Emory University's Winship Cancer Institute in Atlanta, GA, has been granted Comprehensive Cancer Center status, the NCI's highest designation. The center was particularly recognized for its population-based research and extensive clinical trials program.
How the bi-potential hepatoblasts differentiate into hepatocytes and cholangiocytes remains unclear. Here, using single-cell transcriptomic analysis of hepatoblasts, hepatocytes, and cholangiocytes sorted from E10.5 to E17.5 mouse embryos, we found that hepatoblast-to-hepatocyte differentiation occurred gradually followed a linear default pathway. As more cells became fully differentiated hepatocytes, the number of proliferating cells decreased. Surprisingly, the proliferating and quiescent hepatoblasts exhibited homogeneous differentiation states at a given developmental stage. This unique feature enabled us to combine the single-cell and bulk-cell analyses to define the precise timing of the hepatoblast-to-hepatocyte transition, which occurs between E13.5 and E15.5. In contrast to hepatocyte development at almost all levels, hepatoblast-to-cholangiocyte differentiation underwent a sharp detour from the default pathway. New cholangiocyte generation occurred continuously between E11.5 and E14.5, but their maturation states at a given developmental stage were heterogeneous. Even more surprising, the number of proliferating cells increased as more progenitor cells differentiated into mature cholangiocytes. Based on an observation from the single-cell analysis, we also discovered that the protein kinase C (PKC)/mitogen-activated protein kinase (MAPK) signaling pathway promoted cholangiocyte maturation. Conclusions: Our studies have defined distinct pathways for hepatocyte and cholangiocyte development in vivo, which are critically important for understanding basic liver biology and developing effective strategies to induce stem cells to differentiate towards specific hepatic cell fates in vitro. This article is protected by copyright. All rights reserved.
The link between higher procedure volume and better outcomes for surgical procedures is well established. We aimed to determine if procedure volume affected inpatient mortality in patients undergoing transjugular intra-hepatic portosystemic shunt (TIPS). An epidemiological analysis of an all-payer database recording hospitalizations during 2013 in the United States (Nationwide Readmissions Database) was performed. All patients' ≥18 years old undergoing TIPS during a hospital admission (n=5529) without concurrent or prior liver transplantation were selected. All-cause inpatient mortality was assessed. Risk-adjusted mortality was assessed for hospitals categorized into quintiles based on annual TIPS volume; very low (1-4/year), low (5-9/year), medium (10-19/year), high (20-29/year), and very high (≥30/year). TIPS were placed in 5529 patients (57±10.9 years; 37.5% female). Mortality decreased with rising annual TIPS volume (13% for very low to 6% for very high volume hospitals; p<0.01). Elective admissions were more common in hospitals with higher annual TIPS volume (20.3% for very low to 30.8% for very high; p<0.01). On multivariate analysis, compared to hospitals performing ≥30 TIPS per year, only hospitals performing 1-4/year (aOR: 1.9, 95%CI:1.21-3.01; p=0.01), 5-9/year (aOR: 2.0, 95%CI:1.25-3.17; p<0.01), and 10-19/year (aOR: 1.9, 95%CI:1.17-3.00; p=0.01) had higher inpatient mortality (20-29/year [aOR: 1.4, 95%CI:0.84-2.84; p=0.19]). The absolute difference between risk-adjusted mortality rate for very low volume and very high volume hospitals was 6.1% (13.9% vs. 7.8%). TIPS volume of ≤20 TIPS/year, variceal bleeding, and nosocomial infections were independent risk factors for inpatient mortality in patients with both elective and emergent admissions. Conclusions: The risk of inpatient mortality is lower in hospitals performing ≥20 TIPS per year. Future research exploring preventable factors for higher mortality and benefits of patient transfer to higher volume centers is warranted. This article is protected by copyright. All rights reserved.
Status epilepticus is an emergency, however prompt treatment of patients with status epilepticus is challenging. Clinical trials, such as the Established Status Epilepticus Treatment Trial (ESETT), compare effectiveness of antiepileptic medications, and rigorous examination of effectiveness of care delivery is similarly warranted. We reviewed the medical literature on observed deviations from guidelines, clinical significance, and initiatives to improve timely treatment. We found pervasive, substantial gaps between recommended and "real world" practice with regard to timing, dosing, and sequence of antiepileptic therapy. Applying quality improvement methodology at the institutional level can increase adherence to guidelines, and may improve patient outcomes. This article is protected by copyright. All rights reserved.
Objective: The cause of mesial temporal lobe epilepsy (MTLE) is often unknown. We ascertained to what extent newly-diagnosed non-lesional MTLE actually represents familial MTLE (FMTLE).
Methods: We identified all consecutive patients presenting to the Austin Heath First Seizure Clinic with MTLE and a normal MRI or MRI-evidence of hippocampal sclerosis over a 10-year period. Patients' first-degree relatives and pairwise age- and sex-matched controls underwent a comprehensive epilepsy interview. Each interview transcript was reviewed independently by two epileptologists, blinded to relative or control status. Reviewers classified each subject as follows: epilepsy, specifying if MTLE; manifestations suspicious of epilepsy; or unaffected. Physiological déjà vu was noted.
Results: Forty-four patients were included. At the Clinic, MTLE had been recognized to be familial in 2 patients only. Among 242 subjects interviewed, MTLE was diagnosed in 9/121 relatives vs 0/121 controls (p=0.008). All affected relatives had seizures with intense déjà vu and accompanying features; 6 relatives had not been previously diagnosed. Déjà vu experiences which were suspicious, but not diagnostic, of MTLE occurred in 6 additional relatives vs none of the controls (p=0.04). Physiological déjà vu was common, and did not differ significantly between relatives and controls. After completing the relatives' interviews, FMTLE was diagnosed in 8 of 44 patients (18.2%).
Interpretation: FMTLE accounts for almost one-fifth of newly diagnosed non-lesional MTLE, and it is largely unrecognized without direct questioning of relatives. Relatives of patients with MTLE may experience déjà vu phenomena which clinically lie in the 'borderland' between epileptic seizures and physiological déjà vu. This article is protected by copyright. All rights reserved.
OBJECTIVE: Find the optimal Continuous EEG (cEEG) monitoring duration for seizure detection in critically ill patients.
METHODS: We analyzed prospective data from 665 consecutive cEEGs, including clinical factors and time-to-event emergence of EEG findings over 72-hours. Clinical factors were selected using logistic regression. EEG risk factors were selected a priori. Clinical factors were used for baseline (pre-EEG) risk. EEG findings were used for creation of multistate survival model with three states (entry, EEG risk, and seizure). EEG Risk state is defined by emergence of epileptiform patterns.
RESULTS: Clinical variables of greatest predictive value were coma (31% had seizures; OR 1.8; p<0.01) and history of seizures, either remotely or related to acute illness (34% had seizures; OR 3.0; p<0.001). If there were no epileptiform findings on EEG, the risk of seizures within 72-hour was between 9% (no clinical risk factors) and 36% (coma and history of seizures). If epileptiform findings developed the seizure incidence was between 18% (no clinical risk factors) and 64% (coma and history of seizure). In the absence of epileptiform EEG abnormalities, the duration of monitoring needed for seizure risk of <5% was between 0.4hrs (for patients who are not comatose, and no prior seizure) to 16.4hrs (comatose and prior seizure).
INTERPRETATION: The initial risk of seizures on cEEG is dependent on history of prior seizures and presence of coma. The risk of developing seizures on cEEG decays to <5% by 24 hours if no epileptiform EEG abnormalities emerge, independent of initial clinical risk factors. This article is protected by copyright. All rights reserved.
Objective: To identify biomarkers associated with the development of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients treated with natalizumab (NTZ).
Methods: Relapsing-remitting MS (RRMS) patients who developed PML under NTZ therapy (pre-PML) and non-PML natalizumab-treated patients (NTZ-ctr) were included in the study. Cryopreserved peripheral blood mononuclear cells (PBMC) and serum samples collected at baseline, at one- and two-year treated time points, and during PML were analyzed for gene expression by RNA-sequencing and for serum protein levels by LUMINEX and ELISA assays respectively.
Results: Among top differentially expressed genes in the RNA-sequencing between pre-PML and NTZ-ctr patients, pathway analysis revealed a high representation of genes belonging to the following categories: pro-angiogenic factors (MMP9, VEGFA), chemokines (CXCL1, CXCL5, IL8, CCL2), cytokines (IL1B, IFNG), and plasminogen- and coagulation-related molecules (SERPINB2, PLAU, PLAUR, TFPI, THBD). Serum protein levels for these candidates were measured in a two-step manner in a screening cohort and a validation cohort of pre-PML and NTZ-ctr patients. Only MMP9 was validated and, in pre-PML patients MMP9 protein levels were significantly reduced at baseline compared with NTZ-ctr patients and levels remained lower at later time points during NTZ treatment.
Interpretation: The results from this study suggest that the pro-angiogenic factor MMP9 may play a role as biomarker associated with the development of PML in MS patients treated with NTZ. This article is protected by copyright. All rights reserved.
Objectives: To characterize cerebral microbleeds (CMBs) in lacunar stroke patients in the SPS3 trial and to assess their relationship with recurrent stroke and death, and response to assigned treatment.
Methods: SPS3 is a randomized, clinical trial conducted between 2003 and 2011. Patients with recent MRI-documented lacunar infarcts were randomly assigned in a factorial design to target levels of systolic blood pressure (SBP; 130–149 mmHg vs <130 mmHg; open-label) and to antiplatelet treatment (aspirin/clopidogrel vs aspirin/placebo; double-blinded). The current analysis involves 1278 trial participants who had a baseline axial T2*- GRE MRI sequence allowing for CMB detection.
Results: CMBs were present in 30% of 1278 patients (mean age 63 y). Male gender (OR 1.7, 95%CI 1.3-2.3)·, history of hypertension (1.6, 1.2-2.3), increased systolic blood pressure (1.2 per 20 mmHg, 1.1-1.4), non-diabetic (1.4, 1.1-1.9), multiple old lacunar infarcts(1.9, 1.5-2.5) and moderate(1.7, 1.2-2.3) or severe (4.2, 3.0-5.9) white matter hyperintensities on MRI were independently associated with CMBs. During a mean follow-up of 3.3 y, overall stroke recurrence was 2.5% per patient-y. Patients with CMBs had an adjusted two-fold increased risk of recurrent stroke (HR 2.1, 1.4-3.1). CMBs were not a risk factor for death. There were no statistically significant interactions between CMBs and treatment assignments.
Interpretation: Patients with lacunar stroke and CMBs likely harbor a more advanced form of cerebral small vessel disease in need of efficacious therapeutic strategies. This article is protected by copyright. All rights reserved.
June 27, 2017 -- Today, the U.S. Food and Drug Administration is taking two new, important steps to increase competition in the market for prescription drugs and facilitate entry of lower-cost alternatives. The agency published a list of off-patent,...
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June 15, 2017 -- Today, U.S. District Judge Kathleen M. Williams for the Southern District of Florida entered a consent decree of permanent injunction between the United States and Stratus Pharmaceuticals Inc. of Miami, Florida, Sonar Products Inc....
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Toxic leukoencephalopathy represents a process of structural alteration of the white matter. It is caused by substance abuse including drugs such as heroin, cocaine, toluene and ethanol. We reported the clinical, radiological and autopsy findings of a rare case of toxic leukoencephalopathy following chronic methamphetamine (MA) usage. A 34-year-old man with a 3-year history of MA abuse experienced progressive sluggish state, limb weakness, inability to stand and eating disorders, followed by rapid progression to coma and death. Imaging revealed hypodense CT and long T1 and T2 signals in MRI in the white matter of the bilateral periventricular and centrum semiovale regions. Histologically, white matter rarefaction, loss of myelin and axonal injury were observed. This pattern of clinical presentation, radiological manifestations and histological findings show a certain degree of particularity in toxic leukoencephalopathy. Clinically, the condition may be easily misdiagnosed as withdrawal symptoms. In suspected cases, MRI is recommended for diagnosis. The case reported here reminds clinicians and forensic pathologist of the possibility of toxic leukoencephalopathy related to MA abuse.
Recent adverse event reports have raised the question of increased angioedema risk associated with exposure to levetiracetam. To help address this question, the Observational Health Data Sciences and Informatics research network conducted a retrospective observational new-user cohort study of seizure patients exposed to levetiracetam (n = 276,665) across 10 databases. With phenytoin users (n = 74,682) as a comparator group, propensity score-matching was conducted and hazard ratios computed for angioedema events by per-protocol and intent-to-treat analyses. Angioedema events were rare in both the levetiracetam and phenytoin groups (54 vs. 71 in per-protocol and 248 vs. 435 in intent-to-treat). No significant increase in angioedema risk with levetiracetam was seen in any individual database (hazard ratios ranging from 0.43 to 1.31). Meta-analysis showed a summary hazard ratio of 0.72 (95% confidence interval [CI] 0.39–1.31) and 0.64 (95% CI 0.52–0.79) for the per-protocol and intent-to-treat analyses, respectively. The results suggest that levetiracetam has the same or lower risk for angioedema than phenytoin, which does not currently carry a labeled warning for angioedema. Further studies are warranted to evaluate angioedema risk across all antiepileptic drugs.
YAP activates AKT signaling to promote mitotic arrest, polyploidy, and hepatocellular carcinoma.
Current treatments for castration-resistant prostate cancer (CRPC) that target androgen receptor (AR) signaling improve patient survival, yet ultimately fail. Here, we provide novel insights into treatment response for the antiandrogen abiraterone by analyses of a genetically engineered mouse (GEM) model with combined inactivation of Trp53 and Pten, which are frequently comutated in human CRPC. These NPp53 mice fail to respond to abiraterone and display accelerated progression to tumors resembling treatment-related CRPC with neuroendocrine differentiation (CRPC-NE) in humans. Cross-species computational analyses identify master regulators of adverse response that are conserved with human CRPC-NE, including the neural differentiation factor SOX11, which promotes neuroendocrine differentiation in cells derived from NPp53 tumors. Furthermore, abiraterone-treated NPp53 prostate tumors contain regions of focal and/or overt neuroendocrine differentiation, distinguished by their proliferative potential. Notably, lineage tracing in vivo provides definitive and quantitative evidence that focal and overt neuroendocrine regions arise by transdifferentiation of luminal adenocarcinoma cells. These findings underscore principal roles for TP53 and PTEN inactivation in abiraterone resistance and progression from adenocarcinoma to CRPC-NE by transdifferentiation.
Significance: Understanding adverse treatment response and identifying patients likely to fail treatment represent fundamental clinical challenges. By integrating analyses of GEM models and human clinical data, we provide direct genetic evidence for transdifferentiation as a mechanism of drug resistance as well as for stratifying patients for treatment with antiandrogens. Cancer Discov; 7(7); 736–49. ©2017 AACR.
See related commentary by Sinha and Nelson, p. 673.
This article is highlighted in the In This Issue feature, p. 653
A new study in mice demonstrates that activating the RIG-I and STING signaling pathways, normally associated with antiviral immunity, can help protect the intestinal epithelium from damage caused by chemotherapy and radiation following stem cell transplantation. The findings may help in developing strategies to prevent graft-versus-host disease in patients with leukemia and other blood disorders.
Ceritinib has manageable toxicity and achieves whole-body and intracranial responses.
The FDA has approved the ALK inhibitor brigatinib for patients with metastatic non-small cell lung cancer who cannot take crizotinib or whose disease worsened despite its use. The decision was based upon results of a phase II study that assessed two drug doses, with overall response rates of 45% and 56% respectively. The drug's effect on overall survival remains unclear, as does the optimal sequence of brigatinib and the three other ALK inhibitors.
The FDA has approved one PD-1 checkpoint inhibitor, pembrolizumab, and two PD-L1 checkpoint inhibitors, avelumab and durvalumab, to treat metastatic urothelial carcinoma in patients whose disease continues to progress despite platinum-based chemotherapy. This brings the total number of checkpoint inhibitors for the disease to five, prompting questions about how best to use them.
For patients with non-small cell lung cancer and activating EGFR mutations who have had surgery, gefitinib appears to be more effective than chemotherapy in delaying disease recurrence. In a phase III trial, patients given the EGFR inhibitor were disease-free for 10 months longer than those who received chemotherapy.
An autochthonous mouse model of clear cell renal cell carcinoma (ccRCC) recapitulates the human disease.
The FDA has approved the small-molecule inhibitor midostaurin in combination with chemotherapy to treat acute myeloid leukemia. It is the first approved drug for the disease that specifically targets FLT3 mutations, which occur in about a quarter of all AML cases and are associated with particularly poor outcomes.
DNA-damaging agents are widely used in clinical oncology and exploit deficiencies in tumor DNA repair. Given the expanding role of immune checkpoint blockade as a therapeutic strategy, the interaction of tumor DNA damage with the immune system has recently come into focus, and it is now clear that the tumor DNA repair landscape has an important role in driving response to immune checkpoint blockade. Here, we summarize the mechanisms by which DNA damage and genomic instability have been found to shape the antitumor immune response and describe clinical efforts to use DNA repair biomarkers to guide use of immune-directed therapies.
Significance: Only a subset of patients respond to immune checkpoint blockade, and reliable predictive biomarkers of response are needed to guide therapy decisions. DNA repair deficiency is common among tumors, and emerging experimental and clinical evidence suggests that features of genomic instability are associated with response to immune-directed therapies. Cancer Discov; 7(7); 675–93. ©2017 AACR.
Vaccination against human papillomavirus (HPV) reduces the prevalence of oral infection by an estimated 88% among young adults in the United States, a protection that could help reduce rates of HPV-related oropharyngeal cancers, according to data that will be presented at the American Society of Clinical Oncology Annual Meeting in Chicago, IL. However, the population-level benefit will remain low unless more people get vaccinated.
Based on results of the phase III BILCAP study, adjuvant capecitabine should become standard treatment for patients with biliary tract cancer. Among 430 patients who were treated according to the study protocol, capecitabine was associated with a 25% lower risk of death than observation.
GSMDE promotes a switch of chemotherapy-mediated cell death from apoptosis to pyroptosis.
Brigatinib is tolerable and has antitumor activity in crizotinib-resistant ALK-positive NSCLC.
NRP– Treg–derived IFN is a critical mediator of FOXP3+ Treg functional fragility.
Varlilumab activates the CD27 pathway in T cells to promote antitumor activity in solid tumors.
BCR-proficient lymphoma cells exhibit a competitive growth advantage in vitro and in vivo.
Inherited BRCA2 mutations promote genome instability via aldehyde-induced BRCA2 degradation.
Summary: Farge and colleagues describe a novel in vivo approach to identify and study primary acute myeloid leukemia (AML) cells that persist in the marrow after chemotherapy. They discovered that AML cells that persist in the mouse marrow after treatment with cytarabine have increased oxidative phosphorylation and that inhibiting oxidative phosphorylation can restore sensitivity to cytarabine. Cancer Discov; 7(7); 670–2. ©2017 AACR.
See related article by Farge et al., p. 716.
Dissemination of lymphomas in serous effusions is quite common. Cytology aims to contribute in the clinical management of haematologic patients, providing an accurate and rapid diagnosis. Ancillary techniques such as immunocytochemistry and flow cytometry are essential to classify the lymphoma entity. Comprehensive awareness of the clinical picture and previous histologic documentation are essential for a lymphomatous effusion diagnosis. We report an unusual case of monomorphic epitheliotropic intestinal T-cell lymphoma, formerly known as enteropathy associated T-cell lymphoma (EATL) type II, spreading in the pleural cavity. Cell morphology and immunohistochemistry of the pleural fluid were consistent with the histology of a jejunal tumor previously excised. Flow cytometry data were consistent, though not pathognomonic for the disease. Serous effusions with evidence of lymphoma involvement should be thoroughly examined with cytology and adjuvant techniques to provide diagnosis for proper therapeutic strategies.
Numerous studies have shown that being prompted to think about money can predispose people to engage in self-sufficient thinking and behavior—but some findings suggest that demographic characteristics may moderate this type of effect. In a new research article, scientists present results from three experiments that systematically explore these money-priming effects, finding inconsistent evidence for the effect of money primes on various measures of self-sufficient thinking and behavior.
The research is published in Psychological Science, a journal of the Association for Psychological Science.
Psychology researcher Eugene M. Caruso (University of Chicago Booth School of Business) and co-authors Oren Shapira (Stony Brook University) and Justin Landy (also Chicago Booth) were motivated to carry out this systematic exploration after conducting a set of studies in which they observed varied findings that were inconsistent with their predictions.
In their initial studies, Caruso and his collaborators found that the effects of money reminders on participants' thinking often seemed to depend on certain demographic characteristics, a result they were not expecting. In discussing these results, they discovered that colleagues had also observed unpredicted interaction effects in their research in this area.
Importantly, the kinds of interaction effects observed seemed to vary across different studies that used different techniques for activating the concept of money.
"These inconsistent results led us to step back to try to gain a better understanding of whether different money primes lead to similar effects, and whether they interact with sociodemographic characteristics in a reliable, and potentially theoretically meaningful, manner," Caruso explains.
To do this, Caruso, Shapira, and Landy decided to systematically evaluate the effects of various money-priming manipulations on a predetermined set of outcomes while accounting for the potential influence of certain sociodemographic factors, within a single experiment that sampled a diverse group of participants.
In their first experiment, the researchers recruited a total of 2,167 participants for an online study, randomly assigning participants to receive specific primes. For example, some saw a faint image of $100 bills in the background of the instructions screen, others were asked to select the best sizes and shapes for new paper currency, some completed phrases that included money-related terms, while others were asked to imagine having ample access to money. Some participants saw a clear image of $100 bills and were explicitly asked to describe what money meant to them, while others were asked to recall a time when they felt powerful.
The results showed that four of the five money primes did activate the concept of money. Participants exposed to these primes were more likely to complete word stems to create money-related words compared with participants who received a neutral prime or no prime – only those exposed to the background image of money showed no difference in the word completion task relative to their peers.
But the primes seemed to have weak and inconsistent effects on participants' feelings of wealth and self-sufficiency. Only participants who imagined an abundant life reported differences in self-sufficiency, and they actually reported lower self-sufficiency compared with those who received a neutral prime, an unexpected finding.
Additionally, there was little evidence to suggest that the effects of the primes on various outcomes were moderated by any of the demographic characteristics measured, including gender, socioeconomic status, and political ideology.
The researchers observed similar results in a second online experiment with 2,150 participants that omitted the money-activation measure.
In a third experiment, Caruso, Shapira, and Landy conducted a lab-based study with 332 members of the university community. To examine the effects of money primes on self-sufficient behavior, the researchers measured how long participants spent working on a puzzle that was actually unsolvable before they asked for help.
The results echoed those of the previous online studies: The three money primes tested had weak and inconsistent effects across the different outcome measures. Only those participants who unscrambled phrases including money-related terms reported greater feelings of self-sufficiency relative to the comparison group.
"Contrary to what we expected based on the published literature, we did not find that any manipulation consistently affected any dependent measure across our three studies, nor did we find reliable evidence for statistical moderation by sociodemographic characteristics," says Caruso.
The researchers urged caution in interpreting the findings relative to specific published studies, given that the three experiments were not designed to be exact replications of any one study. Rather, this series of experiments can be seen as offering a rigorous and systematic examination of a particular effect.
"Beyond the implications for money-priming research, we hope that our methodological approach—comparing multiple manipulations of a construct and assessing multiple individual-difference moderators within the same heterogeneous sample—can make a broader contribution by supplementing the emerging toolkit of methodologies for establishing the reliability of individual effects and the validity of the theories that attempt to explain them," Caruso concludes.
This work was supported by The University of Chicago Booth School of Business and by a grant from the John Templeton Foundation. The opinions expressed in this publication are those of the authors and do not necessarily reflect the views of the John Templeton Foundation.
All data and materials have been made publicly available via Open Science Framework. The design and analysis plans were preregistered at the Open Science Framework (Study 1, Study 2, and Study 3). The complete Open Practices Disclosure for this article is available online. This article has received badges for Open Data, Open Materials, and Preregistration.
Publication date: Available online 5 July 2017
Source:Women and Birth
Author(s): Stephen J. Robson, Hassan Vally, Abdel-Latif Mohamed, Maggie Yu, Elizabeth M. Westrupp
BackgroundThe proportion of babies born by caesarean section in Australia has almost doubled over the last 25 years. Factors known to contribute to caesarean such as higher maternal age, mothers being overweight or obese, or having had a previous caesarean do not completely account for the increased rate and it is clear that other influences exist.AimTo identify previously unsuspected risk factors associated with caesarean using nationally-representative data from the Longitudinal Study of Australian Children.MethodsData were from the birth cohort, a long-term prospective study of approximately 5000 children that includes richly-detailed data regarding maternal health and exposures during pregnancy. Logistic regression was used to examine the contribution of a wide range of pregnancy, birth and social factors to caesarean.Findings28% of 4862 mothers were delivered by caesarean. The final adjusted analyses revealed that use of diabetes medication (OR=3.1, 95% CI=1.7–5.5, p<0.001) and maternal mental health problems during pregnancy (OR=1.3, CI=1.1–1.6, p=0.003) were associated with increased odds of caesarean. Young maternal age (OR=0.6, CI=0.5–0.7, p<0.001), having two or more children (OR=0.7, CI=0.6–0.9, p<0.001), and fathers having an unskilled occupation (OR=0.7, CI=0.6–1.0, p=0.036) were associated with reduced odds of caesarean.ConclusionOur findings raise the prospect that the effect of additional screening and support for maternal mental health on caesarean rate should be subject of prospective study.
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Neuromyelitis optica spectrum disorders (NMOSD) are demyelinating autoimmune diseases in the central nervous system (CNS) that are characterized by a high relapse rate and the presence of anti-aquaporin 4 anti...
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Locoergional recurrences following surgical resection for cholangiocarcinoma (CCA) cause significant morbidity and mortality. This retrospective analysis explores risk factors for local failures and maps locoregional recurrences in patients who underwent surgery without adjuvant radiation. The recurrence map provides valuable information for delineating optimal planning target volumes for adjuvant radiation.
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Placental hypoxia is associated with maternal hypertension, placental insufficiency and fetal growth restriction. In the pregnant guinea pig, prenatal hypoxia during early gestation inhibits cytotrophoblast invasion of spiral arteries, increases maternal blood pressure and induces fetal growth restriction. This study evaluated the impact of chronic maternal hypoxia on fetal heart structure with 4D echocardiography with spatio-temporal image correlation and tomographic ultrasound (STIC-TUI) and uterine and umbilical artery resistance/pulsatility indices and fetal heart function using pulsed wave Doppler ultrasound. Pregnant guinea pigs were exposed to either normoxia (N=7) or hypoxia (10.5%O2; N=9) at 28-30d gestation and studied at term. Fetal heart structure and outflow tracts were evaluated in the four chamber view. Fetal heart diastolic function was assessed by E/A ratios of both ventricles and systolic function by the myocardial performance index (or Tie) of left ventricles of normoxic (N=21) and hypoxic (N=17) fetuses. There were no structural abnormalities in fetal hearts. However, hypoxia induced asymmetric fetal growth restriction and increased the relative placental weight compared to normoxic controls. Hypoxia increased Doppler resistance/pulsatility of uterine but not umbilical arteries, had no effect on the Tie index, and increased the E/A ratio in left but not right ventricles. Thus, early and prolonged hypoxia increases uterine artery resistance, stimulates placental compensation, and generates fetal growth restriction at term. Further, the enhanced cardiac diastolic filling with no changes in systolic function or umbilical artery resistance suggests that the fetal guinea pig undergoes a compensated, adaptive response of the systemic circulation to prolonged hypoxia exposure.
Normobaric hypoxic conditioning (HC) denotes exposure to hypoxia at rest (passive) or combined with exercise (active). HC has been applied acutely (single exposure) and chronically (repeated exposure) to obese populations for managing/increasing cardio-metabolic health and weight loss. Cardio-metabolic health and weight loss responses of obese populations in response to passive and active HC are unclear. A systematic search for articles published between 2000-2017 was carried out. Studies investigating the effects of HC for improving cardio-metabolic health and weight loss of obese populations were included. Studies investigated passive (n = 7; 5 animal, 2 humans), active (n = 4; all humans) and a combination of (n = 4; 3 animal, 1 human) HC to an inspired oxygen fraction between 4.8-15.0%, during a single session and daily sessions per week, lasting between 5 days and 8 months. Passive HC could reduce insulin concentrations (-37-22%) and increase energy expenditure (+12-16). Active HC may reduce body weight (-4-2%) and blood pressure (-8-3%). Inconclusive findings exist in determining the impact of acute and chronic HC on markers of triglycerides, cholesterol levels and fitness capacity. Studies that included animal models involved exposure to severe levels of hypoxia (inspired oxygen fraction of 5.0%; simulated altitude >10,000 m) that are not suitable for human populations. HC demonstrated positive findings in relation to insulin and energy expenditure, and body weight and blood pressure, for improving the cardio-metabolic health and body weight management of obese populations. Responses of plasma biomarkers to passive and active HC in humans is warranted.
We investigated the underlying molecular mechanisms by which post-exercise cold-water immersion (CWI) may alter key markers of mitochondrial biogenesis following both a single session and six weeks of sprint interval training (SIT). Nineteen males performed a single SIT session, followed by one of two 15-min recovery conditions: cold-water immersion (COLD; 10°C) or a passive room-temperature control (CON; 23°C). Sixteen of these participants also completed six weeks SIT, each session followed immediately by their designated recovery condition. Four muscle biopsies were obtained in total, three during the single SIT session (pre-exercise, post-recovery, and 3 h post-recovery), and one 48h after the last SIT session. Following a single SIT session, phosphorylated (p-) AMPK, p-p38 MAPK, p-p53 and PGC1α mRNA were all increased (P < 0.05). Post-exercise CWI had no effect on these responses. Consistent with the lack of a response following a single session, regular post-exercise CWI had no effect on PGC-1α or p53 protein content. Six weeks of SIT increased peak aerobic power, VO2peak, maximal uncoupled respiration (complexes I and II), and 2-km time-trial performance (P < 0.05). However, regular CWI had no effect on changes in these markers, consistent with the lack of response in the markers of mitochondrial biogenesis. While these observations suggest CWI is not detrimental to endurance adaptations following six weeks of SIT, they question whether post-exercise CWI is an effective strategy to promote mitochondrial biogenesis and improvements in endurance performance.
The beneficial effects of angiotensin converting enzyme (ACE) inhibitors and angiotensin II (AII) receptor antagonists in patients with heart failure secondary to reduced ejection fraction (HFrEF) are felt to result from prevention of the adverse effects of AII on systemic afterload and renal homeostasis. However, AII can activate the sympathetic nervous system and part of the beneficial effects of ACE inhibitors and AII antagonists may result from their ability to inhibit such activation. We examined the acute effects of the ACE inhibitor captopril (25 mg, n = 9) and the AII receptor antagonist losartan (50 mg, n = 10) on hemodynamics as well as total body and cardiac norepinephrine spillover in patients with chronic HFrEF. Hemodynamic and neurochemical measurements were made at baseline and at 1, 2 and 4 hours after oral dosing. Administration of both drugs caused significant reductions in systemic arterial, cardiac filling and pulmonary artery pressures (P < 0.05 vs baseline). There was no significant difference in the magnitude of those hemodynamic effects. Plasma concentrations of AII were significantly decreased by captopril and increased by losartan (P < 0.05 vs baseline for both). Total body sympathetic activity increased in response to both captopril and losartan (P < 0.05 vs baseline for both), however there was no change in cardiac sympathetic activity in response to either drug. The results of the current study do not support the hypothesis that the acute inhibition of the renin angiotensin system has sympathoinhibitory effects in patients with chronic HFrEF.
Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with constitutive activation of the MAPKinase RAS-RAF-MEK-ERK cell signaling pathway. We analyzed 9 LCH cases without BRAF V600 and MAP2K1 mutations by whole exome sequencing. We identified a new somatic BRAF splicing mutation in 2 cases. Both cases were childhood single system (SS) LCH cases, with self-healing outcome of the bone lesions. This mutant consisted in a 9 base pair duplication (c.1511_1517 + 2 duplication), encoding for a predicted mutant protein with insertion of 3 amino acids (p.Arg506_Lys507insLeuLeuArg) in the N-terminal lobe of the kinase domain of BRAF. Transient expression of the c.1511_1517 + 2dup BRAF mutant in HEK293 cells enhanced MAPKinase pathway activation, and was not inhibited by vemurafenib but was inhibited by PLX8394, a second-generation BRAF inhibitor able to inhibit signaling of BRAF monomers and dimers. Future LCH molecular screening panel should include this new mutation to better define its prevalence in LCH and its restriction to autoregressive bone SS LCH.
PURPOSE: Pre-clinical models have shown that the effectiveness of GL-ONC1, a modified <p>oncolytic vaccinia virus, is enhanced by radiation and chemotherapy. The purpose of this study</p> <p>was to determine the safety of GL-ONC1 when delivered intravenously with chemoradiotherapy</p> <p>to patients with primary, non-metastatic head and neck cancer.</p> <p>EXPERIMENTAL DESIGN: Patients with locoregionally advanced unresected, non-metastatic</p> <p>carcinoma of the head/neck, excluding stage III-IVA p16-positive oropharyngeal cancers, were</p> <p>treated with escalating doses and cycles of intravenous GL-ONC1, along with radiotherapy and</p> <p>chemotherapy. The primary aims were to define the maximum tolerated dose (MTD) and doselimiting</p> <p>toxicities, and to recommend a dose for phase II trials.</p> <p>RESULTS: Between May 2012 and December 2014, 19 patients were enrolled. The most</p> <p>frequent adverse reactions included grade 1-2 rigors, fever, fatigue, and rash. Grade 3 adverse</p> <p>reactions included hypotension, mucositis, nausea, and vomiting. In 2 patients, the rash was</p> <p>confirmed as viral in origin by fluorescence imaging and viral plaque assay. In 4 patients, viral</p> <p>presence in tumor was confirmed on mid-treatment biopsy by quantitative polymerase chain</p> <p>reaction. In 1 patient, live virus was confirmed in a tongue tumor 7 days after receiving first dose</p> <p>of virus. The MTD was not reached. With median follow-up of 30 months, 1 year (2 year)</p> <p>progression-free survival and overall survival were 74.4% (64.1%) and 84.6% (69.2%)</p> <p>respectively.</p> <p>CONCLUSION: Delivery of GL-ONC1 is safe and feasible in patients with locoregionally</p> <p>advanced head/neck cancer undergoing standard chemoradiotherapy. A phase II study is</p> <p>warranted to further investigate this novel treatment strategy.
Purpose: To determine if combination therapy with NHS-muIL12 and the anti-PD-L1 antibody avelumab can enhance anti-tumor efficacy in preclinical models relative to monotherapies.<br /><br />Experimental Design: BALB/c mice bearing orthotopic EMT-6 mammary tumors and μMt- mice bearing subcutaneous MC38 tumors were treated with NHS-muIL12, avelumab, or combination therapy; tumor growth and survival were assessed. Tumor recurrence following remission and rechallenge was evaluated in EMT-6 tumor-bearing mice. Immune cell populations within spleen and tumors were evaluated by FACS and immunohistochemistry. Immune gene expression in tumor tissue was profiled by Nanostring assay and plasma cytokine levels were determined by multiplex cytokine assay. The frequency of tumor antigen-reactive IFN--producing CD8+ T cells was evaluated by ELISpot assay. <br /><br />Results: NHS-muIL12 and avelumab combination therapy enhanced antitumor efficacy relative to either monotherapy in both tumor models. Most EMT-6 tumor-bearing mice treated with combination therapy had complete tumor regression. Combination therapy also induced the generation of tumor-specific immune memory, as demonstrated by protection against tumor rechallenge and induction of effector and memory T cells. Combination therapy enhanced cytotoxic NK and CD8+ T cell proliferation and T-bet expression, whereas NHS-muIL12 monotherapy induced CD8+ T cell infiltration into the tumor. Combination therapy also enhanced plasma cytokine levels and stimulated expression of a greater number of innate and adaptive immune genes compared with either monotherapy.<br /><br />Conclusions: These data indicate that combination therapy with NHS-muIL12 and avelumab increased antitumor efficacy in preclinical models, and suggest that combining NHS-IL12 and avelumab may be a promising approach to treating patients with solid tumors.
Purpose: HSP90, a highly conserved molecular chaperone that regulates the function of several oncogenic client proteins is altered in glioblastoma. However, HSP90 inhibitors currently in clinical trials are short-acting, have unacceptable toxicities or are unable to cross the blood brain barrier (BBB). We examined the efficacy of onalespib, a potent, long-acting novel HSP90 inhibitor as a single agent and in combination with temozolomide (TMZ) against gliomas in vitro and in vivo.<br /><br />Experimental Design: The effect of onalespib on HSP90, its client proteins, and on the biology of glioma cell lines and patient-derived glioma-initiating cells (GSC) was determined. Brain and plasma pharmacokinetics of onalespib and its ability to inhibit HSP90 in vivo was assessed in non-tumor bearing mice. Its efficacy as a single agent or in combination with TMZ was assessed in vitro and in vivo using zebrafish and patient derived GSC xenograft mouse glioma models.<br /><br />Results: Onalespib mediated HSP90 inhibition depleted several survival-promoting client proteins such as EGFR, EGFRvIII and AKT, disrupted their downstream signaling and decreased the proliferation, migration, angiogenesis and survival of glioma cell lines and GSCs. Onalespib effectively crossed the BBB to inhibit HSP90 in vivo and extended survival as a single agent in zebrafish xenografts and in combination with TMZ in both zebrafish and GSC mouse xenografts.<br /><br />Conclusions: Our results demonstrate the long-acting effects of onalespib against gliomas in vitro and in vivo which combined with its ability to cross the BBB support its development as a potential therapeutic agent in combination with TMZ against gliomas.
Purpose: We evaluated a Trop-2-targeting antibody conjugated with SN-38 in metastatic small-cell lung cancer (mSCLC) patients. <p>Experimental Design: Sacituzumab govitecan was studied in patients with pretreated (median, 2; range, 1-7) mSCLC who received either 8 or 10 mg/kg i.v. on days 1 and 8 of 21-day cycles. The primary endpoints were safety and objective response rate (ORR); duration of response, progression-free survival (PFS), and overall survival (OS) were secondary endpoints.</p> <p>Results: Sixty percent of patients showed tumor shrinkage from baseline CTs. On an intention-to-treat basis (N= 50), the ORR was 14% (17% for 10 mg/kg group); the median response duration, 5.7 months; the clinical benefit rate (CBR>4 months), 34%; median PFS, 3.7 months; median OS, 7.5 months. There was a suggested improvement in PR, CBR, and PFS with sacituzumab govitecan in second-line patients who were sensitive to frontline therapy, but no difference between frontline chemosensitive vs chemoresistant patients in the overall population. There was a statistically significant higher OS in those patients who received prior topotecan vs no topotecan therapy in a small subgroup. Grade >3 adverse events included neutropenia (34%), fatigue (13%), diarrhea (9%), and anemia (6%). Trop-2 tumor staining was not required for patient selection. No antibodies to the drug conjugate or its components were detected on serial blood collections.</p> <p>Conclusions: Sacituzumab govitecan appears to have a safe and effective therapeutic profile in heavily-pretreated, mSCLC patients, including those who are chemosensitive or chemoresistant to frontline chemotherapy. Additional studies as a monotherapy or combination therapy are warranted.
Purpose: We investigated the role of the human endogenous retrovirus type K (HERV-K) envelope (env) gene in pancreatic cancer (PC). <p>Experimental Design: shRNA was employed to knockdown (KD) the expression of HERV-K in PC cells.</p> <p>Results: HERV-K env expression was detected in seven PC cell lines and in 80% of PC patient biopsies, but not in two normal pancreatic cell lines or uninvolved normal tissues. A new HERV-K splice variant was discovered in several PC cell lines. RT activity and virus-like particles were observed in culture media supernatant obtained from Panc-1 and Panc-2 cells. HERV-K viral RNA levels and anti-HERV-K antibody titers were significantly higher in PC patient sera (N=106) than in normal donor sera (N=40). Importantly, the in vitro and in vivo growth rates of three PC cell lines were significantly reduced after HERV-K KD by shRNA targeting HERV-K env, and there was reduced metastasis to lung after treatment. RNA-seq results revealed changes in gene expression after HERV-K env KD, including RAS and TP53. Furthermore, downregulation of HERV-K Env protein expression by shRNA also resulted in decreased expression of RAS, p-ERK, p-RSK, and p-AKT in several PC cells or tumors.</p> Conclusion: These results demonstrate that HERV-K influences signal transduction via the RAS-ERK-RSK pathway in PC. Our data highlight the potentially important role of HERV-K in tumorigenesis and progression of PC, and indicate that HERV-K viral proteins may be attractive biomarkers and/or tumor-associated antigens, as well as potentially useful targets for detection, diagnosis and immunotherapy of PC.
Purpose: Based on promising preclinical data, we conducted a single arm phase II trial to assess the clinical benefit rate (CBR) of neratinib, defined as complete/partial response (CR/PR) or stable disease (SD) ≥24 weeks, in HER2mut non-amplified metastatic breast cancer (MBC). Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2mut detection. <p>Experimental Methods: Tumor tissue positive for HER2mut was required for eligibility. Neratinib was administered 240mg daily with prophylactic loperamide. ctDNA sequencing was performed retrospectively for 54 patients (14 positive and 40 negative for tumor HER2mut). </p> <p>Results: 2.4% (9/381) tumors sequenced centrally harbored HER2mut (lobular 7.8% vs ductal 1.6%; p=0.026). Thirteen additional HER2mut cases were identified locally. 21 of these 22 HER2mut cases were estrogen receptor positive. Sixteen patients (median age 58 [31-74] years and 3 [2-10] prior metastatic regimens) received neratinib. The CBR was 31% (90%CI 13-55%), including 1 CR, 1 PR and 3 SD ≥24 weeks). Median PFS was 16 (90%CI: 8-31) weeks. Diarrhea (grade 2 44%, grade 3 25%) was the most common adverse event. Baseline ctDNA sequencing identified the same HER2mut in 11 of 14 tumor positive cases (sensitivity 79%, 90%CI: 53-94%) and correctly assigned 32 of 32 informative negative cases (specificity 100%, 90%CI: 91-100%). Additionally ctDNA HER2mut variant allele frequency decreased in 9 of 11 paired samples at week four, followed by an increase upon progression.</p> Conclusions: Neratinib is active in HER2mut, non-amplified MBC. ctDNA sequencing offers a non-invasive strategy to identify patients with HER2mut cancers for clinical trial participation.
<span style="text-decoration: underline;">Purpose:</span> Activation of the receptor tyrosine kinase MET is associated with poor clinical outcome in certain cancers. To target MET more effectively, we developed an antagonistic antibody mixture, Sym015, consisting of two humanized monoclonal antibodies directed against non-overlapping epitopes of MET. <p><span style="text-decoration: underline;">Experimental Design/Results:</span> We screened a large panel of well-annotated human cancer cell lines and identified a subset with highly elevated MET expression. In particular, cell lines of lung cancer and gastric cancer origin demonstrated high MET expression and activation, and Sym015 triggered degradation of MET and significantly inhibited growth of these cell lines. Next, we tested Sym015 in patient- and cell line-derived xenograft models with high MET expression and/or MET exon 14 skipping alterations, and in models harboring MET amplification as a mechanism of resistance to EGFR-targeting agents. Sym015 effectively inhibited tumor growth in all these models and was superior to an analogue of emibetuzumab, a monoclonal IgG4 antibody against MET currently in clinical development. Sym015 also induced antibody-dependent cellular cytotoxicity (ADCC) in vitro, suggesting that secondary effector functions contribute to the efficacy of Sym015.</p> <p>Retrospectively, all responsive, high MET-expressing models were scored as highly MET-amplified by in situ hybridization, pointing to MET amplification as a predictive biomarker for efficacy. Preclinical toxicology studies in monkeys showed that Sym015 was well tolerated, with a pharmacokinetic profile supporting administration of Sym015 every second or third week in humans.</p> <p><span style="text-decoration: underline;">Conclusion:</span> The preclinical efficacy and safety data provide a clear rationale for the ongoing clinical studies of Sym015 in patients with MET-amplified tumors.
Purpose: Bevacizumab, an antibody against endothelial growth factor, is a key but controversial drug in the treatment of metastatic breast cancer. We, therefore, aimed to determine the intrinsic resistance to bevacizumab at the physiological and molecular levels in advanced breast cancer using positron emission tomography (PET), dynamic contrast-enhanced MRI, diffuse optical spectroscopic imaging (DOSI), and multiplex cytokine assays.<br />Experimental Design: In total, 28 patients diagnosed with stage III/IV advanced breast cancer receiving single-agent bevacizumab for 1 week followed by paclitaxel combined with bevacizumab underwent 18F-fluorodeoxyglucose (FDG)-PET, 18F-fluoromisonidazole (FMISO)-PET, and MRI at both baseline and two courses after treatment initiation. Hemodynamic measurement using DOSI and blood sample collection were performed at baseline and multiple times during the first week after the initiation of single-agent bevacizumab. We distinguished non-responders from responders by serial FDG-PET based on their glycolytic changes to chemotherapy.<br />Results: Non-responders showed significantly higher hypoxic activity on FMISO-PET and less tumor shrinkage than responders. Hemodynamic parameters showed higher tumor blood volume and a remarkable decrease in the tissue oxygen level in non-responders compared with responders after the infusion of single-agent bevacizumab. Multiplex cytokine assays revealed increased plasma levels of both pro-angiogenic and hypoxia-related inflammatory cytokines in non-responders and decreased levels in responders. <br />Conclusions: Non-responders exhibited a higher degree of angiogenesis with more severe hypoxia than responders during bevacizumab treatment. These findings demonstrated that the addition of bevacizumab to paclitaxel treatment under hypoxic conditions could be ineffective and may result in acute hypoxia and increased cytokine secretion associated with cancer progression.
Purpose: This study aimed to evaluate the prognostic impact of circulating tumor cells (CTCs) detected in patients with operable or locally advanced breast cancer before and after neoadjuvant therapy (NT) within the clinical trial GeparQuattro.<br />Experimental Design: Data on CTCs enumerated with the CellSearch™ system were available for 213 and 207 patients before and after NT, respectively. Associations of CTCs with disease-free (DFS) and overall survival (OS) were analyzed by non-parametric Kaplan-Meier estimates and parametric Cox regression.<br />Results: After a median follow up of 67.1 months, the detection of ≥1 CTC/7.5 mL and ≥2 CTCs/7.5 mL before NT was associated with reduced DFS (p=0.031 and <0.0001, respectively) and OS (p=0.0057 and p<0.0001, respectively), while CTCs detected after NT did not correlate with DFS or OS. In parametric univariate and multivariate Cox models, ≥1 CTC/7.5 mL, ≥2 CTCs/7.5 mL and absolute CTC numbers before NT revealed to be independent prognostic parameters of DFS and OS. CTC-negative patients with pathological complete response (pCR) exhibited the best prognosis, while those with CTCs and less tumor response were at high risk of tumor relapse. In HER2-positive and triple negative patients ≥2 CTCs/7.5 mL detected before NT also were significantly associated with worse DFS and OS.<br />Conclusion: Detection of CTCs before NT is an independent prognostic factor of impaired clinical outcome and combined with pCR it could be helpful to stratify breast cancer patients for therapeutic interventions.
Purpose: We evaluated tumor burden dynamics in advanced non-small-cell lung cancer (NSCLC) patients treated with commercial PD-1 inhibitors to identify imaging markers associated with improved overall survival (OS). <p>Experimental Design: The study included 160 advanced NSCLC patients treated with commercial nivolumab or pembrolizumab monotherapy as a part of clinical care. Tumor burden dynamics were studied for the association with OS.</p> <p>Results: Tumor burden change at best overall response (BOR) ranged from -100% to +278% (median: +3.5%). Response rate (RR) was 18% (29/160). Current and former smokers had a higher RR than never smokers (p=0.04). Durable disease control for at least 6 months was noted in 26 patients (16%), which included 10 patients with stable disease as BOR. Using a landmark analysis, patients with <20% tumor burden increase from baseline within 8 weeks of therapy had longer OS than patients with ≥20% increase (median OS:12.4 vs. 4.6 months, p<0.001). Patients with <20% tumor burden increase throughout therapy had significantly reduced hazards of death (HR=0.24, Cox p<0.0001) after adjusting for smoking (HR=0.86, p=0.61) and baseline tumor burden (HR=1.55, p=0.062), even though some patients met criteria for RECIST progression while on therapy. One patient (0.6%) had atypical response pattern consistent with pseudoprogression.</p> Conclusions: Objective response or durable disease control was noted in 24% of advanced NSCLC patients treated with commercial PD-1 inhibitors. A tumor burden increase of <20% from baseline during therapy was associated with longer OS, proposing a practical marker of treatment benefit. Pseudoprogression is rare in NSCLCs treated with PD-1 inhibitors.
Purpose: Infusion of highly heterogeneous populations of autologous tumor-infiltrating lymphocytes (TILs) can result in tumor regression of exceptional duration. Initial tumor regression has been associated with persistence of tumor-specific TILs one month after infusion, but mechanisms leading to long-lived memory responses are currently unknown. Here we studied the dynamics of bulk tumor-reactive CD8+ T cell populations in patients with metastatic melanoma following treatment with TILs. <p>Experimental Design: We analyzed the function and phenotype of tumor-reactive CD8+ T cells contained in serial blood samples of sixteen patients treated with TILs</p> <p>Results: Polyfunctional tumor-reactive CD8+ T cells accumulated over time in the peripheral lymphocyte pool. Combinatorial analysis of multiple surface markers (CD57, CD27, CD45RO, PD-1 and LAG-3) showed a unique differentiation pattern of polyfunctional tumor-reactive CD8+ T cells, with highly specific PD-1 upregulation early after infusion. The differentiation and functional status appeared largely stable for up to 1 year post-infusion. Despite some degree of clonal diversification occurring in vivo within the bulk tumor-reactive CD8+ T cells, further analyses showed that CD8+ T cells specific for defined tumor-antigens had similar differentiation status.</p> <p>Conclusions: We demonstrated that tumor-reactive CD8+ T cell subsets which persist after TIL therapy are mostly polyfunctional, display a stable partially differentiated phenotype and express high levels of PD-1. These partially differentiated PD-1+ polyfunctional TILs have a high capacity for persistence and may be susceptible to PD-L1/PD-L2-mediated inhibition.
Purpose: Early detection is essential for treatment plans before onset of metastatic disease. Our purpose was to demonstrate feasibility to detect and monitor estrogen receptor 1 (ESR1) gene mutations at the single circulating tumor cell (CTC) level in metastatic breast cancer (MBC). <br /><br />Experimental Design: We used a CTC molecular characterization approach to investigate heterogeneity of 14 hot spot mutations in ESR1 and their correlation with endocrine resistance. Combining the CellSearch® and DEPArray™ technologies allowed recovery of 71 single CTCs and 12 WBC from 3 ER-positive MBC patients. 40 CTCs and 12 WBC were subjected to whole genome amplification by MALBAC and Sanger sequencing.<br /><br />Results: Among 3 selected patients, 2 had an ESR1 mutation (Y537). One showed two different ESR1 variants in a single CTC and another showed loss of heterozygosity. All mutations were detected in matched cell-free DNA (cfDNA). Furthermore, one had 2 serial blood samples analyzed and showed changes in both cfDNA and CTCs with emergence of mutations in ESR1 (Y537S and T570I), which has not been reported previously.<br /><br />Conclusions: : CTCs are easily accessible biomarkers to monitor and better personalize management of patients with previously demonstrated ER-MBC who are progressing on endocrine therapy. We showed that single CTC analysis can yield important information on clonal heterogeneity, and can be a source of discovery of novel and potential driver mutations. Finally, we also validate a workflow for liquid biopsy that will facilitate early detection of ESR1 mutations, the emergence of endocrine resistance and the choice of further target therapy.
Purpose: Carcinosarcomas (CS) are highly aggressive gynecologic malignancies containing both carcinomatous and sarcomatous elements with heterogeneous HER2/neu expression. We compared the efficacy of SYD985, (Synthon Biopharmaceuticals BV), a novel HER2-targeting antibody-drug conjugate (ADC), to Trastuzumab emtansine (T-DM1, Genentech-Roche) against primary uterine and ovarian CS. <p>Experimental Design: Eight primary CS cell lines were evaluated for HER2/neu surface expression by IHC and gene amplification by FISH assays. The in vitro experiments included cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability and bystander killing. In vivo activity was studied in mouse xenograft and patient-derived-xenograft (PDX) models.</p> <p>Results: SYD985 and T-DM1 induced similar levels of ADCC against CS cell lines with low and high HER2/neu expression when challanged in the presence of effector cells. In contrast, SYD985 was 7 to 54 fold more potent than T-DM1 in the absence of effector cells. SYD985, unlike T-DM1, was active against CS demonstrating low or heterogeneous HER2/neu expression. Specifically, the mean IC50's were 0.060 µg/mL and 3.221 µg/mL (p<0.0001) against HER2/neu 0/1+ cell lines and 0.013 µg/mL and 0.096 µg/mL (p<0.0001) against HER2/neu 3+ cell lines for SYD985 vs T-DM1, respectively. Importantly, unlike T-DM1, SYD985 induced efficient bystander killing of HER2/neu 0/1+ tumor cells admixed with HER2/neu 3+ cells. In vivo studies confirmed that SYD985 is more active than T-DM1 in CS and highly effective against HER2/neu expressing xenografts and PDX.</p> <p>Conclusions: SYD985 may represent a novel and highly effective ADC against HER2-expressing CS. Clinical studies with SYD985 in patients harboring chemotherapy-resistant CS with low/moderate and high HER2 expression are warranted.
Evidence suggests that PD-L1 can be induced with radiotherapy and may be an immune escape mechanism in cancer. Monitoring this response is limited as repetitive biopsies during therapy is impractical, dangerous and misses tumor stromal cells. Monitoring PD-L1 expression in both circulating tumor cells (CTCs) and circulating stromal cells (CStCs) in blood based biopsies might be a practical alternative for sequential, non-invasive assessment of changes in tumor and stromal cells. <br /><br />Peripheral blood was collected before and after radiotherapy from 41 lung cancer patients, as was primary biopsies. We evaluated the expression of PD-L1 and formation of RAD50 foci in CTCs and a CStC subtype, cancer associated macrophage-like cells (CAMLs), in response to DNA damage caused by radiotherapy at the tumor site. <br /> <p>Only 24% of primary biopsies had sufficient tissue for PD-L1 testing, tested with IHC clones 22c3 and 28-8. A CTC or CAML was detectable in 93% and 100% of samples, prior to and after radiotherapy, respectively. RAD50 foci significantly increased in CTCs (>7X, p<0.001) and CAMLs (>10X, p=0.001) after radiotherapy confirming their origin from the radiated site. PD-L1 expression increased overall, 1.6X in CTCs (p=0.021) and 1.8X in CAMLs (p=0.004): however, individual patient PD-L1 expression varied, consistently low/negative (51%), consistently high (17%) or induced (31%).<br /><br />These data suggest that RAD50 foci formation in CTCs and CAMLs may be used to track cells subjected to radiation occurring at primary tumors, and following PD-L1 expression in circulating cells may be used as a surrogate for tracking adaptive changes in immunotherapeutic targets.
Liver dysfunction is a frequent complication after hematopoietic-cell transplantation (HCT). Liver biopsy has an important role for confirming the diagnosis of graft versus host disease (GVHD) or other liver diseases. The histological features of GVHD are not specific, and GVHD and other coexisting diseases may be present in the same biopsy, which makes the histologic interpretation of the liver biopsy more complex and challenging. The aim of the study is to improve the present diagnostic criteria.
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Hereditary diffuse gastric cancer (HDGC) accounts for 1% of gastric cancer cases. For patients with a germline CDH1 mutation, risk-reducing gastrectomy is recommended. However, for those delaying surgery or families with no causative mutation identified, regular endoscopy is advised. This study aimed to determine the yield of signet ring cell carcinoma (SRCC) foci in individuals with a CDH1 pathogenic variant compared with those without and how this varies with successive endoscopies.
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A simple HPLC-UV method has been developed and validated for the quantification of ellagic acid (EA) in ethanol extracts of Eugenia uniflora L. (Myrtaceae) leaves. The ultrasound-assisted extraction (UAE) optimization was performed using a Box Behnken design (33) combined with response surface methodology to study the effects of the ethanol concentration (%, w/w), extraction time (minutes), and temperature (°C) on the EA concentration. The optimized results showed that the highest extraction yield of EA by UAE was 26.0 μg mL−1 when using 44% (w/w) ethanol as the solvent, 22 minutes as the extraction time, and 59°C as the extraction temperature. The concentration of EA in relation to the predicted value was 93.7% ± 0.4. UAE showed a strong potential for EA extraction.
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In this work, we investigated the genetic diversity of HIV-1 and the presence of mutations conferring antiretroviral drug resistance in 50 drug-naïve infected persons in the Republic of Congo (RoC). Samples we...
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Reduced left ventricular ejection fraction (LVEF) ≤30% is the most powerful prognostic indicator for sudden cardiac death (SCD) in patients after myocardial infarction (MI), but there are little data about lon...
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Horm Metab Res
DOI: 10.1055/s-0043-107835
Obesity has increased dramatically worldwide, which is associated with male infertility. Androgen deficiency, impaired spermatogenesis, and erectile dysfunction are characteristics of male infertility. The balance of androgens and estrogens is essential for maintaining normal reproductive function in males. Aromatase, the rate-limiting enzyme in the conversion of androgens into estrogens, is present in various tissues. The expression of aromatase is proportional to body fat mass and causes more fat accumulation, thus forming a vicious cycle. Excessive aromatase activity in adipose tissue leads to increased conversion of androgens into estrogens, eventually results in a reduction of testosterone levels and is the underlying reason for obesity-related infertility. In the male reproductive system, all testicular somatic cells and germ cells express aromatase, except for peritubular myoid cells. The results of studies regarding the effect of aromatase in testicular somatic cells and germ cells have been contradictory. The effect of estrogens in testicular somatic cells is inhibitory, leading to reduced testosterone levels and sperm production; however, it has been observed that aromatase participates in the acquisition of sperm motility. The overall effect of estrogen modulation is an inhibition of spermatogenesis. Aromatase inhibitors are an effective therapy for obesity-associated hypogonadism because they restore normal sex hormone levels and improve semen parameters. This article systematically introduces the basic knowledge of aromatase and provides information of the current advances relating to aromatase in male reproductive function. Increasing our knowledge on the role of aromatase in male obesity could help in proposing new approaches to treat infertile men.
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© Georg Thieme Verlag KG Stuttgart · New York
Article in Thieme eJournals:
Table of contents | Abstract | Full text
Horm Metab Res
DOI: 10.1055/s-0043-112349
Sclerostin inhibits Wnt/β-catenin signaling pathway, thereby decreasing bone formation. Osteoblast stimulating actions of parathyroid hormone (PTH) are mediated by suppression of sclerostin. Thus, sclerostin may reflect both bone metabolism and parathyroid function. The study was aimed to analyze the patterns of the changes of mineral and bone biomarkers for 9 months following kidney transplantation (KTx). Thirty-five patients after KTx were included into a 9-month observational study. Serum creatinine, calcium, phosphorus, 25-OH vitamin D, PTH, fibroblast growth factor 23 (FGF-23), sclerostin, and bone-specific alkaline phosphatase (BAP) were measured before KTx, and 1, 2 weeks, and 1, 2, 3, 4, 5, 6, and 9 months thereafter. Urine sclerostin/creatinine ratio was assessed in parallel from month 1 after KTx. Following KTx most serum markers significantly decreased till the end of observation including PTH (by 58%), phosphorus (37%), sclerostin (31%), BAP (28%), and FGF-23 (82%). Most of the decrease was observed during first 2 months after KTx. Serum calcium was increased by 17%. Urine sclerostin/creatinine ratio increased from month 1 till month 6. At KTx serum FGF-23 correlated only with phosphate (r=0.62, p=0.01) and PTH with BAP (r=0.49, p=0.04) but not with sclerostin. At the end of the study neither serum sclerostin nor FGF-23 correlated with other parameters of mineral and bone metabolism. Sclerostin shows the limited utility as the marker of the resolution of bone and mineral metabolism after KTx.
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© Georg Thieme Verlag KG Stuttgart · New York
Article in Thieme eJournals:
Table of contents | Abstract | Full text
Horm Metab Res
DOI: 10.1055/s-0043-113573
Patients with Graves' disease are known to have low selenium (Se) status, Se supplementation resulting in clinical and biochemical improvement. Selenomethionine (SeMet) in a new soft gel capsule formulation was used in a pilot study in 6 patients with acute Graves' disease and low selenium levels (61.3±12.9 μg/l) before and in 4/6 patients 3 months after combined treatment with methimazole and SeMet 200 μg/day (113.3±46.3 μg/l), as well as in 6 euthyroid controls (82±11.8 μg/l). The biokinetics were studied following ingestion of 200 μg SeMet (single dose) soft gel capsule, Se serum concentrations being measured at various time points within 24 h. Se levels rose variably in all patients and controls. While levels peaked in all subjects following 8 h of intake, the increase was somewhat slower in acute hyperthyroidism as compared to 3 months later when these patients had been rendered euthyroid, this possibly due to derangement of Se storage capacity by SEPP or increased requirements in the acute phase of the disease, leading to depletion of the trace element. The compound was shown to be bioavailable and safe and patients treated for 3 months exhibited higher Se levels at the different time points. These findings are of major importance for sufferers of GD since they indicate that early Se supplementation, with its beneficial antioxidant impact on inflammatory activity, could slow, or possibly even forestall, the clinical progression of the disease.
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© Georg Thieme Verlag KG Stuttgart · New York
Article in Thieme eJournals:
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Horm Metab Res 2017; 49: 493-498
DOI: 10.1055/s-0043-107242
Data on the effects of vitamin D supplementation on metabolic status of patients with polycystic ovary syndrome (PCOS) are scarce. The current study was conducted to evaluate the effects of vitamin D supplementation on metabolic status of patients with PCOS. This randomized double-blind, placebo-controlled trial was performed on 70 vitamin D-deficient (serum concentrations<20 ng/ml) women with phenotype B-PCOS according to the Rotterdam criteria aged 18–40 years old. Participants were randomly allocated into 2 groups to take either 50 000 IU vitamin D (n=35) or placebo (n=35) every 2 weeks for 12 weeks. Metabolic, endocrine, inflammation, and oxidative stress biomarkers were quantified at the beginning of the study and after 12-week intervention. After the 12-week intervention, compared to the placebo, vitamin D supplementation significantly decreased fasting plasma glucose (FPG) (−3.1±7.3 vs. +0.5±6.3 mg/dl, p=0.02), insulin (−1.4±3.6 vs. +2.6±7.0 μIU/ml, p=0.004), homeostasis model of assessment-estimated insulin resistance (−0.3±0.8 vs. +0.6±1.6, p=0.003), homeostasis model of assessment-estimated B cell function (−4.9±13.4 vs. +9.9±26.9, p=0.005), and increased quantitative insulin sensitivity check index (+0.01±0.01 vs. −0.02±0.05, p=0.007). Supplementation with vitamin D also led to significant reductions in serum high-sensitivity C-reactive protein (hs-CRP) (−0.7±1.4 vs. +0.5±2.1 μg/mL, p=0.009) and plasma malondialdehyde (MDA) levels (−0.1±0.5 vs. +0.9±2.1 μmol/l, p=0.01) compared to the placebo. Overall, vitamin D supplementation for 12 weeks in vitamin D-deficient women with phenotype B-PCOS had beneficial effects on glucose homeostasis parameters, hs-CRP, and MDA.
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© Georg Thieme Verlag KG Stuttgart · New York
Article in Thieme eJournals:
Table of contents | Abstract | Full text
Horm Metab Res
DOI: 10.1055/s-0043-112346
The current study was conducted to evaluate the effects of 2 different doses of vitamin D supplementation on metabolic profiles of insulin-resistant patients with polycystic ovary syndrome (PCOS). This randomized double-blind, placebo-controlled trial was performed on 90 insulin-resistant patients with PCOS according to the Rotterdam criteria aged 18–40 years old. Participants were randomly allocated into 3 groups to receive either 4 000 IU of vitamin D (n=30) or 1 000 IU of vitamin D (n=30) or placebo (n=30) per day for 12 weeks. Vitamin D supplementation (4 000 IU), compared with vitamin D (1 000 IU) and placebo, led to reduced fasting plasma glucose (−4.3±8.6 vs. −4.7±7.1 and +0.1±6.7 mg/dl, respectively, p=0.02), serum insulin concentrations (−2.7±2.7 vs. −1.4±4.2 and −0.1±4.1 μIU/ml, respectively, p=0.02), and HOMA-IR (−0.6±0.6 vs. −0.4±1.0 and −0.1±0.9, respectively, p=0.02). In addition, we found significant decreases in mean change of serum triglycerides (−10.3±7.3 vs. −3.6±14.5 and +6.9±23.8 mg/dl, respectively, p=0.001), VLDL- (−2.0±1.5 vs. −0.7±2.9 and +1.4±4.8 mg/dl, respectively, p=0.001), total- (−14.0±9.5 vs. −6.2±24.0 and +7.1±29.7 mg/dl, respectively, p=0.002), LDL- (−10.8±8.3 vs. −5.7±21.9 and +6.8±28.2 mg/dl, respectively, p=0.005), and total-/HDL-cholesterol ratio (−0.2±0.3 vs. −0.1±0.6 and +0.2±0.7 mg/dl, respectively, p=0.003) in the high-dose vitamin D group compared with low-dose vitamin D and placebo groups. Overall, vitamin D supplementation at a dosage of 4 000 IU/day for 12 weeks in insulin-resistant patients with PCOS had beneficial effects of glucose metabolism and lipid profiles compared with 1 000 IU/day of vitamin D and placebo groups.
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© Georg Thieme Verlag KG Stuttgart · New York
Article in Thieme eJournals:
Table of contents | Abstract | Full text
Horm Metab Res
DOI: 10.1055/s-0043-112347
The association between a low-carbohydrate diet (LCD) score and the risk of diabetes mellitus (DM) is contradictory. This study is a systemic review of cohort studies that have focused on the association between the LCD score and DM. We searched PubMed/Medline, Scopus, Embase, ISI Web of Science, and Google Scholar for papers published through January 2017 with no language restrictions. Cohort studies that reported relative risks (RRs) with 95% confidence intervals (CI) for DM were included. Finally, 4 studies were considered for our meta-analysis. The total number of participants ranged from 479 to 85 059. Among 4 cohort studies, 8 081 cases with DM were observed over follow-up durations ranging from 3.6 to 20 years. A marginal significant association was observed between the highest LCD score and the risk of DM (RR=1.17; 95% CI: 0.9, 1.51). Moreover, the RRs for studies with energy adjustments showed a significant association (RR: 1.32; 95% CI: 1.17, 1.49; I2: 0%). Based on our findings, study qualities score of less or equal to 7 had a significant influence on the pooled effect size (RR=1.31, 95%CI: 1.15, 1.49; I2: 0%), whereas the overall RR in the studies with quality score more than 7 was 1.09 (95% CI: 0.73, 1.63). In conclusion, we have found that the highest LCD score was marginally associated with the risk of DM. However, more prospective cohort studies are needed to clarify the effects of the LCD score on the risk of DM.
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© Georg Thieme Verlag KG Stuttgart · New York
Article in Thieme eJournals:
Table of contents | Abstract | Full text
Since first reported in 2002, the rate of methicillin-resistant Staphylococcus aureus (MRSA) among childhood community-associated (CA) S. aureus infection in Taiwan increased significantly up to 2005. There have ...
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In Brazil, due to the rapid increase in programmes for the prevention of mother-to-child transmission (PMTCT), routine programme data are widely available. The objective of this study was to assess the utility...
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Background: Conjunctival ultraviolet autofluorescence (CUVAF) area detected from UVAF photographs is a recently developed potential marker for past sun exposure, but its relationship with sun-related factors has not been fully investigated.
Methods: The study included 339 healthy children ages 5 to 15 years in Melbourne, Australia. Data were collected by questionnaire and examination at school. CUVAF area was measured using a computer program and analyzed as a continuous and dichotomous outcome (any/none).
Results: Fifty-three children (15.6%) had detectable CUVAF, and the youngest age at which a child showed sun damage was 8 years. Compared with silicone skin cast score, there was good inter-grader agreement on CUVAF grading, with Cohen kappa 0.85 [95% confidence interval (CI), 0.65–1.00] for total CUVAF area using both eye photographs. Perfect intra-grader agreement was achieved. Fairer pigmentation, including medium/fair skin color [adjusted odds ratio (AOR), 3.42; 95% CI, 1.02–11.48 vs. dark/olive] and blue/gray eye color (AOR, 4.07; 95% CI, 1.73–9.55 vs. brown) was associated with increased odds of CUVAF. Increasing lifetime sunburn number (e.g., AOR, 2.89; 95% CI, 1.14–7.35 and 4.29; 1.04–17.76 for sunburns 2 to 4 and ≥ 5 times, respectively, vs. no sunburns, trend P = 0.004) and freckling by the end of last summer were associated with increased odds of CUVAF.
Conclusions: CUVAF area can be an a priori objective measure of past sun exposure in pediatric populations for future research.
Impact: To our knowledge, this is the first pediatric study that evaluated associations of sun-related risk factors with CUVAF. Cancer Epidemiol Biomarkers Prev; 26(7); 1146–53. ©2017 AACR.
Background: Lung cancer treatment has become increasingly dependent upon invasive biopsies to profile tumors for personalized therapy. Recently, tumor expression of programmed death-ligand 1 (PD-L1) has gained interest as a potential predictor of response to immunotherapy. Circulating biomarkers present an opportunity for tumor profiling without the risks of invasive procedures. We characterized PD-L1 expression within populations of nucleated cells in the peripheral blood of lung cancer patients in hopes of expanding the role of liquid biopsy in this setting.
Methods: Peripheral blood samples from a multi-institutional prospective study of patients with clinical diagnosis of lung cancer were subjected to cytomorphometric and immunohistochemical evaluation using single-cell, automated slide-based, digital pathology. PD-L1 expression was determined by immunofluorescence.
Results: PD-L1 expression was detected within peripheral circulating cells associated with malignancy (CCAM) in 26 of 112 (23%) non–small cell lung cancer patients. Two distinct populations of nucleated, nonhematolymphoid, PD-L1–expressing cells were identified; cytokeratin positive (CK+, PD-L1+, CD45–) and cytokeratin negative (CK–, PD-L1+, CD45–) cells, both with cytomorphometric features (size, nuclear-to-cytoplasm ratio) consistent with tumor cells. Patients with >1.1 PD-L1(+) cell/mL (n = 14/112) experienced worse overall survival than patients with ≤1.1 PD-L1(+) cell/mL (2-year OS: 31.2% vs. 78.8%, P = 0.00159). In a Cox model adjusting for stage, high PD-L1(+) cell burden remained a significant predictor of mortality (HR = 3.85; 95% confidence interval, 1.64–9.09; P = 0.002).
Conclusions: PD-L1 expression is detectable in two distinct cell populations in the peripheral blood of lung cancer patients and is associated with worse survival.
Impact: These findings could represent a step forward in the development of minimally invasive liquid biopsies for the profiling of tumors. Cancer Epidemiol Biomarkers Prev; 26(7); 1139–45. ©2017 AACR.
Background: To compare associations of symptom prevalence, chronic conditions, and health-related quality of life (HRQOL) between cancer survivors and non-cancer individuals using the U.S. National Health Interview Survey.
Methods: Study samples comprised 604 survivors and 6,166 non-cancer individuals. Symptoms included sensation abnormality, pain, fatigue, cognitive disturbance, depression, and anxiety. Physical and mental HRQOL was measured by the Patient-Reported Outcomes Measurement Information System.
Results: Compared with non-cancer individuals, survivors had higher prevalence in sensation abnormality (OR = 2.4; 95% CI = 1.9 to 3.0), pain (OR = 2.1; 95% CI = 1.7 to 2.6), fatigue (OR = 1.4; 95% CI = 1.1 to 1.8), and decremented physical HRQOL (difference = –3.7; 95% CI = –4.7 to –2.6). The prevalence of individual symptoms was significantly associated with decremented physical HRQOL [range = –5.9 (anxiety) to –8.9 (pain)] and mental HRQOL [range = –4.7 (sensation) to –8.4 (depression)]. The association between cancer experience and physical and mental HRQOL was chiefly explained by the prevalence of six symptoms and presence of chronic conditions. Pain (β = –4.0; 95% CI = –4.5 to –3.6) and ≥2 chronic conditions (β = –9.2; 95% CI = –10.2 to –8.2) significantly decremented physical HRQOL. Depression (β = –5.2; 95% CI = –5.8 to –4.6) and ≥2 chronic conditions (β = –3.3; 95% CI = –4.4 to –2.3) significantly decremented mental HRQOL.
Conclusions: Cancer survivors experience more symptom burden than non-cancer individuals, which is associated with more chronic conditions and impaired HRQOL.
Impacts: Interventions to manage symptom prevalence especially for older cancer survivors and survivors with more chronic conditions may improve their HRQOL outcomes. Cancer Epidemiol Biomarkers Prev; 26(7); 1124–32. ©2017 AACR.
Background: We investigated whether an immune system environment characterized by elevated serum levels of B-cell activation molecules was associated with the subsequent development of classical Hodgkin lymphoma (cHL).
Methods: We measured serum levels of B-cell–stimulatory cytokines, IL6 and IL10, soluble CD30 (sCD30), and total IgE prior to cHL diagnosis in 103 cases and 206 matched controls with archived specimens in the DoD Serum Repository.
Results: Prediagnosis serum sCD30 and IL6 levels had strong positive associations with risk of a cHL diagnosis 0 to 1 year prior to diagnosis [sCD30 OR = 5.5; 95% confidence interval (CI), 3.4–9.0; IL6 OR = 4.6; 95% CI, 2.9–7.5] and >1 year to 2 years pre-cHL diagnosis (sCD30 OR = 3.3; 95% CI, 1.6–6.7; IL6 OR = 2.9; 95% CI, 1.3–6.5). We observed similar, albeit not consistently significant positive associations, over 4 or more years preceding diagnosis. We did not observe a clear association with IgE levels. Of note, detectable IL10 levels were significantly associated with Epstein–Barr virus (EBV)-positive cHL cases compared with EBV-negative cases.
Conclusion: In this prospective analysis, elevated sCD30 and IL6 levels and detectable IL10 preceded cHL diagnosis.
Impact: The associations of these cytokines with cHL risk may reflect the production of these molecules by proliferating nascent cHL tumor cells, or by immune cells responding to their presence, prior to clinical detection. The stable elevation in cHL risk, 4 or more years prediagnosis, also suggests that a B-cell–stimulatory immune system milieu precedes, and may promote, lymphomagenesis. Cancer Epidemiol Biomarkers Prev; 26(7); 1114–23. ©2017 AACR.
Background: Although several studies have investigated excessive salt intake as a risk factor for gastric precancerous lesions, such as atrophic gastritis and intestinal metaplasia, the evidence is insufficient to make a conclusion. We evaluated the association between gastric precancerous lesions and salt intake.
Methods: From 2008 to 2015, the medical records of 728 subjects who underwent upper gastrointestinal endoscopy and sodium excretion in 24-hour urine tests were retrospectively reviewed. Sixty-six subjects were excluded due to diuretics use (n = 55), diagnosis with a gastric neoplasm (n = 4), or the cases of intestinal metaplasia in the absence of atrophy (n = 7), so 662 subjects were included. Atrophic gastritis and intestinal metaplasia were diagnosed by endoscopic findings. The subjects were grouped into three levels by tertiles of 24-hour urine sodium excretion.
Results: A total of 192 (29.0%) had atrophic gastritis without intestinal metaplasia and 112 (16.9%) had atrophic gastritis with intestinal metaplasia. A total of 276 subjects (61.5%) were infected with Helicobacter pylori (H. pylori). In multivariate analyses, H. pylori infection [OR = 14.17; 95% confidence interval (CI), 7.12–28.22) was associated with atrophic gastritis without intestinal metaplasia. Highest levels of sodium excretion (OR = 2.870; 95% CI, 1.34–6.14), heavy smoking (≥20 pack-years) (OR = 2.75; 95% CI, 1.02–7.39), and H. pylori infection (OR = 3.96; 95% CI, 2.02–7.76) were associated with atrophic gastritis with intestinal metaplasia.
Conclusions: Our endoscopy-based study suggested that high salt intake could be associated with an increased risk of atrophic gastritis with intestinal metaplasia.
Impact: Low salt diet might be helpful to prevent gastric carcinogenesis. Cancer Epidemiol Biomarkers Prev; 26(7); 1133–8. ©2017 AACR.
Purpose: To examine associations of prediagnosis high-sensitivity C-reactive protein (hsCRP) with breast cancer incidence and postdiagnosis survival and to assess whether associations are modified by body mass index (BMI).
Methods: A prospective analysis of the Women's Health Initiative was conducted among 17,841 cancer-free postmenopausal women with baseline hsCRP measurements. Cox proportional hazards models were used to examine associations between hsCRP concentrations and (i) breast cancer risk (n cases = 1,114) and (ii) all-cause mortality after breast cancer diagnosis. HRs are per 1 SD in log hsCRP.
Results: hsCRP was not associated with breast cancer risk overall [HR = 1.05; 95% confidence interval (CI), 0.98–1.12]; however, an interaction between BMI and hsCRP was observed (Pinteraction = 0.02). A 1 SD increase in log hsCRP was associated with 17% increased breast cancer risk (HR = 1.17; 95% CI, 1.03–1.33) among lean women (BMI < 25), whereas no association was observed among overweight/obese (BMI ≥ 25) women. Prediagnosis hsCRP was not associated with overall mortality (HR, 1.04; 95% CI, 0.88–1.21) after breast cancer diagnosis; however, an increased mortality risk was apparent among leaner women with higher hsCRP levels (HR, 1.39, 95% CI, 1.03–1.88).
Conclusions: Prediagnosis hsCRP levels are not associated with postmenopausal breast cancer incidence or survival overall; however, increased risks are suggested among leaner women. The observed effect modification is in the opposite direction of a previous case–control study finding and warrants further investigation.
Impact: Associations of higher CRP levels with incident breast cancer and survival after breast cancer may depend on BMI. Cancer Epidemiol Biomarkers Prev; 26(7); 1100–6. ©2017 AACR.
Background: Tobacco exposure is often quantified by serum or saliva concentrations of the primary nicotine metabolite, cotinine. However, average cotinine concentrations are higher in African Americans (AA) compared with Whites with similar smoking levels. Cotinine is metabolized by UGT2B10 and CYP2A6, and low UGT2B10 activity is common in AA, due to the prevalence of a UGT2B10 splice variant.
Methods: UGT2B10 activity was phenotyped in 1,446 smokers (34% AA) by measuring the percentage of cotinine excreted as a glucuronide. Urinary total nicotine equivalents (TNE), the sum of nicotine and 6 metabolites, were determined to quantify smoking dose, and cotinine and 3'-hydroxycotinine were quantified in saliva (study 1) or serum (study 2).
Results: Ninety-seven smokers (78% AA) were null for UGT2B10 activity, and the saliva and serum cotinine levels, after adjustment for TNE and cigarettes per day (CPD), were 68% and 48% higher in these smokers compared with nonnull smokers (P < 0.001). After adjustment for TNE and CPD, salivary cotinine was 35% higher, and serum cotinine 24% higher in AA versus White smokers, but with additional adjustment for UGT2B10 activity, there were no significant differences in saliva and serum cotinine concentrations between these two groups.
Conclusions: UGT2B10 activity significantly influences plasma cotinine levels, and higher cotinine concentrations in AA versus White smokers (after adjustment for smoking dose) result from lower levels of UGT2B10-catalyzed cotinine glucuronidation by AA.
Impact: UGT2B10 activity or genotype should be considered when using cotinine as a tobacco exposure biomarker, particularly in populations such as AA with high frequencies of UGT2B10 nonfunctional variants. Cancer Epidemiol Biomarkers Prev; 26(7); 1093–9. ©2017 AACR.
Background: Histopathologic examination alone can be inadequate for diagnosis of certain melanocytic neoplasms. Recently, a 23-gene expression signature was clinically validated as an ancillary diagnostic test to differentiate benign nevi from melanoma. The current study assessed the performance of this test in an independent cohort of melanocytic lesions against clinically proven outcomes.
Methods: Archival tissue from primary cutaneous melanomas and melanocytic nevi was obtained from four independent institutions and tested with the gene signature. Cases were selected according to pre-defined clinical outcome measures. Malignant lesions were defined as stage I–III primary cutaneous melanomas that produced distant metastases (metastatic to sites other than proximal sentinel lymph node(s)) following diagnosis of the primary lesion. Melanomas that were metastatic at the time of diagnosis, all re-excisions, and lesions with <10% tumor volume were excluded. Benign lesions were defined as cutaneous melanocytic lesions with no adverse long-term events reported.
Results: Of 239 submitted samples, 182 met inclusion criteria and produced a valid gene expression result. This included 99 primary cutaneous melanomas with proven distant metastases and 83 melanocytic nevi. Median time to melanoma metastasis was 18 months. Median follow-up time for nevi was 74.9 months. The gene expression score differentiated melanoma from nevi with a sensitivity of 93.8% and a specificity of 96.2%.
Conclusions: The results of gene expression testing closely correlate with long-term clinical outcomes of patients with melanocytic neoplasms.
Impact: Collectively, this provides strong evidence that the gene signature adds valuable adjunctive information to aid in the accurate diagnosis of melanoma. Cancer Epidemiol Biomarkers Prev; 26(7); 1107–13. ©2017 AACR.
