with carbamazepine-induced Stevens-Johnson syndrome (p = 5.63 × 10−15). In addition, HLA-A*24:02 was associated significantly with Stevens-Johnson syndrome induced by the aromatic antiepileptic drugs as a group (p = 1.02 × 10−5) and by individual drugs (carbamazepine p = 0.015, lamotrigine p = 0.005, phenytoin p = 0.027). Logistic regression analysis revealed a multiplicative interaction between HLA-B*15:02 and HLA-A*24:02. Positivity for HLA-A*24:02 and/or HLA-B*15:02 showed a sensitivity of 72.5% and a specificity of 69.0%. The presence of HLA-A*24:02 in cases with maculopapular exanthema was also significantly higher than in controls (p = 0.023). Meta-analysis of data from Japan, Korea, Malaysia, Mexico, Norway, and China revealed a similar association.Conclusions:HLA-A*24:02 is a common genetic risk factor for cutaneous adverse reactions induced by aromatic antiepileptic drugs in the southern Han Chinese and possibly other ethnic populations. Pretreatment screening is recommended for people in southern China.

High Prevalence of Q80K Among NS3 Resistance-Associated Substitutions in Subtype 1a Patients with Chronic Hepatitis C Prior to Treatment with Direct Acting Antivirals: The Croatian Data

Background: Therapy for chronic hepatitis C is based on direct-acting antiviral drugs (DAA) that include protease inhibitors, polymerase inhibitors, as well as inhibitors of NS5A protein. Resistance-associated substitutions (RAS) can be associated with inadequate treatment outcomes with DAA. People with HCV subtype 1a infection carrying Q80K polymorphism could have a reduced treatment response to a protease inhibitor simeprevir. The data on the prevalence of Q80K polymorphism and other RAS worldwide are quite variable. Objectives: The study goal was to analyze the frequency of Q80K polymorphism and other substitutions associated with HCV resistance to NS3 inhibitors in patients previously not treated with simeprevir infected with HCV subtype 1a from Croatia. Methods: The study included 136 people with chronic hepatitis C and infected with HCV subtype 1a receiving clinical care at the department of viral hepatitis of the University hospital for infectious diseases, Zagreb and Croatian reference center for viral hepatitis from July 2015 to April 2016. All participants were not previously treated with simeprevir and not co-infected with HIV. Detection of Q80K polymorphism and other substitutions associated with resistance to NS3 inhibitors was performed by population-based sequencing on ABI PRISM® 3100 genetic analyzer. Phylogenetic tree was constructed using the Maximum Likelihood method and supported with a bootstrap test of 1000 replicates. Geno2Pheno algorithm was used for the interpretation of sequences, detection of resistance associated substitutions and determination of the clade of the sequence. Results: The prevalence of Q80K polymorphism was observed in 42.6% of patients while resistance to simeprevir (mediated by other RAS as well) was detected in 46.3% of patients. Phylogenetic analysis of subtype 1a sequences showed the separation into 2 clades and Q80K polymorphism was exclusively present in clade I isolates. Other RAS detected in the patients included V36L, T54S, V55A, S122R, and I170T. Conclusions: In conclusion, the prevalence of Q80K polymorphism was found to be rather high in patients with chronic hepatitis C infected with clade I subtype 1a while other substitutions associated with resistance to protease inhibitors were rarely found in Croatian cohort. The results of this study confirm the need for pre-treatment screening for Q80K in subtype 1a patients considered for simeprevir treatment.

The adverse impact of surveillance intervals on the sensitivity of FDG-PET/CT for the detection of distant metastases in head and neck cancer patients

The presence of distant metastases at initial evaluation influences treatment selection, since no effective systemic treatment for disseminated head and neck squamous cell carcinoma (HNSCC) is currently available. The reported sensitivity for the detection of distant metastases by contrast-enhanced (ce)CT and FDG-PET(/CT) differs substantially between studies. We hypothesized that these sensitivity values are highly dependent on the reference standard use, e.g., follow-up term. Therefore, we analyze our results of FDG-PET/CT (including chest ceCT) with long-term follow-up and compare these findings with data from the literature, with particular interest in the different reference standards. Forty-six HNSCC patients with high-risk factors underwent pretreatment screening for distant metastases by FDG-PET/CT (including chest ceCT). In 16 (35%) patients, distant metastases were detected during screening (6 patients) or during a mean follow-up of 39.4 months after screening (10 patients). The sensitivity and negative predictive value were 83.3 and 97.2% when 6 months, 60.0 and 89.9% when 12 months, and 37.5 and 72.2% when 30 months follow-up were used as reference standard, respectively. This is comparable with reported studies with similar reference standards. This critical appraisal on the reference standards used in our and reported studies shows room for improvement for the detection of distant metastases to refrain more patients from unnecessary extensive locoregional treatment for occult metastatic HNSCC.

Hepatitis B Reactivation in Rheumatic Diseases: Screening and Prevention.

Hepatitis B virus (HBV) reactivation (HBVr) has been an increasingly recognized and appreciated risk of immunosuppressive therapies in rheumatic patients. Despite its potential for significant morbidity and mortality, HBVr is a fully preventable complication with appropriate pretreatment screening and close monitoring of susceptible patients. Better knowledge of the risk for HBVr with the different antirheumatic agents and the establishment of the new-generation oral antivirals in clinical practice has greatly improved the design of screening and therapeutic algorithms. In this review, all available data regarding HBVr in rheumatic patients are critically presented and a screening and therapeutic algorithm is proposed.

Clinical and subjective evaluation of implants in patients with hypodontia: a two-year observation study.

Hypodontia compromises appearance and function and is challenging to manage clinically. To assess the impact of implant retained crowns on quality of life of patients and to determine clinical performance of implant retained crowns in these patients. In a 24-month prospective observation study, patients with non-syndromic mild hypodontia manifested with missing teeth in the anterior maxilla were included. Pre-treatment screening included a clinical and radiographic examination and completion of an OHIP-20. Narrow neck SLActive TiZr implants (Roxolid® , Straumann AG, Switzerland) were provided and restored with single unit crowns. Implant stability was recorded at time of placement and abutment connection. Standardized radiographs were recorded at time of surgery, abutment connection and 12- and 24-month follow-up visits, and distance between implant shoulder and first bone contact was measured. Oral health-related quality of life was calculated using OHIP-20 scores at 12- and 24-month visits compared with pre-treatment scores. Pink (PES) and white (WES) aesthetic scores were used to objectively assess aesthetic outcome of treatment. Twenty implants were placed in 12 patients (seven females, five males; mean [SD] age 19.33 [2.37] years). There was a significant improvement in oral health-related quality of life following treatment (P=0.026), and the effect size of this change was 1.17 indicating a large clinically meaningful change. Mean PES and WES scores were high, indicated a satisfactory aesthetic outcome at 24months. Crestal bone-level changes were considered small. Favourable clinical outcomes were observed. Implant retained crowns had a large and clinically meaningful impact on quality of life of patients with hypodontia.

Abstract LB-186: Development and validation of a novel RNA in situ hybridization assay to detect RNA polymerase I activity in vivo

Abstract Increased ribosome biogenesis is a critical process requisite for the cancer cell phenotype as it is required to doulbe protein levels for cell replication. Ribosome synthesis is a complex process that is stimulated by a number of well-studied oncogenic pathways (MYC, mTOR, RAS-RAF-ERK) and repressed by tumor suppressors (pRb, p53, PTEN, p14/ARF). A key first step in ribosome biogenesis is the increased synthesis by RNA Polymerase I (Pol I) of the precursor rRNA, referred to as 45S rRNA, that is later processed into the 28S, 5.8S and 18S mature rRNA forms. This process is compartmentalized into the nucleolus. As such, the pharmacological inhibition of RNA Pol I is becoming a potentially important therapeutic strategy in cancer (PMIDs 20055700, 23953479, 24434211). A validated assay that can reflect relative levels of Pol I activity in routinely obtained tissue specimens would be a useful tool. For example it would allow the pretreatment screening (as a predictive biomarker) for those tumors likely to respond to Pol I inhibition, and, could also serve as a pharmacodynamic biomarker of Pol I inhibition. The 5’ external transcribed spacer (5’ETS) of the nascent precursor 45S transcript is rapidly removed and degraded; thus, its levels can be used as a surrogate for new rRNA transcription. We employed branched DNA amplified RNA in situ hybridization using probes developed with Advanced Cellular Diagnostics (ACD RNAscope 2.0). The 5’ ETS/45S CISH signal was restricted to nucleoli. The signal was markedly attenuated in cell lines and in formalin fixed paraffin embedded (FFPE) prostate tissue slices after pharmacological inhibition of RNA Pol I using BMH-21 or actinomycin D, demonstrating validity as a measure of RNA Pol I transcriptional activity. In clinical human prostate FFPE tissue sections and TMAs there was a marked increase in the signal in the presumptive precursor lesion (high grade prostatic intraepithelial neoplasia/HGPIN, n = 25) and in invasive adenocarcinoma lesions (n = 72, Kruskal-Wallis, p = 0.0001 and p = 0.0001, respectively) compared with normal luminal epithelium. These results are consistent with prior work using RT-PCR showing an increase in 5’ ETS/45S rRNA levels in prostate cancer tissues. In adenocarcinomas, the increase in 5’ ETS/45S signal was present throughout all Gleason scores and pathological stages at radical prostatectomy, with no marked difference among these. We developed and analytically validated a chromogenic in situ hybridization (CISH) protocol using RNAscope for detecting the 5’ external transcribed spacer (ETS) of the precursor 45S ribosomal RNA in FFPE human tissues. This novel assay was used to show increased rRNA transcription in human clinical samples of PIN and carcinoma, and should prove useful for detection of increased rRNA production in various tumor types and as a novel pharmacodynamic biomarker in clinical trials of RNA Pol I inhibitors. Citation Format: Gunes Guner, Paul Sirajuddin, Qizhi Zheng, Hester Liu, Ibrahim Kulac, Marikki K. Laiho, Angelo M. De Marzo. Development and validation of a novel RNA in situ hybridization assay to detect RNA polymerase I activity in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-186.

Cardiac monitoring of high-dose verapamil in cluster headache: An international Delphi study.

In many patients, high-dose verapamil (HDV) is the only effective prophylactic treatment for cluster headache. Although cardiac adverse events and EKG abnormalities are relatively common, evidence-based guidelines for screening and monitoring patients on HDV are lacking. Using the Delphi approach, we interviewed 22 international clinical experts in cardiac rhythm disorders to formulate EKG guidelines for the pretreatment screening and monitoring of cluster headache patients using HDV. The panel agreed only on performing pretreatment EKG to screen for pre-existing cardiac arrhythmia. Pretreatment EKG was deemed not necessary by most panel members for patients who did not have cardiac adverse events during a previous period of cluster headache attacks treated with HDV. Half the panel advised Holter EKG for patients on verapamil ≥ 480 mg/day. The highest recommended daily doses varied between 240 and 960 mg. Contraindications for use of verapamil largely followed FDA guidelines. Experts in cardiac rhythm disorders agreed on pretreatment EKG monitoring, but no consensus was reached on EKG monitoring during HDV treatment and around dose adjustments.

Incidence and risk factors of synchronous colorectal cancer in patients with esophageal cancer: an analysis of 480 consecutive colonoscopies before surgery.

The precise incidence rates of multiple primary colorectal cancers in esophageal cancer patients are unknown. In total, 480 consecutive patients with esophageal cancers surgically resected in the Kumamoto University Hospital received preoperative total colonoscopy for the assessment of colorectal disease between April 2005 and February 2016. We retrospectively investigated the occurrence of synchronous colorectal cancer with esophageal cancer. In addition, we examined the risk factors for the incidence of multiple primary colorectal cancers. Of the 480 patients, 14 (2.9%) had synchronous colorectal cancers, 13 had well-differentiated tubular adenocarcinomas, and 1 had papillary adenocarcinoma. Other 14 patients had metachronous colorectal cancer. The current incidence rates of synchronous and total (both synchronous and metachronous) colorectal cancers outnumbered those in normal healthy population and those in esophageal cancer patients which previously reported by The Japan Esophageal Society. The age≥70years (hazard ratio 4.82, 95% confidence interval 1.473-15.78; p=0.009) and Brinkman index≥800 (hazard ratio 3.47, 95% confidence interval 1.056-11.37; p=0.040) were the independent risk factors for the incidence of synchronous colorectal cancer. They were also the independent risk factors for the incidence of total colorectal cancer. The results of the present study suggested that pretreatment screening with total colonoscopy is meaningful for patients with esophageal cancer, because the frequency of synchronous colorectal cancer was not negligible. Particularly, in patients>70years and with history of heavy smoking, pretreatment colonoscopy might be necessary.

Abstract A11: NGS-based tumor genomic profiling to identify ovarian cancer patients who benefit from the PARP inhibitor rucaparib.

Abstract Background: PARP inhibitors (PARPi) are synthetically lethal to tumor cells with homologous recombination deficiency (HRD). HRD can result from deleterious BRCA1/2 mutations (BRCAmut) or other mechanisms that have not been fully elucidated. Regardless of mechanism, HRD leads to a common phenotype of genome-wide loss of heterozygosity (LOH). It has been hypothesized that this genomic phenotype can be used to identify BRCA wild-type (BRCAwt) HRD tumors likely sensitive to PARPi. Using comprehensive next generation sequencing (NGS)-based tumor genomic profiling, we developed an HRD assay for potential use as a companion diagnostic for rucaparib in high-grade ovarian cancer (HGOC) by combining tumor BRCA1/2 status and quantification of genomic LOH. Methods: In the phase 2 study ARIEL2 Part 1 (NCT01891344), pre-treatment screening biopsies and archival formalin-fixed paraffin embedded tumor specimens were profiled using Foundation Medicine's NGS-based HRD assay, which detects all classes of genomic alterations, including base substitutions, insertions/deletions, and homozygous deletions in BRCA1/2. Genomic LOH was assessed by sequencing >3,500 evenly-distributed single nucleotide polymorphisms across the genome and quantifying the extent of genomic LOH. A pre-specified genomic LOH cutoff was determined using publicly available SNP array data of ovarian tumors to predict platinum sensitivity as a surrogate marker for PARPi sensitivity. Response was assessed by RECIST v1.1 and GCIG CA-125 response criteria. Results: As of July 1 2015, 195 archival tumor and 152 screening biopsy samples (142 matched pairs) from 206 HGOC patients enrolled (204 patients treated) in ARIEL2 Part 1 were successfully profiled using the NGS-based HRD assay. Some screening biopsies were not suitable for successful NGS-based HRD assessment primarily because of insufficient tumor nuclei or inadequate tumor volume. Most matched pairs of archival and pre-trial screening samples exhibited similar genomic LOH profiles (r=0.86); however, 14% of screening samples had higher genomic LOH compared with archival samples collected more than one year earlier. All BRCA1/2 germline and somatic mutated tumors had high genomic LOH in the screening samples. Receiver operating characteristic analysis of genomic LOH showed utility in identifying RECIST/CA-125 responders to rucaparib (AUC=0.72, p<1e-4), with slightly better predictive utility using screening samples compared to archival samples (AUC=0.72 vs 0.69). Using the pre-specified genomic LOH cutoff, high genomic LOH tumors were detected in 54% of evaluable BRCAwt patients; significantly different overall response rates were found in patients with high vs low genomic LOH tumors (48% vs 26%; chi-square p=0.0074). Conclusions: We developed an NGS-based HRD assay that assesses tumor BRCA1/2 and genomic LOH to prospectively identify HGOC patients who may benefit from rucaparib treatment. The optimized NGS-based HRD assay will be prospectively tested in the ongoing portion of the phase 2 study (ARIEL2 Part 2, NCT01891344) and a phase 3 maintenance study (ARIEL3, NCT01968213) that will investigate rucaparib in HGOC. Citation Format: Iain A. McNeish, Kevin K. Lin, James X. Sun, Sandra Goble, Amit Oza, Robert L. Coleman, Clare L. Scott, Gottfried Konecny, Anna V. Tinker, David M. O'Malley, Rebecca Kristeleit, Ling Ma, James D. Brenton, Katherine Bell-McGuinn, Ana Oaknin, Alexandra Leary, Elaina Mann, Heidi Giordano, Roman Yelensky, Mitch Raponi, Elizabeth Swisher. NGS-based tumor genomic profiling to identify ovarian cancer patients who benefit from the PARP inhibitor rucaparib. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A11.

Pretreatment screening for distant metastases in the Dutch head and neck centers: 10 years later

To evaluate the current practice and change in practice concerning screening for distant metastases in head and neck squamous cell carcinoma patients, we performed a survey with the same questionnaire as 10 years ago among the eight centers of the Dutch Head and Neck Society treating head and neck cancer in The Netherlands. Factors related to extensive lymph node metastases are the most frequent indication for screening for distant metastases. The combinations of whole body PET-CT and contrast-enhanced chest CT are nowadays the diagnostic techniques for routinely screening for distant metastases. Screening for distant metastases is performed more frequently than 10 years ago. Although the sensitivity of the diagnostic pathway needs to be improved, most centers are satisfied with the current diagnostic pathway. A reduction of variation in indications and diagnostic techniques used for screening for distant metastases is observed during the last 10 years. In future guidelines patients’ selection and diagnostic tests need to be specified in more detail.

The status of industrial and municipal effluent treatment with membrane bioreactor technology

The status of MBR technology has been scrutinised with reference to (a) available commercial technologies and their characteristics, (b) key design and performance parameters of existing full-scale installations, and (c) practitioner perception. The key design and operating parameters of flux and COD removal were considered with reference to 100 installations, 40 based on municipal and 60 on industrial wastewater treatment. The perception of practitioners was appraised through a conventional survey, with 186 respondents.A review of the commercial products revealed polyvinylidene difluoride (PVDF) to be the most prevalent membrane material, accounting for almost half of all products, and provided both in flat sheet (FS) and hollow fibre (HF) configurations. Polyethylsulphone (PES) and polyolefinic membranes (polyethylene, PE and polypropylene, PP) were also found to be available in FS and HF configurations respectively. Almost all products had a nominal membrane pore size between 0.03 and 0.4μm.Design fluxes in Lm−2h−1 (LMH) for municipal wastewater treatment were predominantly in the 15–25LMH range, 18.5±4.8LMH on average, for the average daily flow (ADF), and in the 20–30LMH range, 26.0±6.6LMH on average, for peak daily flow (PDF). Fluxes were lower, and dependent on both process configuration and effluent quality, for industrial effluents; the most challenging effluents (landfill leachate) were associated with the lowest fluxes. As expected, treatment capability related roughly to the feedwater BOD/COD ratio, with more than 90% COD removal achieved for food and beverage effluents (for which BOD/COD ratios were largely above 0.5) – comparable with municipal wastewater treatment.Respondents to the survey, around 85% of whom were practitioners, identified pre-treatment (screening) as presenting the greatest technical challenge to MBR operation.

Tolerability and safety of weekly primaquine against relapse of Plasmodium vivax in Cambodians with glucose-6-phosphate dehydrogenase deficiency.

BackgroundPrimaquine is used to prevent Plasmodium vivax relapse; however, it is not implemented in many malaria-endemic countries, including Cambodia, for fear of precipitating primaquine-induced acute haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase deficiency (G6PDd). Reluctance to use primaquine is reinforced by a lack of quality safety data. This study was conducted to assess the tolerability of a primaquine regimen in Cambodian severely deficient G6PD variants to ascertain whether a weekly primaquine could be given without testing for G6PDd.MethodsFrom January 2013 to January 2014, Cambodians with acute vivax malaria were treated with dihydroartemisinin/piperaquine on days (D) 0, 1 and 2 with weekly doses of primaquine 0.75 mg/kg for 8 weeks (starting on D0, last dose on D49), and followed until D56. Participants’ G6PD status was confirmed by G6PD genotype and measured G6PD activity. The primary outcome was treatment completion without primaquine toxicity defined as any one of: (1) severe anaemia (haemoglobin [Hb] <7 g/dL), (2) a >25 % fractional fall in Hb from D0, (3) the need for a blood transfusion, (4) haemoglobinuria, (5) acute kidney injury (an increase in baseline serum creatinine >50 %) or (6) methaemoglobinaemia >20 %.ResultsWe enrolled 75 patients with a median age of 24 years (range 5–63); 63 patients (84 %) were male. Eighteen patients were G6PDd (17/18 had the Viangchan variant) and had D0 G6PD activity ranging from 0.1 to 1.5 U/g Hb (median 0.85 U/g Hb). In the 57 patients with normal G6PD (G6PDn), D0 G6PD activity ranged from 6.9 to 18.5 U/g Hb (median 12 U/g Hb). Median D0 Hb concentrations were similar (P = 0.46) between G6PDd (13 g/dL, range 9.6–16) and G6PDn (13.5 g/dL, range 9–16.3) and reached a nadir on D2 in both groups: 10.8 g/dL (8.2–15.3) versus 12.4 g/dL (8.8–15.2) (P = 0.006), respectively. By D7, five G6PDd patients (27.7 %) had a >25 % fall in Hb, compared to 0 G6PDn patients (P = 0.00049). One of these G6PDd patients required a blood transfusion (D0–D5 Hb, 10.0–7.2 g/dL). No patients developed severe anaemia, haemoglobinuria, a methaemoglobin concentration >4.9 %, or acute kidney injury.ConclusionsVivax-infected G6PDd Cambodian patients demonstrated significant, mostly transient, falls in Hb and one received a blood transfusion. Weekly primaquine in G6PDd patients mandates medical supervision and pre-treatment screening for G6PD status. The feasibility of implementing a package of G6PDd testing and supervised primaquine should be explored.Trial registrationThe trial was registered on 3/1/2013 and the registration number is ACTRN12613000003774.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-015-0441-1) contains supplementary material, which is available to authorized users.

Abstract 582: Prognostic and predictive value of plasma protein signatures in a phase I/II trial of abituzumab combined with cetuximab/irinotecan in second-line KRAS wild-type metastatic colorectal cancer (mCRC)

Abstract The humanized monoclonal IgG2 antibody abituzumab (EMD 525797, DI17E6) inhibits αν integrin heterodimers. The phase I/II POSEIDON trial (NCT01008475) demonstrated a trend toward improved overall survival (OS) in codon 2 KRAS wild-type mCRC. Integrin ανβ6 expression (immunohistochemistry based) above median identified a poor prognosis patient (pt) subgroup and was predictive of improved OS. Previous exploratory analysis identified individual plasma proteins as negatively prognostic and predictive for OS with abituzumab treatment. We report here the results of exploratory bioinformatic analyses aimed at identifying prognostic or predictive pretreatment plasma protein signatures. Plasma proteins were analyzed (highly protein-specific aptamers [SomaLogic system]) in samples taken at pretreatment screening. Analyses focused on 888 proteins that passed quality control. Groups of genes, termed signatures, with common function or regulation captured in the MSigDB database formed the basis for our analyses. We identified a set of signatures comprising genes with coherent expression patterns that we analyzed for the association of their scores with OS in the treatment arms. Cox models were analyzed per signature to assess the association of continuous and median-thresholded signature scores with OS in the standard of care (SoC) arm to identify prognostic markers, in the biomarker high/low groups, or across all patients to identify predictive markers. Pretreatment plasma samples from 192/216 pts (122 samples from pts treated with abituzumab; 70 from pts treated with SoC alone) with full SomaLogic data were available for analysis of protein levels and signature scores. Sixty-two signatures comprised genes with coherent expression patterns across samples. Among these, we identified a poor-prognosis signature comprising five proteins expressed in neutrophils (CD48, MPO, ELANE, CTSG, PECAM1; HR = 3.28 [1.72-6.28]; uncorrected p = 0.0003; Bonferroni-corrected p = 0.02). Other signatures predicted benefit from abituzumab when scores were higher (or lower) than median, but were not prognostic in the SoC arm. These signatures yielded HRs of 0.40-0.55 and uncorrected p values &amp;lt;0.05 when OS of treated and untreated pts were compared in signature-selected populations (results did not withstand multiple testing corrections). The functional coherence of the identified prognostic signature, i.e. all proteins are expressed in neutrophils, is striking. High neutrophil protein levels identify poor prognosis pts. This signature may indicate an antitumor neutrophilic response in these pts, and may be a surrogate for tumor burden. The predictive plasma protein signatures constitute stratification hypotheses to be assessed in future exploratory biomarker analyses in abituzumab trials in mCRC. Citation Format: Josef Straub, Eike Staub, Miriam Lohr, Giorgio Massimini, Elena Élez, Josep Tabernero. Prognostic and predictive value of plasma protein signatures in a phase I/II trial of abituzumab combined with cetuximab/irinotecan in second-line KRAS wild-type metastatic colorectal cancer (mCRC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 582. doi:10.1158/1538-7445.AM2015-582

Identification of Patients With Variants in TPMT and Dose Reduction Reduces Hematologic Events During Thiopurine Treatment of Inflammatory Bowel Disease

More than 20% of patients with inflammatory bowel disease (IBD) discontinue thiopurine therapy because of severe adverse drug reactions (ADRs); leukopenia is one of the most serious ADRs. Variants in the gene encoding thiopurine S-methyltransferase (TPMT) alter its enzymatic activity, resulting in higher levels of thiopurine metabolites, which can cause leukopenia. We performed a prospective study to determine whether genotype analysis of TPMT before thiopurine treatment, and dose selection based on the results, affects the outcomes of patients with IBD. In a study performed at 30 Dutch hospitals, patients were assigned randomly to groups that received standard treatment (control) or pretreatment screening (intervention) for 3 common variants of TPMT (TPMT*2, TPMT*3A, and TPMT*3C). Patients in the intervention group found to be heterozygous carriers of a variant received 50% ofthe standard dose of thiopurine (azathioprine or 6-mercaptopurine), and patients homozygous for a variant received 0%-10% of the standard dose. We compared, in an intention-to-treat analysis, outcomes of the intervention (n=405) and control groups (n= 378) after 20 weeks of treatment. Primary outcomes were the occurrence of hematologic ADRs (leukocyte count < 3.0*10(9)/L or reduced platelet count <100*10(9)/L) and disease activity (based on the Harvey-Bradshaw Index for Crohn's disease [n= 356] or the partial Mayo score for ulcerative colitis [n= 253]). Similar proportions of patients in the intervention and control groups developed a hematologic ADR (7.4% vs 7.9%; relative risk, 0.93; 95% confidence interval, 0.57-1.52) in the 20 weeks of follow-up evaluation; the groups also had similar mean levels of disease activity (P= .18 for Crohn's disease and P= .14 for ulcerative colitis). However, a significantly smaller proportion of carriers of the TPMT variants in the intervention group (2.6%) developed hematologic ADRs compared with patients in the control group (22.9%) (relative risk, 0.11; 95% confidence interval, 0.01-0.85). Screening for variants in TPMT did not reduce the proportions of patients with hematologic ADRs during thiopurine treatment for IBD. However, there was a 10-fold reduction in hematologic ADRs among variant carriers who were identified and received a dose reduction, compared with variant carriers who did not, without differences in treatment efficacy. ClinicalTrials.gov number: NCT00521950.

18FDG SUV in the primary tumor and lymph node metastases is not predictive for development of distant metastases in high risk head and neck cancer patients

Pretreatment screening on distant metastases is particularly useful in head and neck squamous cell carcinoma (HNSCC) patients with high risk factors. In a retrospective study of 88 patients with previously identified clinical high risk factors the predictive value of standardized uptake value (SUV) of 18F-fluorodeoxyglucose (FDG) in the primary tumor and in the lymph node metastases for the development of distant metastases was examined. Different SUVs corrected for plasma glucose levels and body mass index were calculated and analysed in different patient groups: all patients (n=88), patients with a follow up >6months (n=73), not previously treated patients (n=51) and not previously treated patients with a follow up >6months (n=40). Twenty-four of the 88 (27%) high risk HNSCC patients were diagnosed with distant metastases during screening and follow up. No correlation was found between different SUVs of the primary tumor and lymph nodes metastases and the development of distant metastases. SUVs of primary tumor and lymph node on FDG-PET are not predictive for distant metastases in a (selected) group of patients with already high risk factors for distant metastases.

Pretreatment Screening for Hepatitis B Virus Infection in Patients with Systemic Lupus Erythematosus.

Hepatitis B virus (HBV) infection is one of the most common diseases, and approximately two billion people are infected with HBV in the world. Until recently, hepatitis B surface antigen (HBsAg)-negative patients, carrying hepatitis B surface antibody (anti-HBs) and/or hepatitis B core antibody (anti-HBc), have been considered to have achieved the resolution of HBV infection; however, among those patients, the reactivation of HBV has been increasingly reported after chemotherapy, hematopoietic stem cell transplantation, or immunosuppressive therapy. The reactivation of HBV can cause lethal hepatitis called de novo hepatitis B. Therefore, serological examination for HBV infection before starting immunosuppressive therapy is now recommended for all patients with rheumatic diseases. Systemic lupus erythematosus (SLE) is one of the autoimmune diseases characterized by the production of autoantibodies and usually requires immunosuppressive therapy. However, to date, a few reports are available regarding the prevalence and time course of HBV infection in patients with SLE under immunosuppressive therapy. In this review, we update the prevalence and time course of HBV infection in lupus patients using our data and previous papers available, with a special emphasis on occult HBV infection and a decrease of HBV-related antibodies (anti-HBs and anti-HBc) under immunosuppressive therapy. This review also highlights the screening and management of HBV infection currently recommended and the potential role of HBV infection in the pathogenesis of SLE. Throughout the present review, we recommend the pretreatment screening for HBV infection in patients with SLE as well as patients with other rheumatic diseases.

Pretreatment screening on distant metastases and head and neck cancer patients: Validation of risk factors and influence on survival

Previously identified high risk factors for development of distant metastases are: three or more lymph node metastases, bilateral lymph node metastases, lymph nodes larger than 6cm, low jugular lymph node metastases, locoregional tumor recurrence and second primary tumors. The aims of this study were to validate these specific risk factors and to investigate the impact of time (i.e. during screening or follow-up) of detection of distant metastases on survival. From a total of 301 HNSCC patients with high risk factors who were scheduled for extensive treatment and underwent pretreatment screening on distant metastases using chest CT and/or whole body PET(-CT) (in some patients combined with whole body MRI), the high risk factors, the development and time point of distant metastases and survival were analyzed. Forty-four percent developed distant metastases. Multivariate analysis revealed that bilateral lymph node metastases is the strongest predictive factor. Locoregional recurrence and second primary tumor were the risk factors associated with the lowest cumulative incidence. However, if the risk factor locoregional recurrence was split into local and regional recurrences, regional recurrence became a high risk factor. The more high risk factors a patient had the lower the 5-year distant metastases free survival was. Patients with distant metastases detected pretreatment has a significant worse survival (corrected for lead time bias) compared to patients with distant metastases diagnosed during follow-up. The validity of three or more lymph node metastases, bilateral lymph node metastases, lymph nodes larger than 6cm, low jugular lymph node metastases and regional recurrence as high risk factors for the development of distant metastases was confirmed. If more high risk factors are present the cumulative incidence of distant metastases increases significantly. The detection of distant metastases by pretreatment screening worsens the overall survival as compared to distant metastases detected during follow-up.