Correction to: [89Zr]Zr-cetuximab PET/CT as biomarker for cetuximab monotherapy in patients with RAS wild-type advanced colorectal cancer.

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[89Zr]Zr-cetuximab PET/CT as biomarker for cetuximab monotherapy in patients with RAS wild-type advanced colorectal cancer.

PURPOSE: One-third of patients with RAS wild-type mCRC do not benefit from anti-EGFR monoclonal antibodies. This might be a result of variable pharmacokinetics and insufficient tumor targeting. We evaluated cetuximab tumor accumulation on [89Zr]Zr-cetuximab PET/CT as a potential predictive biomarker and determinant for an escalating dosing strategy. PATIENTS AND METHODS: PET/CT imaging of [89Zr]Zr-cetuximab (37 MBq/10 mg) after a therapeutic pre-dose (500 mg/m2 ≤ 2 h) cetuximab was performed at the start of treatment. Patients without visual tumor uptake underwent dose escalation and a subsequent [89Zr]Zr-cetuximab PET/CT. Treatment benefit was defined as stable disease or response on CT scan evaluation after 8 weeks. RESULTS: Visual tumor uptake on [89Zr]Zr-cetuximab PET/CT was observed in 66% of 35 patients. There was no relationship between PET positivity and treatment benefit (52% versus 80% for PET-negative, P = 0.16), progression-free survival (3.6 versus 5.7 months, P = 0.15), or overall survival (7.1 versus 9.4 months, P = 0.29). However, in 67% of PET-negative patients, cetuximab dose escalation (750-1250 mg/m2) was applied, potentially influencing outcome in this group. None of the second [89Zr]Zr-cetuximab PET/CT was positive. Eighty percent of patients without visual tumor uptake had treatment benefit, making [89Zr]Zr-cetuximab PET/CT unsuitable as a predictive biomarker. Tumor SUVpeak did not correlate to changes in tumor size on CT (P = 0.23), treatment benefit, nor progression-free survival. Cetuximab pharmacokinetics were not related to treatment benefit. BRAF mutations, right-sidedness, and low sEGFR were correlated with intrinsic resistance to cetuximab. CONCLUSION: Tumor uptake on [89Zr]Zr-cetuximab PET/CT failed to predict treatment benefit in patients with RAS wild-type mCRC receiving cetuximab monotherapy. BRAF mutations, right-sidedness, and low sEGFR correlated with intrinsic resistance to cetuximab.

Radiomics analysis of pre-treatment [18F]FDG PET/CT for patients with metastatic colorectal cancer undergoing palliative systemic treatment.

BACKGROUND: The aim of this study was to assess radiomics features on pre-treatment [18F]FDG positron emission tomography (PET) as potential biomarkers for response and survival in patients with metastatic colorectal cancer (mCRC). METHODS: Patients with mCRC underwent [18F]FDG PET/computed tomography (CT) prior to first- or third-line palliative systemic treatment. Tumour lesions were semiautomatically delineated and standard uptake value (SUV), metabolically active tumour volume (MATV), total lesion glycolysis (TLG), entropy, area under the curve of the cumulative SUV-volume histogram (AUC-CSH), compactness and sphericity were obtained. RESULTS: Lesions of 47 patients receiving third-line systemic treatment had higher SUVmax, SUVpeak, SUVmean, MATV and TLG, and lower AUC-CSH, compactness and sphericity compared to 52 patients receiving first-line systemic treatment. Therefore, first- and third-line groups were evaluated separately. In the first-line group, anatomical changes on CT correlated negatively with TLG (ρ = 0.31) and MATV (ρ = 0.36), and positively with compactness (ρ = -0.27) and sphericity (ρ = -0.27). Patients without benefit had higher mean entropy (p = 0.021). Progression-free survival (PFS) and overall survival (OS) were worse with a decreased mean AUC [hazard ratio (HR) 0.86, HR 0.77] and increase in mean MATV (HR 1.15, HR 1.22), sum MATV (HR 1.14, HR 1.19), mean TLG (HR 1.16, HR 1.22) and sum TLG (HT1.12, HR1.18). In the third-line group, AUC-CSH correlated negatively with anatomical change (ρ = 0.21). PFS and OS were worse with an increased mean MATV (HR 1.27, HR 1.68), sum MATV (HR 1.35, HR 2.04), mean TLG (HR 1.29, HR 1.52) and sum TLG (HT 1.27, HR 1.80). SUVmax and SUVpeak negatively correlated with OS (HR 1.19, HR 1.21). Cluster analysis of the 10 radiomics features demonstrated no complementary value in identifying aggressively growing lesions or patients with impaired survival. CONCLUSION: We demonstrated an association between improved clinical outcome and pre-treatment low tumour volume and heterogeneity as well as high sphericity on [18F]FDG PET. Future PET imaging research should include radiomics features that incorporate tumour volume and heterogeneity when correlating PET data with clinical outcome.

Optimal use of anti-EGFR monoclonal antibodies for patients with advanced colorectal cancer: a meta-analysis.

This meta-analysis was performed to determine the optimal use of anti-EGFR mAb in the treatment of metastasized colorectal cancer (mCRC). Seventeen randomized clinical trials were included, all evaluating the added value of anti-EGFR mAb to standard treatment line in patients with KRAS wild-type mCRC. Hazard and odds ratios were pooled using a random effect model, weighted according to cohort size. Pooled data of six first- and two second-line studies demonstrated a significantly improved ORR (OR 1.62, CI 1.27-2.04; OR 4.78, CI 3.39-6.75, respectively) and PFS (HR 0.79, CI 0.67-0.94; HR 0.80, CI 0.71-0.91, respectively) with the addition of anti-EGFR mAb to chemotherapy, while OS remained similar. Two third-line anti-EGFR mAb monotherapy studies revealed an improved PFS and OS (HR 0.44, CI 0.35-0.52; HR 0.55, CI 0.41-0.74). Addition of anti-EGFR versus anti-VEGF mAb to first-line chemotherapy was evaluated in three studies; ORR and PFS were comparable, while OS was improved (HR 0.8, CI 0.65-0.97). The influence of the chemotherapy backbone on anti-EGFR mAb efficacy, evaluated with meta-regression, indicated a higher ORR with irinotecan-based versus oxaliplatin-based regimens, but comparable PFS and OS. Reported toxicity (≥3 grade) increased ~20% in all treatment lines with the addition of anti-EGFR mAb. Anti-EGFR treatment significantly improves response and survival outcome of patients with (K)RAS wild-type mCRC, regardless of treatment line or chemotherapeutic backbone. Saving anti-EGFR mAb as third-line monotherapy is a valid and effective option to prevent high treatment burden caused by combination therapy. Combination treatment with anti-EGFR mAb to achieve radical resection of metastases needs further investigation.

Deep neuromuscular block to optimize surgical space conditions during laparoscopic surgery: a systematic review and meta-analysis.

Neuromuscular block (NMB) is frequently used in abdominal surgery to improve surgical conditions by relaxation of the abdominal wall and prevention of sudden muscle contractions. The evidence supporting routine use of deep NMB is still under debate. We aimed to provide evidence for the superiority of routine use of deep NMB during laparoscopic surgery. We performed a systematic review and meta-analysis of studies comparing the influence of deep vs moderate NMB during laparoscopic procedures on surgical space conditions and clinical outcomes. Trials were identified from Medline, Embase, and Central databases from inception to December 2016. We included randomized trials, crossover studies, and cohort studies. Our search yielded 12 studies on the effect of deep NMB on the surgical space conditions. Deep NMB during laparoscopic surgeries improves the surgical space conditions when compared with moderate NMB, with a mean difference of 0.65 (95% confidence interval (CI): 0.47-0.83) on a scale of 1-5, and it facilitates the use of low-pressure pneumoperitoneum. Furthermore, deep NMB reduces postoperative pain scores in the postanaesthesia care unit, with a mean difference of - 0.52 (95% CI: -0.71 to - 0.32). Deep NMB improves surgical space conditions during laparoscopic surgery and reduces postoperative pain scores in the postanaesthesia care unit. Whether this leads to fewer intraoperative complications, an improved quality of recovery, or both after laparoscopic surgery should be pursued in future studies. The review methodology was specified in advance and registered at Prospero on July 27, 2016, registration number CRD42016042144.

Deep neuromuscular block to optimize surgical space conditions during laparoscopic surgery: a systematic review and meta-analysis / 中华麻醉学杂志

Neuromuscular block (NMB) is frequently used in abdominal surgery to improve surgical conditions by relaxation of the abdominal wall and prevention of sudden muscle contractions.The evidence supporting routine use of deep NMB is still under debate.We aimed to provide evidence for the superiority of routine use of deep NMB during laparoscopic surgery.We performed a systematic review and metaanalysis of studies comparing the influence of deep vs moderate NMB during laparoscopic procedures on surgical space conditions and clinical outcomes.Trials were identified from Medline,Embase,and Central databases from inception to December 2016.We included randomized trials,crossover studies,and cohort studies.Our search yielded 12 studies on the effect of deep NMB on the surgical space conditions.Deep NMB during laparoscopic surgeries improves the surgical space conditions when compared with moderate NMB,with a mean difference of 0.65 [95％ confidence interval (CI):0.47-0.83] on a scale of 1-5,and it facilitates the use of low-pressure pneumoperitoneum.Furthermore,deep NMB reduces postoperative pain scores in the postanaesthesia care unit,with a mean difference of-0.52 (95％ CI:-0.71 to -0.32).Deep NMB improves surgical space conditions during laparoscopic surgery and reduces postoperative pain scores in the postanaesthesia care unit.Whether this leads to fewer intraoperative complications,an improved quality of recovery,or both after laparoscopic surgery should be pursued in future studies.The review methodology was specified in advance and registered at Prospero on July 27,2016,registration number CRD42016042144.

Cardiovascular risk factors and non-invasive assessment of subclinical atherosclerosis in youth.

UNLABELLED: Our understanding of the natural history of atherosclerosis in childhood and its response to cardiovascular (CV) risk factor reduction have been hampered by the lack of a reliable, non-invasive measure of atherosclerosis. Carotid intima media thickness (IMT), a surrogate marker of atherosclerosis in adults, is increased in youth heterozygous for familial hypercholesterolemia (FH) and declines with lipid lowering pharmacotherapy. The age at which vascular changes can be reliably identified using IMT and the influence of CV risk factors beyond FH on IMT remains unclear. OBJECTIVE: To examine the influence of demographic, family history, anthropometric characteristics and traditional CV risk factors on IMT in children 5-16 years of age (mean age 11 year). METHODS: In a cross-sectional study, we assessed IMT in 148 children (51 with elevated low density lipoprotein (LDL)-cholesterol, 44 with overweight and 53 controls). Measures included: family history of premature coronary heart disease (CHD), physical activity, pubertal stage, smoking history, fasting glucose, insulin, lipid profile, apolipoproteins A1 and B, anthropometry, blood pressure and IMT. RESULTS: The groups were similar for age and family history of premature CHD. Compared to controls, average maximum IMT (0.403+/-0.04 vs 0.387+/-0.029) and average mean IMT were elevated in the hyperlipidemia group (p<0.05), but not in the overweight group (max IMT 0.393+/-0.034; p vs control=0.17). Using multiple regression modelling, age, family history of premature CHD and apoliprotein A1 and B predicted 17% of the variability in IMT. No measure of adiposity predicted IMT. CONCLUSION: Age is an important predictor of IMT in youth. Among traditional CV risk factors, dyslipidemia and family history of premature CHD are independent predictors of IMT.

O(6)-alkylguanine-DNA alkyltransferase DNA repair in mycobacteria: pathogenic and non-pathogenic species differ.

SETTING: DNA repair genes assist the organism in maintaining DNA integrity in the face of environmental (mutagenic) stress. The genome sequences of M. tuberculosis and M. bovis demonstrate sequences suggestive of an O(6)-alkylguanine-DNA alkyltransferase DNA repair activity similar to that seen in almost all other bacterial and eukaryotic organisms. The near ubiquitousness of this gene implies an important function. OBJECTIVE: Our aim was to ascertain whether mycobacteria exert an alkyltransferase response to mutagen (streptozotocin) stimulation and whether alkyltransferase activity is essential for mycobacterial survival. DESIGN: Alkyltransferase activity in slow- and fast-growing mycobacterial species was determined in the presence and absence of sublethal concentrations of an alkylating agent streptozotocin. The intracellular survival and response to anti-tuberculosis drugs of an alkyltransferase knockout strain of M. bovis BCG was also determined. RESULTS: We demonstrate the presence of O(6)-alkylguanine alkyltransferase (cellular methyltransferase activity) in mycobacterial species and that there is an inducible and constitutive form in fast-growing mycobacteria (M. smegmatis), whereas only the constitutive form exists in the pathogenic or slow-growing species (M. bovis BCG) under the conditions tested. The overall activity of the constitutive form is high. We also show that intracellular growth of M. bovis BCG in macrophages is reduced when the alkyltransferase gene is absent. The presence of alkyltransferase activity appears to assist the organism in reducing the effects of isoniazid, since interruption of the gene confers sensitivity to the drug. CONCLUSIONS: We conclude that for the slow-growing mycobacteria, an inducible response is not essential as their ecological niche is stable and protected, but that the presence of the alkyltransferase activity confers a growth advantage in macrophages and offers some protection against antibiotics.

Mycobacterial growth in human macrophages: variation according to donor, inoculum and bacterial strain.

The microbicidal capacity of the macrophage is frequently evaded by mycobacteria, leading to tuberculosis (TB). We investigated a number of parameters affecting the rate of growth of mycobacteria in human monocyte-derived macrophages (MDM). The results show a great deal of variation in the growth of both Mycobacterium bovis BCG and M. tuberculosis H37Rv, using a large number of human macrophage donors, (132 and 40, respectively), but no correlation was seen with the TB status of the MDM donor. Clumping of the mycobacteria resulted in more vigorous growth in MDM, suggesting that inoculum size could affect disease progression. The growth rates of 17 clinical isolates of M. tuberculosis were measured in macrophages derived from three donors and no consistent or marked differences between isolates were observed over the 5-day period of growth measurement. However, all 17 clinical strains grew consistently faster than H37Rv in the same experiments.

Diversity of in vitro cytokine responses by human macrophages to infection by mycobacterium tuberculosis strains.

Macrophages are an important component in the first line of defence of the innate immune system. They are capable of producing cytokines in response to bacterial challenge, as well as in response to cytokine stimuli from other cells in the immune system. The microbicidal response of human monocyte-derived macrophages in vitro, induced by exogenously added cytokines, is highly variable. We found that tumour necrosis factor-alpha (TNF-alpha) and granulocyte-macrophage colony-stimulating factor (GM-CSF) could have either stimulatory or inhibitory effects on intracellular BCG killing, depending on the macrophage donor. Macrophages infected in vitro by various clinical isolates of Mycobacterium tuberculosis or the laboratory strain H37Rv, produced varying levels of both TNF-alpha and IFN-gamma. Certain M. tuberculosis strains tended to be associated with high cytokine production in each of three independent experiments, indicating that strains may differ in the host response elicited to infection.

Factors influencing peak expiratory flow in teenage boys.

BACKGROUND: Peak expiratory flow (PEF) is a useful measure of pulmonary health status and is frequently utilised in asthma management. Reduction in PEF is usually indicative of onset of asthma symptoms. However, use can be made of PEF values only if normal values are known. The definition of normal range is always difficult and may vary between regions and be affected by a variety of factors. OBJECTIVE: To establish PEF values for teenage boys in a Cape Town suburb and examine factors that possibly influence this measurement. SETTING: A high school for boys in the southern suburbs of Cape Town. METHODS: Measurements of PEF were taken for 124 boys. Subjects were approximately 16 years old and apparently healthy at the time of survey. Further details were provided by means of a questionnaire. RESULTS: PEF ranged from 350 to 760 l/min, with a mean (+/- standard deviation (SD)) of 539 +/- 68 l/min. Factors expected to influence PEF included height and mass, whereas unexpected factors included sport intensity and academic grade. A trend to reduced peak flow was already evident in boys who smoked and boys from homes where a parent smoked. Regression analysis suggested peak flow differences in our population compared with the standard reference. CONCLUSION: Interpretation of results obtained from peak-flow instruments should take into account additional knowledge concerning the individual. Further surveys of the South African population and of different groups should be done to establish local standards and factors influencing PEF.

Isolation of DNA from Mycobacterium tubercolosis.

Research into and identification of Mycobacterium tuberculosis can take on a number of facets, many of which involve the use of DNA at one stage or another. The quality and quantity of DNA required will depend on the end-use requirement. For example, good yields of pure, high-molecular-weight DNA uncontaminated by DNA from other sources (i.e., homogeneous) are optimal for the generation of cosmid libraries and sequencing (1), Southern hybridization (2-6), or microarray analysis (7) for genome studies, whereas relatively crude DNA (fragmented DNA or DNA from multiple sources [i.e., heterogeneous]) may be adequate for PCR-based diagnosis (8-12) or amplification of regions of the genome for other purposes, e.g., identification of mutations conferring drug resistance (13,14).

Genetic susceptibility to tuberculosis in Africans: a genome-wide scan.

Human genetic variation is an important determinant of the outcome of infection with Mycobacterium tuberculosis. We have conducted a two-stage genome-wide linkage study to search for regions of the human genome containing tuberculosis-susceptibility genes. This approach uses sibpair families that contain two full siblings who have both been affected by clinical tuberculosis. For any chromosomal region containing a major tuberculosis-susceptibility gene, affected sibpairs inherit the same parental alleles more often than expected by chance. In the first round of the screen, 299 highly informative genetic markers, spanning the entire human genome, were typed in 92 sibpairs from The Gambia and South Africa. Seven chromosomal regions that showed provisional evidence of coinheritance with clinical tuberculosis were identified. To identify whether any of these regions contained a potential tuberculosis-susceptibility gene, 22 markers from these regions were genotyped in a second set of 81 sibpairs from the same countries. Markers on chromosomes 15q and Xq showed suggestive evidence of linkage (lod = 2.00 and 1.77, respectively) to tuberculosis. The potential identification of susceptibility loci on both chromosomes 15q and Xq was supported by an independent analysis designated common ancestry using microsatellite mapping. These results indicate that genome-wide linkage analysis can contribute to the mapping and identification of major genes for multifactorial infectious diseases of humans. An X chromosome susceptibility gene may contribute to the excess of males with tuberculosis observed in many different populations.

Mannose-binding protein B allele confers protection against tuberculous meningitis.

Inhalation is the principal mode of entry for Mycobacterium tuberculosis in humans. Primary infection is usually restricted to the lungs and contiguous lymph nodes. In a subset of infected individuals, predominantly children, the infection is spread hematogenously to the meninges. The host factors that influence the development of tuberculous meningitis have not been well elucidated. The mannose-binding protein (MBP), a serum protein, is considered as an "ante-antibody." MBP has been shown to bind mycobacteria and acts as an opsonin in vitro. Although MBP plays a role in first-line host defense, it may under certain circumstances be deleterious to the host. In tuberculosis (TB), MBP may assist the spread of this intracellular pathogen. Therefore, we hypothesized that MBP genotypes that result in a phenotype of low MBP levels might be protective. We studied a well-defined South African population in which TB has reached epidemic levels. We found that the MBP B allele (G54D), which disrupts the collagen region of the protein and results in low MBP levels, was found in 22 of 79 (28%) of the TB-negative controls from the same community, compared with 12 of 91 (13%) of the patients with pulmonary TB (p < 0.017), and 5 of 64 (8%) of patients with tuberculous meningitis (p < 0.002). In addition, we found significantly lower serum MBP concentrations in TB-negative controls compared with postacute phase, fully recovered TB patients (p < 0.004). These findings suggest that the MBP B allele affords protection against tuberculous meningitis.

Potentiation of isoniazid activity against Mycobacterium tuberculosis by melatonin.

The limited number of effective antituberculosis drugs available necessitates optimizing current treatments. We show that melatonin, which is synthesized in the pineal gland, can cause at least a threefold increase in the efficacy of isoniazid. This suggests that tuberculosis chemotherapy can be improved by innate molecules such as melatonin.

Garlic extract therapy in children with hypercholesterolemia.

OBJECTIVE: To determine whether garlic extract therapy is efficacious and safe in children with hypercholesterolemia. DESIGN: Randomized, double-blind, placebo-controlled clinical trial. SETTING: Specialized pediatric lipid disorders ambulatory clinic. PARTICIPANTS: Thirty pediatric patients, aged 8 to 18 years, who had familial hyperlipidemia and a minimum fasting total cholesterol level greater than 4.8 mmol/L (> 185 mg/dL). INTERVENTION: An 8-week course of a commercially available garlic extract (Kwai [Lichtwer Pharma, Berlin, Germany], 300 mg, 3 times a day) or an identical placebo. MAIN OUTCOME MEASURES: Absolute and relative changes in fasting lipid profile parameters. RESULTS: The groups were equivalent at baseline and compliance was similar in the 2 groups (P = .45). There was no significant relative attributable effect of garlic extract on fasting total cholesterol (+0.6% [95% confidence interval, -5.8% to +6.9%1) or low-density lipoprotein cholesterol (-0.5% [95% confidence interval, -8.7% to +7.6%]). The lower limits of the confidence intervals did not include -10%, the minimum relative attributable effect believed to be clinically important. Likewise, no significant effect was seen on the levels of high-density lipoprotein, triglycerides, apolipoprotein B-100, lipoprotein (a), fibrinogen, homocysteine, or blood pressure. There was a small effect on apolipoprotein A-I (+10.0% [95% confidence interval, +1.2% to +16.5%] P=.03). There were no differences in adverse effects between groups. CONCLUSION: Garlic extract therapy has no significant effect on cardiovascular risk factors in pediatric patients with familial hyperlipidemia.

Acceptability and compliance with two forms of cholestyramine in the treatment of hypercholesterolemia in children: a randomized, crossover trial.

OBJECTIVE: To compare the acceptability, compliance, and effectiveness of two forms of cholestyramine resin in the treatment of hypercholesterolemia in children. STUDY DESIGN: Patients aged 10 to 18 years with familial hypercholesterolemia were enrolled in a randomized, crossover trial of two 8-week periods of either a pill or powder form of cholestyramine at a dose of 8 gm/day. RESULTS: Of 40 children enrolled, 38 completed both medication periods, with a median age of 13 years (range, 10 to 18). At the end of the study, 82% preferred the pill form, 16% the powder form and 2% neither form. Mean (+/-SD) compliance as assessed by the amount of medication taken was significantly greater for pills (61% +/- 31%) than powder (50% +/- 30%, p = 0.01). The form of the medication increased compliance by at least 25% for 16 patients (42%), 13 in favor of pills and 3 in favor of powder. Compliance was not associated with patient attitudes and perceptions of hypercholesterolemia, demographics, family history, previous experience with lipid-lowering medication, or lipid profile parameters. Significant mean reductions in low-density lipoprotein cholesterol concentrations were noted for both pills (-10% +/- 20%, p = 0.006) and powder (-15% +/- 17%, p = 0.0001), with no significant difference between forms (p = 0.16). CONCLUSIONS: A change in bile acid-binding resin formulation from powder to pills significantly increases acceptability and compliance in some children with hypercholesterolemia.