Biliary tract cancers (BTC) are rare and often diagnosed in late stages with advanced, nonresectable disease. The targeted agents panitumumab and bevacizumab have shown promising outcomes in ...combination with chemotherapy in other gastrointestinal (GI) cancers. We wanted to investigate if panitumumab or bevacizumab was the most promising drug to add to chemotherapy. Eighty‐eight patients were randomized to combination chemotherapy supplemented by either panitumumab 6 mg/kg or bevacizumab 10 mg/kg on Day 1 in Arm A and Arm B, respectively. All patients received gemcitabine 1000 mg/m2 on Day 1, oxaliplatin 60 mg/m2 on Day 1 and capecitabine 1000 mg/m2 twice daily from Days 1 to 7. Treatment was repeated every 2 weeks until progression or for a maximum of 6 months. At progression, crossover was made to the other treatment arm. The primary endpoint was progression‐free survival (PFS) at 6 months. With 19 of 45 in Arm A and 23 of 43 in Arm B PFS at 6 months, the primary endpoint was not met. The overall response rate (ORR) was 45% vs 20% (P = .03), median PFS was 6.1 months vs 8.2 months (P = .13) and median overall survival (OS) was 9.5 months vs 12.3 months (P = .47) in Arm A and Arm B, respectively. Our study showed no consistent differences between adding panitumumab or bevacizumab to chemotherapy in nonresectable BTC and none of the two regimens qualify for testing in Phase III. However, we found a higher response rate in the panitumumab arm with potential implication for future trials in the neoadjuvant setting.
What's new?
Many patients with advanced biliary tract cancer (BTC) do not benefit from surgical resection, leaving chemotherapy and supportive care as primary treatment options. Here, in a phase II trial involving patients with inoperable BTC without KRAS exon 2 mutations, the authors investigated whether either bevacizumab or panitumumab, monoclonal antibody therapies targeting specific growth factor receptors, improved survival when given in addition to chemotherapy. Analyses show no significant difference in efficacy between the two drugs, nor was either combination approach superior in terms of survival compared to chemotherapy alone. Future studies should examine associations between molecular targets and BTC genetic subtypes.
To investigate the association between tobacco smoking and disease activity, treatment adherence and treatment responses among patients with psoriatic arthritis (PsA) initiating the first tumour ...necrosis factor α inhibitor therapy (TNFi) in routine care.
Observational cohort study based on the Danish nationwide DANBIO registry. Kaplan-Meier plots, logistic and Cox regression analyses by smoking status (current/previous/never smoker) were calculated for treatment adherence, ACR20/50/70-responses and EULAR-good-response. Additional stratified analyses were performed according to gender and TNFi-subtype (adalimumab/etanercept/infliximab).
Among 1388 PsA patients included in the study, 1148 (83%) had known smoking status (33% current, 41% never and 26% previous smokers). Median follow-up time was 1.22 years (IQR 0.44-2.96). At baseline, current smokers had lower Body Mass Index (27 kg/m(2) (23-30)/28 kg/m(2) (24-31)) (median (IQR)), shorter disease duration (3 years (1-8)/5 years (2-10)), lower swollen joint count (2 (0-5)/3 (1-6)), higher visual-analogue-scale (VAS) patient global (72 mm (54-87)/68 mm (50-80)), VAS fatigue (72 mm (51-86)/63 mm (40-77)) and Health Assessment Questionnaire (HAQ) score (1.1 (0.7 to 1.5)/1.0 (0.5 to 1.5)) than never smokers (all p<0.05). Current smokers had shorter treatment adherence than never smokers (1.56 years (0.97 to 2.15)/2.43 years (1.88 to 2.97), (median (95% CI)), log rank p=0.02) and poorer 6 months' EULAR-good-response rates (23%/34%), ACR20 (24%/33%) and ACR50 response rates (17%/24%) (all p<0.05), most pronounced in men. In current smokers, the treatment adherence was poorer for infliximab (HR) 1.62, 95% CI 1.06 to 2.48) and etanercept (HR 1.74, 1.14 to 2.66) compared to never smokers, but not for adalimumab (HR 0.80, 0.52 to 1.23).
In PsA, smokers had worse baseline patient-reported outcomes, shorter treatment adherence and poorer response to TNFi's compared to non-smokers. This was most pronounced in men and in patients treated with infliximab or etanercept.
To investigate the incidence of cancer in arthritis patients treated with or without TNFα inhibitors (TNF-I).
Arthritis patients from the DANBIO database were followed-up for cancer in the Danish ...Cancer Registry during 2000-2008.
Hazard ratio for cancer overall was 1.02 (95% confidence interval (CI) 0.80-1.30) in 3347 TNF-I-treated RA patients compared to non-treated. Excess among TNF-I-treated was found for colon cancer (HR 3.52 (95%CI 1.11-11.15), whereas 6 and 0 ovarian cancer cases were observed in treated and non-treated patients, respectively. Compared to the general population, TNF-I-treated RA patients had increased risk for cancer overall, cancer in lymphatic-haematopoietic tissue and non-melanoma skin cancer, while non-RA patients had no increase in overall cancer risk.
Our results suggest that TNF-I therapy in routine care is not associated with an overall excess of cancer in arthritis patients, but observed increased risks of colon and ovarian cancer need further investigation.
Obesity is a heritable disorder, with children of obese fathers at higher risk of developing obesity. Environmental factors epigenetically influence somatic tissues, but the contribution of these ...factors to the establishment of epigenetic patterns in human gametes is unknown. Here, we hypothesized that weight loss remodels the epigenetic signature of spermatozoa in human obesity. Comprehensive profiling of the epigenome of sperm from lean and obese men showed similar histone positioning, but small non-coding RNA expression and DNA methylation patterns were markedly different. In a separate cohort of morbidly obese men, surgery-induced weight loss was associated with a dramatic remodeling of sperm DNA methylation, notably at genetic locations implicated in the central control of appetite. Our data provide evidence that the epigenome of human spermatozoa dynamically changes under environmental pressure and offers insight into how obesity may propagate metabolic dysfunction to the next generation.
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•Distinct sncRNA expression and DNA methylation profiles in sperm from obese humans•Differentially methylated genes are related to brain function•The spermatozoal epigenome is dynamically remodeled after bariatric surgery•Differential methylation clusters with known SNPs of obesity
Donkin et al. show that spermatozoa from obese men carry a distinct epigenetic signature compared to lean men, in particular at genes controlling brain development and function. The sperm methylome is dynamically remodeled after gastric-bypass-induced weight loss, notably at gene regions implicated in the central control of appetite.
Little is known about the effect of long-term diet patterns on the composition and functional potential of the human salivary microbiota. In the present study, we sought to contribute to the ongoing ...elucidation of dietary effects on the oral microbial community by examining the diversity, composition and functional potential of the salivary microbiota in 160 healthy vegans and omnivores using 16S rRNA gene amplicon sequencing. We further sought to identify bacterial taxa in saliva associated with host inflammatory markers. We show that compositional differences in the salivary microbiota of vegans and omnivores is present at all taxonomic levels below phylum level and includes upper respiratory tract commensals (e.g. Neisseria subflava, Haemophilus parainfluenzae, and Rothia mucilaginosa) and species associated with periodontal disease (e.g. Campylobacter rectus and Porphyromonas endodontalis). Dietary intake of medium chain fatty acids, piscine mono- and polyunsaturated fatty acids, and dietary fibre was associated with bacterial diversity, community structure, as well as relative abundance of several species-level operational taxonomic units. Analysis of imputed genomic potential revealed several metabolic pathways differentially abundant in vegans and omnivores indicating possible effects of macro- and micro-nutrient intake. We also show that certain oral bacteria are associated with the systemic inflammatory state of the host.
Imbalances of gut microbiota composition are linked to a range of metabolic perturbations. In the present study, we examined the gut microbiota of women with gestational diabetes mellitus (GDM) and ...normoglycaemic pregnant women in late pregnancy and about 8 months postpartum.
Gut microbiota profiles of women with GDM (n = 50) and healthy (n = 157) pregnant women in the third trimester and 8 months postpartum were assessed by 16S rRNA gene amplicon sequencing of the V1-V2 region. Insulin and glucose homeostasis were evaluated by a 75 g 2-h oral glucose tolerance test during and after pregnancy.
Gut microbiota of women with GDM was aberrant at multiple levels, including phylum and genus levels, compared with normoglycaemic pregnant women. Actinobacteria at phylum level and Collinsella, Rothia and Desulfovibrio at genus level had a higher abundance in the GDM cohort. Difference in abundance of 17 species-level operational taxonomic units (OTUs) during pregnancy was associated with GDM. After adjustment for pre-pregnancy body mass index (BMI), 5 of the 17 OTUs showed differential abundance in the GDM cohort compared with the normoglycaemic pregnant women with enrichment of species annotated to Faecalibacterium and Anaerotruncus and depletion of species annotated to Clostridium (sensu stricto) and to Veillonella. OTUs assigned to Akkermansia were associated with lower insulin sensitivity while Christensenella OTUs were associated with higher fasting plasma glucose concentration. OTU richness and Shannon index decreased from late pregnancy to postpartum regardless of metabolic status. About 8 months after delivery, the microbiota of women with previous GDM was still characterised by an aberrant composition. Thirteen OTUs were differentially abundant in women with previous GDM compared with women with previous normoglycaemic pregnancy.
GDM diagnosed in the third trimester of pregnancy is associated with a disrupted gut microbiota composition compared with normoglycaemic pregnant women, and 8 months after pregnancy, differences in the gut microbiota signatures are still detectable. The gut microbiota composition of women with GDM, both during and after pregnancy, resembles the aberrant microbiota composition reported in non-pregnant individuals with type 2 diabetes and associated intermediary metabolic traits.
Gene silencing by DNA hypermethylation of CpG islands is a well‐characterized phenomenon in cancer. The effect of hypomethylation in particular of non‐CpG island genes is much less well described. By ...genome‐wide screening, we identified 105 genes in microsatellite stable (MSS) colorectal adenocarcinomas with an inverse correlation (Spearman's ρ ≤ −0.40) between methylation and expression. Of these, 35 (33%) were hypomethylated non‐CpG island genes and two of them, APOLD1 (Spearman's ρ = −0.82) and SRPX2 (Spearman's ρ = −0.80) were selected for further analyses. Hypomethylation of both genes were localized events not shared by adjacent genes. A set of 662 FFPE DNA samples not only confirmed that APOLD1 and SRPX2 are hypomethylated in CRC but also revealed hypomethylation to be significantly (p < 0.01) associated with tumors being localized in the left side, CpG island methylator phenotype negative, MSS, BRAF wt, undifferentiated and of adenocarcinoma histosubtype. Demethylation experiments supported SRPX2 being epigenetically regulated via DNA methylation, whereas other mechanisms in addition to DNA methylation seem to be involved in the regulation of APOLD1. We further identified miR‐149 as a potential novel post‐transcriptional regulator of SRPX2. In carcinoma tissue, miR‐149 was downregulated and inversely correlated to SRPX2 (ρ = −0.77). Furthermore, ectopic expression of miR‐149 significantly reduced SRPX2 transcript levels. Our study highlights that in colorectal tumors, hypomethylation of non‐CpG island‐associated promoters deregulate gene expression nearly as frequent as do CpG‐island hypermethylation. The hypomethylation of SRPX2 is focal and not part of a large block. Furthermore, it often translates to an increased expression level, which may be modulated by miR‐149.
What's new?
DNA hypo‐ and hypermethylation both occur frequently in colorectal cancer, yet so far most attention has focused on the role of hypermethylation in silencing critical genes with CpG island promoters. This study provides evidence that hypomethylation of non‐CpG island promoters deregulate gene expression nearly as frequently as does the hypermethylation of CpG island promoters. The authors identified 35 genes whose non‐CpG island promoters were hypomethylated and expression levels inversely correlated. Hypomethylation of SRPX2 also correlated with poorly differentiated tumors, indicating its important role during CRC progression. The authors further identified miR‐149 as a potential novel post‐transcriptional regulator of SRPX2.
The role of glucose-stimulated release of GLP-1 in the development of obesity and type 2 diabetes is unclear. We assessed GLP-1 response to oral glucose in a large study population of lean and obese ...men and women with normal and impaired glucose regulation. Circulating concentrations of glucose, insulin, and GLP-1 during an oral glucose tolerance test (OGTT) were analyzed in individuals with normal glucose tolerance (NGT) (n = 774), prediabetes (n = 525), or screen-detected type 2 diabetes (n = 163) who attended the Danish ADDITION-PRO study (n = 1,462). Compared with individuals with NGT, women with prediabetes or type 2 diabetes had 25% lower GLP-1 response to an OGTT, and both men and women with prediabetes or type 2 diabetes had 16-21% lower 120-min GLP-1 concentrations independent of age and obesity. Obese and overweight individuals had up to 20% reduced GLP-1 response to oral glucose compared with normal weight individuals independent of glucose tolerance status. Higher GLP-1 responses were associated with better insulin sensitivity and β-cell function, older age, and lesser degree of obesity. Our findings indicate that a reduction in GLP-1 response to oral glucose occurs prior to the development of type 2 diabetes and obesity, which can have consequences for early prevention strategies for diabetes.
Low Physical Activity Accentuates the Effect of the FTO rs9939609 Polymorphism on Body Fat Accumulation
Camilla H. Andreasen 1 ,
Kirstine L. Stender-Petersen 1 ,
Mette S. Mogensen 1 ,
Signe S. ...Torekov 1 ,
Lise Wegner 1 ,
Gitte Andersen 1 ,
Arne L. Nielsen 1 ,
Anders Albrechtsen 2 ,
Knut Borch-Johnsen 1 3 4 ,
Signe S. Rasmussen 1 ,
Jesper O. Clausen 1 ,
Annelli Sandbæk 5 ,
Torsten Lauritzen 5 ,
Lars Hansen 6 ,
Torben Jørgensen 3 ,
Oluf Pedersen 1 4 and
Torben Hansen 1
1 Steno Diabetes Center, Gentofte, Denmark
2 Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark
3 Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark
4 Faculty of Health Science, University of Aarhus, Aarhus, Denmark
5 Department of General Practice, University of Aarhus, Aarhus, Denmark
6 Science and Medicine, Novo Nordisk, Bagsværd, Denmark
Address correspondence and reprint requests to Camilla H. Andreasen, Steno Diabetes Center, Niels Steensens Vej 1, NLC2.13,
DK-2820 Gentofte, Denmark. E-mail: cila{at}novonordisk.com
Abstract
OBJECTIVE— Three independent studies have shown that variation in the fat mass and obesity-associated ( FTO ) gene associates with BMI and obesity. In the present study, the effect of FTO variation on metabolic traits including obesity, type 2 diabetes, and related quantitative phenotypes was examined.
RESEARCH DESIGN AND METHODS— The FTO rs9939609 polymorphism was genotyped in a total of 17,508 Danes from five different study groups.
RESULTS— In studies of 3,856 type 2 diabetic case subjects and 4,861 normal glucose-tolerant control subjects, the minor A-allele of
rs9939609 associated with type 2 diabetes (odds ratio 1.13 95% CI 1.06–1.20, P = 9 × 10 −5 ). This association was abolished when adjusting for BMI (1.06 0.97–1.16, P = 0.2). Among 17,162 middle-aged Danes, the A-allele associated with overweight (1.19 1.13–1.24, P = 1 × 10 −12 ) and obesity (1.27 1.20–1.34, P = 2 × 10 −16 ). Furthermore, obesity-related quantitative traits such as body weight, waist circumference, fat mass, and fasting serum
leptin levels were significantly elevated in A-allele carriers. An interaction between the FTO rs9939609 genotype and physical activity ( P = 0.007) was found, where physically inactive homozygous risk A-allele carriers had a 1.95 ± 0.3 kg/m 2 increase in BMI compared with homozygous T-allele carriers.
CONCLUSIONS— We validate that variation in FTO is associated with type 2 diabetes when not adjusted for BMI and with an overall increase in body fat mass. Furthermore,
low physical activity seems to accentuate the effect of FTO rs9939609 on body fat accumulation.
BIGTT, β-cell function, insulin sensitivity, and glucose tolerance testing
BIGTT-AIR, BIGTT acute insulin response
BIGTT-Si, BIGTT insulin sensitivity index
SDC, Steno Diabetes Center
SNP, single-nucleotide polymorphism
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 17 October 2007. DOI: 10.2337/db07-0910.
C.H.A. and K.L.S.-P. contributed equally to this article.
K.B.-J. has received honorarium for invited lectures by Novo Nordisk, Bristol-Myers Squibb, Novartis, Pfizer, Hermedico, and
AstraZeneca.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0910 .
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted October 10, 2007.
Received July 4, 2007.
DIABETES
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Background: PD-1/PD-L1 inhibitors have improved survival for patients with non-small cell lung cancer (NSCLC), but better prognostic biomarkers are needed. Methods: We prospectively collected ...plasma from 82 patients with NSCLC before initiating treatment with PD-1/PD-L1 inhibitors and before treatment cycles 2-4. We used the NK Vue assay to measure interferon gamma (IFNγ) as a surrogate for natural killer cell activity (NKA) with a cutoff of 250 pg/mL. Circulating tumor DNA (ctDNA) in the form of methylated HOXA9 was measured by droplet digital PCR. ctDNA status was classified as detectable or undetectable ctDNA. Results: Patients were classified into three groups according to IFNγ levels at the available time points. The NKA-low group had a persistently low level of IFNγ or dropped to and remained at a low level after baseline (<250 pg/mL, n=29), the NKA-mixed group experienced either an increase from low to normal levels or vice versa (n=34), while the NKA-high group maintained a normal level of IFNγ (≥250 pg/mL, n=13). The median PFS was 64 days (95% confidence interval (CI) 48-115 days), 228 days (95% CI 146-353 days), and 214 days (95% CI 101-693 days), respectively, for NKA-low, NKA-mixed, and NKA-high (p=0.003). The median OS was 170 days (95% CI 110-285 days), 487 days (95% CI 361-761 days), and 1,131 days (95% CI 235 days to not reached), respectively (p<0.001). Patients were divided according to detectable (ctDNA+, n=41) or undetectable (ctDNA-, n=32) ctDNA after one treatment cycle. Median PFS was 97 days (95% CI 58-192 days) and 228 days (95% CI 146-353 days), respectively, for ctDNA+ and ctDNA- (p=0.018). Median OS was 235 days (95% CI 170-525 days) and 544 days (95% CI 361-1158 days), respectively (p=0.007). A score combining NKA and ctDNA both measured after the first treatment cycle had a strong prognostic impact. Group 1 had a low level of IFNγ (<250 pg/mL) and detectable ctDNA (n=27), group 2 had either low levels of IFNγ and undetectable ctDNA or vice versa (n=29), and group 3 had normal levels of IFNγ (≥250 pg/mL) and undetectable ctDNA (n=15). Median PFS was 69 days (95% CI 48-213 days), 183 days (95% CI 102-235 days), and 307 days (95% CI 140-693 days), respectively, for group 1, 2, and 3 (p=0.022). Median OS was 221 days (95% CI 121-539 days), 419 days (95% CI 235-650 days), and 1,158 days (95% CI 250 days to not reached), respectively (p=0.002). Biomarker score 1 was a marker of poor prognosis for OS with a hazard ratio (HR) of 3.971 (95% CI 1.763-8.943, p=0.001) compared to biomarker score 3. It remained statistically significant with a HR of 5.560 (95% CI 2.359-13.101, n=71, p<0.001) when adjusting for PD-L1 status, histology, and performance status. Conclusions: A biomarker score combining the levels of NKA and ctDNA status after the first cycle of treatment may be used to stratify the prognosis in patients with NSCLC treated with PD-1/PD-L1 inhibitors.
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