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Δευτέρα 23 Απριλίου 2018

Concurrent presentation of an intraductal tubulopapillary neoplasm and intraductal papillary mucinous neoplasm in the branch duct of the pancreas, with a superior mesenteric artery aneurysm: a case report

Abstract

Background

Since the concept of intraductal tubulopapillary neoplasm (ITPN) was introduced in the current World Health Organization classification of tumors, the number of reports of ITPN occurrence has increased gradually. However, ITPN is usually located in the main pancreatic duct, with few reports of a branch duct ITPN. As a result, imaging protocols for the diagnosis of a branch duct ITPN have not been established.

Case presentation

We report a case of a concurrent presentation of a branch duct ITPN and intraductal papillary mucinous neoplasm (IPMN) in the head of the pancreas, with a superior mesenteric artery (SMA) aneurysm. Initially, the cystic masses in the pancreatic head were diagnosed as branch duct IPMNs, with treatment consisting of a pylorus-preserving pancreaticoduodenectomy, in combination with an aneurysmectomy performed for treatment of the SMA aneurysm. Pathological examination confirmed these cysts were a combination of branch-type ITPN and IPMN. The patient recovered from the treatment without complication, with no evidence of recurrence over a period of 34 months post-surgery.

Conclusion

This case report of a synchronous presentation of an ITPN and IPMN indicates the difficulty in differentiating these two types of neoplasms in the branch duct of the pancreatic head.



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Differentiation of dental restorative materials combining energy-dispersive X-ray fluorescence spectroscopy and post-mortem CT

Abstract

Today, post-mortem computed tomography (CT) is routinely used for forensic identification. Mobile energy-dispersive X-ray fluorescence (EDXRF) spectroscopy of a dentition is a method of identification that has the potential to be easier and cheaper than CT, although it cannot be used with every dentition. In challenging cases, combining both techniques could facilitate the process of identification and prove to be advantageous over chemical analyses. Nine dental restorative material brands were analyzed using EDXRF spectroscopy. Their differentiability was assessed by comparing each material's x-ray fluorescence spectrum and then comparing the spectra to previous research investigating differentiability in CT. To verify EDXRF's precision and accuracy, select dental specimens underwent comparative electron beam excited x-ray spectroscopy (EDS) scans, while the impact of the restorative surface area was studied by scanning a row of dental specimens with varying restorative surface areas (n = 10). EDXRF was able to differentiate all 36 possible pairs of dental filling materials; however, dual-energy CT was only able to differentiate 33 out of 36. The EDS scans showed correlating x-ray fluorescence peaks on the x-ray spectra compared to our EDXRF. In addition, the surface area showed no influence on the differentiability of the dental filling materials. EDXRF has the potential to facilitate corpse identification by differentiating and comparing restorative materials, providing more information compared to post-mortem CT alone. Despite not being able to explicitly identify a brand without a control sample or database, its fast and mobile use could accelerate daily routines or mass victim identification processes. To achieve this goal, further development of EDXRF scanners for this application and further studies evaluating the method within a specific routine need to be performed.



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Imagining a Positive Outcome Biases Subsequent Memories

Imagining that a future event will go well may lead you to remember it more positively after it's over, according to findings from research published in Psychological Science, a journal of the Association for Psychological Science.

"Our results suggest that imagining an upcoming event can essentially 'color' your memory for that event once it comes to pass," says psychological scientist Aleea Devitt of Harvard University, first author on the study.

"Research has shown that healthy adults tend to have an unrealistically favorable outlook, and our studies suggest that one potential benefit of this optimism might be that we remember events in a more positive way, which could contribute to general well-being," she explains.

Daydreaming about the future is a common experience and many of the events we muse about eventually come to pass. Devitt and study coauthor Daniel L. Schacter, also of Harvard University, hypothesized that simulating a future event may produce a mental representation that ultimately competes with and alters memory for the event after it has happened.

In one experiment, the researchers presented 27 participants with a series of 12 randomly-selected scenarios. For each scenario, participants imagined the event going well (or going poorly) and described it aloud for 3 minutes.

After a 15-minute break, the researchers told the participants to imagine that it was a year later and that they were going to learn how the events turned out. The participants then read brief narratives of the events, each of which contained some positive, negative, and neutral details.

On a subsequent recognition test 48 hours later, they saw 12 details (some positive and some negative) for each narrative, and indicated whether those details had appeared in the narrative.

Emotional content mattered: Participants incorrectly identified more positive details as "true" than they did negative details.

Importantly, how they imagined the event influenced what they remembered from the narrative later. Participants were more likely to mistakenly identify positive details as "true" if they had previously imagined the event going well. Imagining a negative outcome before learning how an event turned out did not seem to influence participants' memory for the event details.

A second experiment produced similar results, showing that imagining a positive event, either in the future or the past, biased participants' subsequent recall toward positive details. Participants who imagined scenarios in a positive light also rated the actual event more positively when they took the recognition test.

"These results suggest that adopting an optimistic outlook can actually transfer to a rosier reflection once those upcoming experiences become part of the personal past," says Devitt.

Devitt and Schacter are now investigating whether a similar phenomenon occurs among healthy old adults, as research has shown that older adults tend to imagine events with less detail but also show an overall positive bias in attention and memory.

This work was supported by a National Institute on Aging grant (R01 AG08441) awarded to Daniel L. Schacter.

All data and materials have been made publicly available via Harvard Dataverse. The complete Open Practices Disclosure for this article is available online. This article has received badges for Open Data and Open Materials.



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Genotype and Phenotype in Multiple Sclerosis—Potential for Disease Course Prediction?

Abstract

Purpose of review

This review will examine the current evidence that genetic and/or epigenetic variation may influence the multiple sclerosis (MS) clinical course, phenotype, and measures of MS severity including disability progression and relapse rate.

Recent findings

There is little evidence that MS clinical phenotype is under significant genetic control. There is increasing evidence that there may be genetic determinants of the rate of disability progression. However, studies that can analyse disability progression and take into account all the confounding variables such as treatment, clinical characteristics, and environmental factors are by necessity longitudinal, relatively small, and generally of short duration, and thus do not lend themselves to the assessment of hundreds of thousands of genetic variables obtained from GWAS. Despite this, there is recent evidence to support the association of genetic loci with relapse rate.

Summary

Recent progress suggests that genetic variations could be associated with disease severity, but not MS clinical phenotype, but these findings are not definitive and await replication. Pooling of study results, application of other genomic techniques including epigenomics, and analysis of biomarkers of progression could functionally validate putative severity markers.



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Identification of novel mutations in LprG (rv1411c), rv0521, rv3630, rv0010c, ppsC, cyp128 associated with pyrazinoic acid/pyrazinamide resistance in Mycobacterium tuberculosis [PublishAheadOfPrint]

Despite progress, the mechanisms of action and resistance of pyrazinamide (PZA) are not well understood. Here, we characterized 109 mutants resistant to pyrazinoic acid (POA), the active form of PZA, and found while most (101/109=93%) mutants had panD mutations, and 4 had clpC1 mutation (S91G)(4/109=4%), new mutations in lprG (rv1411c) and rv0521 (4/109=4%), rv3630, rv0010c, ppsC and cyp128 (cytochrome P450 128) were identified, shedding new light on mechanisms of action and resistance of PZA in M. tuberculosis.



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Antimicrobial Activity of Murepavadin Tested against Clinical Isolates of Pseudomonas aeruginosa from the United States, Europe, and China [PublishAheadOfPrint]

Murepavadin (formerly POL7080), a 14-amino-acid cyclic peptide, and comparators were tested by broth microdilution method against 1,219 isolates from 112 medical centers. Murepavadin (MIC50/90, 0.12/0.12 mg/L) was 4- to 8-fold more active than colistin (MIC50/90, 1/1 mg/L) and polymyxin B (MIC50/90, 0.5/1 mg/L) and inhibited 99.1% of isolates at ≤0.5 mg/L. Only 4 isolates (0.3%) exhibited murepavadin MIC >2 mg/L. Murepavadin was equally active against isolates from Europe, the United States, and China.



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Evaluation of Amphotericin B Lipid Formulations for Treatment of Severe Coccidioidomycosis [PublishAheadOfPrint]

Background

Patients with severe coccidioidomycosis infections are often treated with either amphotericin-B lipid complex (ABLC) or liposomal amphotericin-B (L-AmB). Outcomes data with these agents in severe coccidioidomycosis are currently lacking. The purpose of this study is to evaluate the efficacy and toxicity of ABLC and L-AmB in treating severe coccidioidomycosis.

Methods

A retrospective, pre-post study design was employed. Chart reviews were completed from 01/01/2005 to 12/31/2014 for all patients who received lipid-based amphotericin B. Inclusion criteria having a follow up complement fixation (CF) titer or a treatment emergent adverse event (TEAE) prior to follow up. Those with meningeal involvement and pregnant patients were excluded. Treatment outcomes were assessed based on documented completion of therapy as well symptoms, complement fixation (CF) titer, and changes to laboratory monitoring parameters.

Results

A total of 108 patients were identified, 69 of which met the inclusion criteria. There were no statistical differences in demographics or disease burden in those that received ABLC and those that received L-AmB, except those who received L-AmB were more likely to have previously diagnosed chronic kidney disease (nL-AmB=4, 12.5% vs nABLC=0, 0.0%; p=0.042) and have a lower creatinine clearance at the start of therapy (L-AmB=79.6 mg/dL vs ABLC=100.4mg/dL; p=0.008). Successful treatment was achieved in 27 (73.0%) of ABLC patients and 22 (68.8%) of L-AmB patients (p=0.700). Amphotericin B was discontinued due to documented completion of therapy for 17 (45.9%) ABLC patients and 18 (56.3%) L-AmB patients (p=0.553). Acute kidney injury (AKI) was the documented reason of treatment cessation for 10 (27.0%) ABLC and 1 (3.1%) L-AmB patient (p=0.007).

Conclusion

ABLC and L-AmB both appear to be equally efficacious in the treatment of severe coccidioidomycosis. L-AmB may have less renal toxicity than ABLC and may be the preferred 88 agent in baseline renal impairment.



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Analysis of clinical drug-drug interaction data to predict uncharacterized interaction magnitudes between antiretroviral drugs and co-medications [PublishAheadOfPrint]

Despite their high potential for drug-drug-interactions (DDI), clinical DDI studies of antiretroviral drugs (ARVs) are often lacking, because the full range of potential interactions cannot feasibly or pragmatically be studied, with some high-risk DDI studies also ethically difficult to undertake. Thus, a robust method to screen and to predict the likelihood of DDIs is required.

We developed a method to predict DDIs based on two parameters: the degree of metabolism by specific enzymes such as CYP3A and the strength of an inhibitor or inducer. These parameters were derived from existing studies utilizing paradigm substrates, inducers and inhibitors of CYP3A, to assess the predictive performance of this method by verifying predicted magnitudes of changes in drug exposure against clinical DDI studies involving ARVs.

The derived parameters were consistent with the FDA classification of sensitive CYP3A substrates and the strength of CYP3A inhibitors and inducers. Characterized DDI magnitudes (n = 68) between ARVs and co-medications were successfully quantified meaning 53%, 85% and 98% of the predictions were within 1.25-fold (0.80 – 1.25), 1.5-fold (0.66 – 1.48) and 2-fold (0.66 – 1.94) of the observed clinical data. In addition, the method identifies CYP3A substrates likely to be highly or conversely minimally impacted by CYP3A inhibitors or inducers, thus categorizing the magnitude of DDIs.

The developed effective and robust method has the potential to support a more rational identification of dose adjustment to overcome DDIs being particularly relevant in a HIV-setting giving the treatments complexity, high DDI risk and limited guidance on the management of DDIs.



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Population Pharmacokinetic Model for Vancomycin Used in Open Heart Surgery: Model-Based Evaluation of Standard Dosing Regimens [PublishAheadOfPrint]

The purpose of this study was to investigate the population pharmacokinetics of vancomycin in patients undergoing open heart surgery. In this observational pharmacokinetic study, multiple blood samples were drawn over a 48-h period of intravenous vancomycin in patients who were undergoing open heart surgery. Blood samples were analysed using the Architect i4000SR Immunoassay Analyzer. Population pharmacokinetic models were developed using Monolix 4.4 software. Pharmacokinetic-pharmacodynamic (PK-PD) simulations were performed to explore the ability of different dosage regimens to achieve the pharmacodynamic targets. One-hundred and sixty-eight blood samples were analysed from 28 patients. The pharmacokinetics of vancomycin was best described by a two-compartment model with between-subject variability in CL, V of the central compartment, and V of the peripheral compartment. CL and central compartment V of vancomycin were related to CLCR, body weight, and albumin concentration. Dosing simulations showed that standard dosing regimens of 1 and 1.5 g failed to achieve the PK-PD target of AUC0--24/MIC > 400 for an MIC of 1 mg/L, while high weight-based dosing regimens were able to achieve the PK-PD target. In summary, administration of standard doses of 1 and 1.5 g of vancomycin two times daily provided inadequate antibiotic prophylaxis in patients undergoing open heart surgery. The same findings were obtained when 15 mg/kg and 20 mg/kg doses of vancomycin were administered. Achieving the PK-PD target required higher doses (25 mg/kg and 30 mg/kg) of vancomycin.



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Increasing Rates of Penicillin Sensitivity in Staphylococcus aureus [PublishAheadOfPrint]

Recent publications have reported on the rise of penicillin sensitive staphylococcus aureus (PSSA)....



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Pathogenic Nocardia cyriacigeorgica and Nocardia nova evolve to resist trimethoprim-sulfamethoxazole by both expected and unexpected pathways [PublishAheadOfPrint]

Nocardia spp. are Gram positive opportunistic pathogens that affect largely immunocompromised patients leading to serious pulmonary or systemic infections. Combination therapy using the folate biosynthesis pathway inhibitors, trimethoprim and sulfamethoxazole (TMP-SMX) is commonly used as an antimicrobial therapy. Not surprisingly, as antibiotic therapies for nocardiosis can extend for many months, resistance to TMP-SMX has emerged. Using experimental evolution, we surveyed the genetic basis of adaptation to TMP-SMX across 8 strains of Nocardia nova and 2 strains of Nocardia cyriacigeorgica. Employing both continuous experimental evolution to provide longitudinal information on the order of changes and characterization of resistant end-point isolates, we observe changes that are consistent with modification of two enzymes of the folate biosynthesis pathway: dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS/FolP) with the mutations often clustered near the active site of the enzymes. While changes to DHFR and DHPS might be expected, we also noted that mutations in a previously undescribed homolog of DHPS (DHPS2/FolP2) that was annotated as "non-functional" were also sufficient to generate TMP-SMX resistance which serves as a cautionary tale for the use of automated annotation by investigators and for future drug discovery against this genus. Additionally, folP2 overlapped with glucosyl-3-phosphoglycerate synthase. Remarkably, an adaptive frameshift mutation within the overlapping region resulted in a new in-frame fusion to the downstream gene to produce a potentially new bifunctional enzyme. How a single potentially bifunctional DHPS2 might confer resistance is unclear. However, it highlights the unexpected ways in which adaptive evolution finds novel solutions to selection.



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In Vitro Activity of Ceftazidime-Avibactam Against Isolates from Patients in a Phase 3 Clinical Trial for the Treatment of Complicated Intra-Abdominal Infections [PublishAheadOfPrint]

Increasing prevalence of multidrug-resistant Gram-negative pathogens has generated a requirement for new treatment options. Avibactam, a novel non-β-lactam β-lactamase inhibitor, restores activity of ceftazidime against Ambler class A, C and some class D β-lactamase-producing strains of Enterobacteriaceae and Pseudomonas aeruginosa. In vitro activity of ceftazidime-avibactam versus comparators was evaluated against 1,440 clinical isolates obtained in a phase 3 clinical trial in patients with complicated intra-abdominal infections (cIAI; NCT01499290).

Overall, in vitro activity was determined for 803 Enterobacteriaceae, 70 P. aeruginosa, 304 Gram-positive aerobes and 255 anaerobes isolated at baseline from 1,066 randomized patients. Susceptibility was determined by broth microdilution.

The most commonly isolated Gram-negative, Gram-positive and anaerobic pathogens were Escherichia coli (n = 549), Streptococcus anginosus (n = 130) and Bacteroides fragilis (n = 96), respectively. Ceftazidime-avibactam was highly active against isolates of Enterobacteriaceae, with an overall MIC90 of 0.25 mg/l. In contrast, the MIC90 for ceftazidime alone was 32 mg/l. The MIC90 value for ceftazidime-avibactam (4 mg/l) was one dilution lower than that of ceftazidime alone (8 mg/l) against isolates of Pseudomonas aeruginosa. The ceftazidime-avibactam MIC90 for 109 ceftazidime-non-susceptible Enterobacteriaceae isolates was 2 mg/l and the MIC range for 6 ceftazidime-non-susceptible P. aeruginosa isolates was 8 to 32 mg/l. MIC90 values were within the range of susceptibility for the study drugs permitted per protocol in the phase 3 study to provide coverage for aerobic Gram-positive and anaerobic pathogens.

These findings demonstrate the in vitro activity of ceftazidime-avibactam against bacterial pathogens commonly observed in cIAI patients, including ceftazidime-non-susceptible Enterobacteriaceae.



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Enterobacter cloacae complex isolated from shrimps from Vietnam encoding blaIMI-1, resistant to carbapenems but not cephalosporins. [PublishAheadOfPrint]

In August of 2017, a batch of Penaeus monodon (Asian tiger shrimp) and Penaues vannamei (White leg shrimp), originating from fish farms in Vietnam, were screened for the presence of carbapenamase producing Enterobacteriaceae (CPE)....



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Retained activity of an O25b specific monoclonal antibody against Mcr-1 producing Escherichia coli ST131 [PublishAheadOfPrint]

Plasmid-encoded colistin resistance is emerging among extra-intestinal pathogenic Escherichia coli including the epidemic clone ST131-H30. Mcr-1 transfers a phosphoethanolamine to the lipid A portion of LPS conferring resistance to polymyxins. We investigated whether this modification changed the activity of the monoclonal antibody, ASN-4 specific to the O25b side-chain of ST131 LPS. We confirmed that, unlike colistin, ASN-4 retained its bactericidal and endotoxin neutralizing activity and therefore offer a treatment option against extremely drug-resistant ST131 isolates.



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Combination Therapy and the Evolution of Resistance: The Theoretical Merits of Synergism and Antagonism in Cancer

The search for effective combination therapies for cancer has focused heavily on synergistic combinations because they exhibit enhanced therapeutic efficacy at lower doses. Although synergism is intuitively attractive, therapeutic success often depends on whether drug resistance develops. The impact of synergistic combinations (vs. antagonistic or additive combinations) on the process of drug-resistance evolution has not been investigated. In this study, we use a simplified computational model of cancer cell numbers in a population of drug-sensitive, singly-resistant, and fully-resistant cells to simulate the dynamics of resistance evolution in the presence of two-drug combinations. When we compared combination therapies administered at the same combination of effective doses, simulations showed synergistic combinations most effective at delaying onset of resistance. Paradoxically, when the therapies were compared using dose combinations with equal initial efficacy, antagonistic combinations were most successful at suppressing expansion of resistant subclones. These findings suggest that, although synergistic combinations could suppress resistance through early decimation of cell numbers (making them "proefficacy" strategies), they are inherently fragile toward the development of single resistance. In contrast, antagonistic combinations suppressed the clonal expansion of singly-resistant cells, making them "antiresistance" strategies. The distinction between synergism and antagonism was intrinsically connected to the distinction between offensive and defensive strategies, where offensive strategies inflicted early casualties and defensive strategies established protection against anticipated future threats. Our findings question the exclusive focus on synergistic combinations and motivate further consideration of nonsynergistic combinations for cancer therapy.Significance: Computational simulations show that if different combination therapies have similar initial efficacy in cancers, then nonsynergistic drug combinations are more likely than synergistic drug combinations to provide a long-term defense against the evolution of therapeutic resistance. Cancer Res; 78(9); 1–13. ©2018 AACR.

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Workshop Report for Cancer Research: Defining the Shades of Gy: Utilizing the Biological Consequences of Radiotherapy in the Development of New Treatment Approaches—Meeting Viewpoint



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Patients Prefer Doctors Who Engage in Face-to-Face Visits

MONDAY, April 23, 2018 -- Patients prefer physicians who engage in face-to-face (F2F) clinic visits, rather than those using an examination room computer (ERC), according to a research letter published online April 19 in JAMA Oncology. Ali Haider,...

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Controlling High Blood Pressure Could Prevent Dementia

MONDAY, April 23, 2018 -- Controlling high blood pressure in older African-Americans may prevent future dementia, according to a study published recently in the Journal of General Internal Medicine. Michael D. Murray, Pharm.D., from the Regenstrief...

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Electric Cars Safe With Cardiac Implantable Electronic Devices

MONDAY, April 23, 2018 -- Electric cars seem to be safe for patients with cardiac implantable electronic devices (CIEDs), and do not result in electromagnetic interference (EMI), according to a study published online April 24 in the Annals of...

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Factors ID'd to Predict Fatty Liver in Obese Teens

MONDAY, April 23, 2018 -- Ethnicity/race, markers of insulin resistance, and genetic factors might help identify obese youth at risk for developing fatty liver, according to a study published online April 17 in Hepatology. Domenico Tricò, M.D.,...

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Flexible Sigmoidoscopy Cuts CRC Incidence, Mortality in Men

MONDAY, April 23, 2018 -- Flexible sigmoidoscopy screening is associated with reduced colorectal cancer (CRC) incidence and mortality in men, but not women, according to a study published online April 24 in the Annals of Internal Medicine. Øyvind...

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Cycling Towards Progress: Ribociclib, CDK 4/6 inhibitor for Breast Cancer

Ribociclib is an orally active, highly selective inhibitor of cyclin-dependent kinase (CDK) 4 and 6. It is the second CDK 4/6 inhibitor approved for hormone receptor-positive breast cancer. The addition of ribociclib to an aromatase inhibitor has resulted in marked improvements in progression-free survival for patients with metastatic breast cancer.



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Integrative kinome profiling identifies mTORC1/2 inhibition as treatment strategy in ovarian clear cell carcinoma

Purpose: Advanced stage ovarian clear cell carcinoma (OCCC) is unresponsive to conventional platinum-based chemotherapy. Frequent alterations in OCCC include deleterious mutations in the tumor suppressor ARID1A and activating mutations in the PI3K subunit PIK3CA. In this study, we aimed to identify currently unknown mutated kinases in OCCC patients and test druggability of downstream affected pathways in OCCC models. Experimental Design: In a large set of OCCC patients (n=124), the human kinome (518 kinases) and additional cancer related genes were sequenced and copy number alterations were determined. Genetically characterized OCCC cell lines (n=17) and OCCC patient-derived xenografts (n=3) were used for drug testing of ERBB tyrosine kinase inhibitors erlotinib and lapatinib, the PARP inhibitor olaparib and the mTORC1/2 inhibitor AZD8055. Results: We identified several putative driver mutations in kinases at low frequency that were not previously annotated in OCCC. Combining mutations and copy number alterations, 91% of all tumors are affected in the PI3K/AKT/mTOR pathway, the MAPK pathway or the ERBB family of receptor tyrosine kinases and 82% in the DNA repair pathway. Strong p-S6 staining in OCCC patients suggests high mTORC1/2 activity. We consistently found that the majority of OCCC cell lines are especially sensitive to mTORC1/2 inhibition by AZD8055 and not towards drugs targeting ERBB family of receptor tyrosine kinases or DNA repair signaling. We subsequently demonstrated the efficacy of mTORC1/2 inhibition in all our unique OCCC patient-derived xenograft models. Conclusions: These results propose mTORC1/2 inhibition as an effective treatment strategy in OCCC.



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Clinicopathological risk factors for an invasive breast cancer recurrence after ductal carcinoma in situ - A nested case-control study

Purpose: Ductal carcinoma in situ (DCIS) is treated to prevent progression to invasive breast cancer. Yet, most lesions will never progress, implying that overtreatment exists. Therefore, we aimed to identify factors distinguishing harmless from potentially hazardous DCIS using a nested case-control study. Experimental Design: We conducted a case-control study nested in a population-based cohort of DCIS patients treated with breast conserving surgery (BCS) alone (n=2,658) between 1989-2005. We compared clinical, pathological, and immunohistochemical DCIS characteristics of 200 women who subsequently developed ipsilateral invasive breast cancer (iIBC; cases) and 474 women who did not (controls), in a matched setting. Median follow-up time was 12.0 years (interquartile range 9.0-15.3). Conditional logistic regression models, were used to assess associations of various factors with subsequent iIBC risk after primary DCIS. Results: High COX-2 protein expression showed the strongest association with subsequent iIBC (odds ratio [OR]=2.97, 95% confidence interval [95%CI] 1.72-5.10). In addition, HER2 overexpression (OR=1.56, 95%CI 1.05-2.31) and presence of periductal fibrosis (OR=1.44, 95%CI 1.01-2.06) were associated with subsequent iIBC risk. Patients with HER2+/COX-2high DCIS had a 4-fold higher risk of subsequent iIBC (vs. HER2-/COX-2low DCIS), and an estimated 22.8% cumulative risk of developing subsequent iIBC at 15 years. Conclusions: With this unbiased study design and representative group of DCIS patients treated by BCS alone, COX-2, HER2, and periductal fibrosis were revealed as promising markers predicting progression of DCIS into iIBC. Validation will be done in independent data sets. Ultimately, this will aid individual risk stratification of women with primary DCIS.



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21-gene recurrence score assay predicts benefit of post-mastectomy radiotherapy in T1-2 N1 breast cancer

Purpose: Post-mastectomy radiotherapy (PMRT) yields improvements in both locoregional control and overall survival (OS) for women with T1-2 N1 breast cancer. The value of PMRT in this population has been questioned given advances in systemic therapy. The 21-gene Recurrence Score (RS) assay was evaluated as a predictor of OS among women with T1-2 N1 breast cancer who received or did not receive PMRT. Experimental Design: An observational cohort study was performed on women with T1-2 N1 estrogen receptor-positive breast cancer from the National Cancer Database (NCDB) and, as a validation cohort, from the Surveillance, Epidemiology, and End Results (SEER) registry who underwent mastectomy and were evaluated for RS. Multivariable parametric accelerated failure time models were used to estimate associations of RS and PMRT with OS using propensity score-adjusted matched cohorts. Results: In both the NCDB (N=7,332) and SEER (N=3,087) cohorts, there was a significant interaction of RS and PMRT with OS (P=0.009 and P=0.03, respectively). PMRT was associated with longer OS in women with a low RS (NCDB: time-ratio (TR)=1.70, 95% CI=1.30-2.22, P<0.001; SEER: TR=1.85, 95% CI=1.33-2.57, P<0.001), but not in women with an intermediate RS (NCDB: TR=0.89, 95% CI=0.69-1.14, P=0.35; SEER: TR=0.84, 95% CI=0.62-1.14, P=0.26), or a high RS (NCDB: TR=1.10, 95% CI=0.91-1.34, P=0.33; SEER: TR=0.79, CI=0.50-1.23, P=0.28). Conclusions: Longer survival associated with PMRT was limited to women with a low RS. PMRT may confer the greatest OS benefit for patients at lowest risk of distant recurrence. These results caution against omission of PMRT among women with low RS.



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A model of overall survival predicts treatment outcomes with atezolizumab vs chemotherapy in non-small cell lung cancer based on early tumor kinetics

Purpose: Standard endpoints often poorly predict overall survival (OS) with immunotherapies. We investigated the predictive performance of model-based tumor growth inhibition (TGI) metrics using data from atezolizumab clinical trials in patients with non-small cell lung cancer. Methods: OS benefit with atezolizumab vs docetaxel was observed in both POPLAR (phase II) and OAK (phase III) although progression-free survival was similar between arms. A multivariate model linking baseline patient characteristics and on-treatment tumor growth rate constant (KG), estimated using time profiles of sum of longest diameters (RECIST 1.1) to OS, was developed using POPLAR data. The model was evaluated to predict OAK outcome based on estimated KG at TGI data cutoffs ranging from 10 to 122 weeks. Results: In POPLAR, TGI profiles in both arms crossed at 25 weeks, with more shrinkage with docetaxel and slower KG with atezolizumab. A log-normal OS model, with albumin and number of metastatic sites as independent prognostic factors and estimated KG, predicted OS hazard ratio (HR) in sub-populations of patients with varying baseline PD-L1 expression in both POPLAR and OAK: model-predicted OAK HR (95% prediction interval): 0.73 (0.63-0.85) vs 0.73 observed. The POPLAR OS model predicted greater than 97% chance of success of OAK (significant OS HR, P < 0.05) from the 40-week data cutoff onward with 50% of the total number of tumor assessments when a successful study was predicted from 70 weeks onward based on observed OS. Conclusions: KG has potential as a model-based early endpoint to inform decisions in cancer immunotherapy studies.



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Baseline Tumor Size Is an Independent Prognostic Factor for Overall Survival in Patients With Melanoma Treated With Pembrolizumab

Purpose: To assess the association of baseline tumor size (BTS) with other baseline clinical factors and outcomes in pembrolizumab-treated patients with advanced melanoma in KEYNOTE-001 (NCT01295827). Experimental Design: BTS was quantified by adding the sum of the longest dimensions of all measurable baseline target lesions. BTS as a dichotomous and continuous variable was evaluated with other baseline factors using logistic regression for objective response rate (ORR) and Cox regression for overall survival (OS). Nominal P values with no multiplicity adjustment describe the strength of observed associations. Results: Per central review by RECIST v1.1, 583 of 655 patients had baseline measurable disease and were included in this post hoc analysis. Median BTS was 10.2 cm (range, 1-89.5). Larger median BTS was associated with Eastern Cooperative Oncology Group performance status 1, elevated lactate dehydrogenase (LDH), stage M1c disease, and liver metastases (with or without any other sites) (all P ≤ 0.001). In univariate analyses, BTS below the median was associated with higher ORR (44% vs 23%; P < 0.001) and improved OS (hazard ratio, 0.38; P < 0.001). In multivariate analyses, BTS below the median remained an independent prognostic marker of OS (P < 0.001) but not ORR. In 459 patients with available tumor programmed death ligand 1 (PD-L1) expression, BTS below the median and PD-L1-positive tumors were independently associated with higher ORR and longer OS. Conclusions: BTS is associated with many other baseline clinical factors but is also independently prognostic of survival in pembrolizumab-treated patients with advanced melanoma.



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TAS2R38 Predisposition to Bitter Taste Associated with Differential Changes in Vegetable Intake in Response to a Community-Based Dietary Intervention

Although vegetable consumption associates with decreased risk for a variety of diseases, few Americans meet dietary recommendations for vegetable intake. TAS2R38 encodes a taste receptor that confers bitter taste sensing from chemicals found in some vegetables. Common polymorphisms in TAS2R38 lead to coding substitutions that alter receptor function and result in the loss of bitter taste perception. Our study examined whether bitter taste perception TAS2R38 diplotypes associated with vegetable consumption in participants enrolled in either an enhanced or a minimal nutrition counseling intervention. DNA was isolated from the peripheral blood cells of study participants (N = 497) and analyzed for polymorphisms. Vegetable consumption was determined using the Block Fruit and Vegetable screener. We tested for differences in the frequency of vegetable consumption between intervention and genotype groups over time using mixed effects models. Baseline vegetable consumption frequency did not associate with bitter taste diplotypes (p = 0.937), however after six months of the intervention, we observed an interaction between bitter taste diplotypes and time (p = 0.046). Participants in the enhanced intervention increased their vegetable consumption frequency (p = 0.020) and within this intervention group, the bitter non-tasters and intermediate-bitter tasters had the largest increase in vegetable consumption. In contrast, in the minimal intervention group, the bitter tasting participants reported a decrease in vegetable consumption. Bitter-non tasters and intermediate-bitter tasters increased vegetable consumption in either intervention more than those who perceive bitterness. Future precision medicine applications could consider genetic variation in bitter taste perception genes when designing dietary interventions.



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Regulation of Global Transcription in Escherichia coli by Rsd and 6S RNA

In Escherichia coli, the sigma factor 70 directs RNA polymerase to transcribe growth-related genes, while 38 directs transcription of stress response genes during stationary phase. Two molecules hypothesized to regulate RNA polymerase are the protein Rsd, which binds to 70, and the non-coding 6S RNA which binds to the RNA polymerase-70 holoenzyme. Despite multiple studies, the functions of Rsd and 6S RNA remain controversial. Here we use RNA-Seq in five phases of growth to elucidate their function on a genome-wide scale. We show for the first time that Rsd and 6S RNA facilitate 38 activity throughout bacterial growth, while 6S RNA also regulates widely different genes depending upon growth phase. We discover novel interactions between 6S RNA and Rsd and show widespread expression changes in a strain lacking both regulators. Finally, we present a mathematical model of transcription which highlights the crosstalk between Rsd and 6S RNA as a crucial factor in controlling sigma factor competition and global gene expression.



https://ift.tt/2F8SU4V

{-}{-}RNA Polymerase II Transcription Attenuation at the Yeast DNA Repair Gene, DEF1, Involves Sen1-Dependent and Polyadenylation Site-Dependent Termination

Termination of RNA Polymerase II (Pol II) activity serves a vital cellular function by separating ubiquitous transcription units and influencing RNA fate and function. In the yeast Saccharomyces cerevisiae, Pol II termination is carried out by cleavage and polyadenylation factor (CPF-CF) and Nrd1-Nab3-Sen1 (NNS) complexes, which operate primarily at mRNA and non-coding RNA genes, respectively. Premature Pol II termination (attenuation) contributes to gene regulation, but there is limited knowledge of its prevalence and biological significance. In particular, it is unclear how much crosstalk occurs between CPF-CF and NNS complexes and how Pol II attenuation is modulated during stress adaptation. In this study, we have identified an attenuator in the DEF1 DNA repair gene, which includes a portion of the 5'-untranslated region (UTR) and upstream open reading frame (ORF). Using a plasmid-based reporter gene system, we conducted a genetic screen of 14 termination mutants and their ability to confer Pol II read-through defects. The DEF1 attenuator behaved as a hybrid terminator, relying heavily on CPF-CF and Sen1 but without Nrd1 and Nab3 involvement. Our genetic selection identified 22 cis-acting point mutations that clustered into four regions, including a polyadenylation site efficiency element that genetically interacts with its cognate binding-protein Hrp1. Outside of the reporter gene context, a DEF1 attenuator mutant increased mRNA and protein expression, exacerbating the toxicity of a constitutively active Def1 protein. Overall, our data support a biologically significant role for transcription attenuation in regulating DEF1 expression, which can be modulated during the DNA damage response.



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Prognostic value of isolated tumour cells in sentinel lymph nodes in early-stage breast cancer: a prospective study

Prognostic value of isolated tumour cells in sentinel lymph nodes in early-stage breast cancer: a prospective study

Prognostic value of isolated tumour cells in sentinel lymph nodes in early-stage breast cancer: a prospective study, Published online: 24 April 2018; doi:10.1038/s41416-018-0052-7

Prognostic value of isolated tumour cells in sentinel lymph nodes in early-stage breast cancer: a prospective study

https://ift.tt/2HJDMAc

Chronic Consumption of Sweeteners and Its Effect on Glycaemia, Cytokines, Hormones, and Lymphocytes of GALT in CD1 Mice

Background. The consumption of sweeteners has increased in recent years, being used to control body weight and blood glucose. However, they can cause increased appetite, modification of immune function, and secretion of hormones in the GALT. Objective. To assess the effect of chronic sweetener consumption on glycaemia, cytokines, hormones, and GALT lymphocytes in CD1 mice. Material and Methods. 72 CD1 mice divided into 3 groups were used: (a) baseline, (b) middle, and (c) final. Groups (b) and (c) were divided into 4 subgroups: (i) Control, (ii) Sucrose, (iii) Sucralose, and (iv) Stevia. The following were determined: body weight, hormones (GIP, insulin, and leptin), lymphocytes CD3+T cells and CD19+B cells, IgA+ plasma cells, and cytokines (IL-4, IL-5, IFN-γ, and TNF-α). Results. Sucralose reduces secretion of GIP and glycaemia but does not modify insulin concentration, increases body weight, and reduces food intake. Stevia increases the secretion of GIP, insulin, leptin, body weight, and glycaemia but keeps food consumption normal. Sucralose and Stevia showed a higher percentage of CD3+T cells, CD19+B cells, and IgA+ plasma cells in Peyer's patches, but only Stevia in lamina propria. Conclusion. Sweeteners modulate the hormonal response of cytokines and the proliferation of lymphocytes in the intestinal mucosa.

https://ift.tt/2qUJhSo

Bim is an Independent Prognostic Marker in Intrahepatic Cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver malignant tumor and has a poor prognosis. The prognostic factors associated with outcome remain poorly defined. In this study, we investigated the role of an important cell apoptosis initiator, Bcl-2 interacting mediator of cell death (Bim), by evaluating its expression and association with other clinicopathologic features in ICCs. We analyzed 56 cases of ICC with clinical follow-up. The expression of Bim in ICC cells and other cellular components was evaluated by immunohistochemistry.

https://ift.tt/2vHdeuN

Upregulation of long non-coding RNA M26317 correlates with tumor progression and poor prognosis in gastric cancer

To investigate the expression and clinical significance of long non-coding RNA (lnc RNA) in gastric cancer, we applied microarray analysis to obtain expression profiles of protein coding genes and lncRNAs in tumor and paired adjacent non-tumor tissues. We found that 41 lncRNAs were upregulated and 31 lncRNAs were downregulated more than 2-fold in gastric cancer versus noncancerous tissues (ratio>2.0, P<.01). We established a co-expression network of the differentially expressed lncRNAs and targeted coding genes that included 17 lncRNAs and 16 coding genes.

https://ift.tt/2HH0IQz

Mucinous intrahepatic cholangiocarcinoma: a distinct variant

Mucinous variant of intrahepatic cholangiocarcinoma (iCC) is rare, and its clinicopathological features and prognosis are far less clear. Six patients who had iCCs with more than 50% of mucinous component and 79 conventional iCCs were included in the study. The mean size of mucinous and conventional iCCs was 6.2cm and 6.0cm, respectively. The majority of patients (83%) with mucinous iCC presented at T3 stage or above, compared to 28% of the conventional group (p<0.01). Three patients with mucinous iCC (50%) died within 1year.

https://ift.tt/2vEXyZ0

Maternal caffeine intake during pregnancy and childhood growth and overweight: results from a large Norwegian prospective observational cohort study

Objectives

To study the association between maternal caffeine intake during pregnancy and the child's weight gain and overweight risk up to 8 years.

Design

Prospective nationwide pregnancy cohort.

Setting

The Norwegian Mother and Child Cohort Study.

Participants

A total of 50 943 mothers recruited from 2002 to 2008 and their children, after singleton pregnancies, with information about average caffeine intake assessed at mid-pregnancy.

Outcome measure

Child's body size information at 11 age points from 6 weeks to 8 years. We defined excess growth in infancy as a WHO weight gain z-score of >0.67 from birth to age 1 year, and overweight according to the International Obesity Task Force. We used a growth model to assess individual growth trajectories.

Results

Compared with pregnant women with low caffeine intake (<50 mg/day, 46%), women with average (50–199 mg/day, 44%), high (≥200–299 mg/day, 7%) and very high (≥300 mg/day, 3%) caffeine intakes had an increased risk of their child experiencing excess growth in infancy, after adjustment for confounders (OR=1.15, 95% CI 1.09 to 1.22, OR=1.30, 95% CI 1.16 to 1.45, OR=1.66, 95% CI 1.42 to 1.93, respectively). In utero exposure to any caffeine was associated with higher risk of overweight at age 3 years and 5 years, while the association persisted at 8 years, only for very high exposures. Any caffeine intake was associated with increased body mass index from infancy to childhood. Children prenatally exposed to caffeine intake >200 mg/day had consistently higher weight. Very high caffeine exposures were associated with higher weight gain velocity from infancy to age 8 years.

Conclusion

Any caffeine consumption during pregnancy is associated with a higher risk of excess infant growth and of childhood overweight, mainly at preschool ages. Maternal caffeine intake may modify the overall weight growth trajectory of the child from birth to 8 years. This study adds supporting evidence for the current advice to reduce caffeine intake during pregnancy.



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FXR Deletion in Hepatocytes does not Affect the Severity of Alcoholic Liver Disease in Mice

Emerging evidence has shown that FXR activation ameliorates the development of alcoholic liver diseases (ALD) while whole-body deficiency of FXR in mice leads to more severe ALD. However, it's unknown whether the enhanced susceptibility to ALD development in FXR−/− mice is due to deficiency of hepatic FXR or increased toxicity secondary to increased bile acid (BA) levels. Hepatocyte-specific FXR knockout mice (FXRhep−/−) present similar BA levels compared to wild-type mice, and are therefore a useful model to study a direct role of hepatic FXR in ALD development.

https://ift.tt/2Jl0I64

☆EUS–guided reconstruction of the biliary system in a patient post right hemihepatectomy



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A strong sense of coherence associated with reduced risk of anxiety disorder among women in disadvantaged circumstances: British population study

Objective

Many patients receiving medical treatment for anxiety relapse or do not improve. Research has therefore been turning to coping mechanisms as a way to decrease anxiety rates. Previously, we showed that living in a deprived area significantly increases the risk of anxiety in women, but not in men. The objective of this study is to assess whether sense of coherence (coping mechanism) buffers the influence of area deprivation on women's risk of generalised anxiety disorder using data from the European Prospective Investigation of Cancer-Norfolk.

Design

Large, population study.

Setting

UK population-based cohort.

Participants

30 445 people over the age of 40 years were recruited through general practice registers in England. Of these, 20 919 completed a structured health and lifestyle questionnaire used to assess generalised anxiety disorder and sense of coherence. Area deprivation was measured using 1991 Census data, and sense of coherence and anxiety were examined in 1996–2000. 10 183 women had data on all variables.

Main outcome measure

Past-year generalised anxiety disorder defined according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition.

Results

In this study, 2.6% (260/10 183) of women had generalised anxiety disorder. In those with a strong sense of coherence, area deprivation was not significantly associated with anxiety (OR 1.29, 95% CI 0.77 to 2.17). However, among women with a weak sense of coherence, those living in deprived areas were almost twice as likely to have generalised anxiety disorder compared with those living in more affluent areas (OR 1.99, 95% CI 1.37 to 2.91).

Conclusion

The number of women living in deprived conditions is large worldwide, and significant numbers are affected by generalised anxiety disorder. Sense of coherence moderates the association between area deprivation and anxiety in women; therefore, interventions targeting coping mechanisms may need to be considered for people with anxiety.



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Do Electric Cars Interfere With Pacemakers and Defibrillators?



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Sigmoidoscopy Screening for Colorectal Cancer



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Comparison of Rates of Firearm and Nonfirearm Homicide and Suicide in Black and White Non-Hispanic Men, by U.S. State

Background:
The extent to which differences in homicide and suicide rates in black versus white men vary by U.S. state is unknown.
Objective:
To compare the rates of firearm and nonfirearm homicide and suicide in black and white non-Hispanic men by U.S. state and to examine whether these deaths are associated with state prevalence of gun ownership.
Design:
Surveillance study.
Setting:
50 states and the District of Columbia, 2008 to 2016. Cause-of-death data were abstracted by using the Centers for Disease Control and Prevention's WONDER (Wide-ranging Online Data for Epidemiologic Research) database.
Participants:
Non-Hispanic black and non-Hispanic white males, all ages.
Measurements:
Absolute rates of and rate differences in firearm and nonfirearm homicide and suicide in black and white men.
Results:
During the 9-year study period, 84 113 homicides and 251 772 suicides occurred. Black–white differences in rates of firearm homicide and suicide varied widely across states. Relative to white men, black men had between 9 and 57 additional firearm homicides per 100 000 per year, with black men in Missouri, Michigan, Illinois, Indiana, and Pennsylvania having more than 40 additional firearm homicides per 100 000 per year. White men had between 2 fewer and 16 more firearm suicides per 100 000 per year, with the largest inequalities observed in southern and western states and the smallest in the District of Columbia and densely populated northeastern states.
Limitations:
Some homicides and suicides may have been misclassified as deaths due to unintentional injury. Survey data on state household gun ownership were collected in 2004 and may have shifted during the past decade.
Conclusion:
The large state-to-state variation in firearm homicide and suicide rates, as well as the racial inequalities in these numbers, highlights states where policies may be most beneficial in reducing homicide and suicide deaths and the racial disparities in their rates.
Primary Funding Source:
McGill University and the National Institutes of Health.

https://ift.tt/2HZNOet

Electric Cars and Electromagnetic Interference With Cardiac Implantable Electronic Devices: A Cross-sectional Evaluation



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Integrated Inpatient Medical and Psychiatric Care: Experiences of 5 Institutions

Some hospitalized patients with comorbid, chronic medical and psychiatric illnesses may benefit from admission to an integrated unit that can provide care for both conditions. This commentary describes integrated medical–psychiatric inpatient care units implemented in 5 U.S. institutions, the facilitators of and barriers to this model, and the benefits in terms of patient outcomes and provider satisfaction.

https://ift.tt/2HWB48b

Why “More Research Is Needed,” Despite Overall Certainty: Women and Colorectal Cancer Screening

Holme and colleagues offer the latest evidence that adds to and challenges our understanding of the optimal screening approach for colorectal cancer (CRC). The study confirms the effectiveness of screening sigmoidoscopy to reduce CRC incidence and mortality among men but not among women. The editorialist discusses the findings and why more research is needed.

https://ift.tt/2FaAMYu

Long-Term Effectiveness of Sigmoidoscopy Screening on Colorectal Cancer Incidence and Mortality in Women and Men A Randomized Trial

Background:
The long-term effects of sigmoidoscopy screening on colorectal cancer (CRC) incidence and mortality in women and men are unclear.
Objective:
To determine the effectiveness of flexible sigmoidoscopy screening after 15 years of follow-up in women and men.
Design:
Randomized controlled trial. (ClinicalTrials.gov: NCT00119912)
Setting:
Oslo and Telemark County, Norway.
Participants:
Adults aged 50 to 64 years at baseline without prior CRC.
Intervention:
Screening (between 1999 and 2001) with flexible sigmoidoscopy with and without additional fecal blood testing versus no screening. Participants with positive screening results were offered colonoscopy.
Measurements:
Age-adjusted CRC incidence and mortality stratified by sex.
Results:
Of 98 678 persons, 20 552 were randomly assigned to screening and 78 126 to no screening. Adherence rates were 64.7% in women and 61.4% in men. Median follow-up was 14.8 years. The absolute risks for CRC in women were 1.86% in the screening group and 2.05% in the control group (risk difference, −0.19 percentage point [95% CI, −0.49 to 0.11 percentage point]; HR, 0.92 [CI, 0.79 to 1.07]). In men, the corresponding risks were 1.72% and 2.50%, respectively (risk difference, −0.78 percentage point [CI, −1.08 to −0.48 percentage points]; hazard ratio [HR], 0.66 [CI, 0.57 to 0.78]) (P for heterogeneity = 0.004). The absolute risks for death of CRC in women were 0.60% in the screening group and 0.59% in the control group (risk difference, 0.01 percentage point [CI, −0.16 to 0.18 percentage point]; HR, 1.01 [CI, 0.77 to 1.33]). The corresponding risks for death of CRC in men were 0.49% and 0.81%, respectively (risk difference, −0.33 percentage point [CI, −0.49 to −0.16 percentage point]; HR, 0.63 [CI, 0.47 to 0.83]) (P for heterogeneity = 0.014).
Limitation:
Follow-up through national registries.
Conclusion:
Offering sigmoidoscopy screening in Norway reduced CRC incidence and mortality in men but had little or no effect in women.
Primary Funding Source:
Norwegian government and Norwegian Cancer Society.

https://ift.tt/2HUwRSq

BAP1 induces cell death via interaction with 14-3-3 in neuroblastoma

BAP1 induces cell death via interaction with 14-3-3 in neuroblastoma

BAP1 induces cell death via interaction with 14-3-3 in neuroblastoma, Published online: 24 April 2018; doi:10.1038/s41419-018-0500-6

BAP1 induces cell death via interaction with 14-3-3 in neuroblastoma

https://ift.tt/2HGSXKr

Prognostic value of isolated tumour cells in sentinel lymph nodes in early-stage breast cancer: a prospective study



https://ift.tt/2Hpk4WY

Webinar: How data is being used to improve patient care

NHTSA's Office of EMS will discuss how two EMS agencies are using data to not only improve performance, but demonstrate value

https://ift.tt/2qTrwCR

Impact of Telehealth Interventions on Processes and Quality of Care for Patients With ESRD

Caring for patients with end-stage renal disease (ESRD) requiring dialysis is intensive and expensive. Telehealth may improve the access and efficiency of ESRD care. For this perspective, we systematically reviewed studies that examined the effectiveness of telehealth versus or in addition to usual care for ESRD management. 10 studies were identified, including 7 randomized trials and 3 cohort studies. Study populations, modes of delivery (including telephone, telemetry, or videoconferencing), and the outcomes evaluated varied substantially between studies.

https://ift.tt/2Hn0V8b

Blood Lead Levels and Decreased Kidney Function in a Population-Based Cohort

Environmental lead exposure has been associated with decreased kidney function, but evidence from large prospective cohort studies examining low exposure levels is scarce. We assessed the association of low levels of lead exposure with kidney function and kidney disease.

https://ift.tt/2HJuTqk

Impact of a Primary Care CKD Registry in a US Public Safety-Net Health Care Delivery System: A Pragmatic Randomized Trial

Many individuals with chronic kidney disease (CKD) do not receive guideline-concordant care. We examined the impact of a team-based primary care CKD registry on clinical measures and processes of care among patients with CKD cared for in a public safety-net health care delivery system.

https://ift.tt/2HrWTeY

Getting Inside the Expert’s Head: An Analysis of Physician Cognitive Processes During Trauma Resuscitations

Crisis resource management skills are integral to leading the resuscitation of a critically ill patient. Despite their importance, crisis resource management skills (and their associated cognitive processes) have traditionally been difficult to study in the real world. The objective of this study was to derive key cognitive processes underpinning expert performance in resuscitation medicine, using a new eye-tracking–based video capture method during clinical cases.

https://ift.tt/2Hp3lTV

Whither the Jones Criteria?

In this volume of The Journal, Licciardi et al from Turin, Italy, report their experience using the newest version of the Jones Criteria for the diagnosis of acute rheumatic fever (ARF) and appear to validate the rationale for the revision.1

https://ift.tt/2HlIroB

Critical issues underlying expenditures for adolescent idiopathic scoliosis surgery: questioning the surgical treatment motivation

We read with interest the study from Workman et al.1 They presented the representative hospital expenditures of adolescent idiopathic scoliosis (AIS) surgery, based on a national database. Analyzing 16 992 cases, they noted that the primary contribution for hospital cost was derived from spinal implants. Because AIS surgery carries a heavy burden to limited health resources, critical issues exist before deciding whether to treat surgically children and adolescents with a benign spinal deformity such as AIS.

https://ift.tt/2HJE7mw

Brain Hydatid in a Child

A 4.5-year-old boy was brought to the emergency room with a history of multiple generalized tonic–clonic seizures for 1 day. On examination, there was no focal neurologic deficit and no signs of increased intracranial pressure. The fundus examination was normal, as was the examination of other body systems. The patient was administered anticonvulsants and the seizures were controlled. The T1- and T2-weighted magnetic resonance imaging of his brain showed a well-circumscribed, spherical, cystic lesion in the right temporal region, with no calcification or wall enhancement, causing a mass effect, consistent with a diagnosis of a hydatid cyst (Figure, A and B).

https://ift.tt/2qTsLCS

Deficiencies in the conduct and reporting of pediatric clinical trials

We read with interest the report by Gates et al evaluating deficiencies in the conduct and reporting of randomized, controlled trials in pediatrics.1 This work appropriately calls attention to limitations in pediatric research related to study design and selective reporting that negatively impact the quality of available evidence.

https://ift.tt/2HluDKH

Prevalence of Nephrocalcinosis in Pseudohypoparathyroidism: Is Screening Necessary?

The prevalence of nephrocalcinosis in persons with pseudohypoparathyroidism has not been systematically examined. We conducted a retrospective study of renal imaging and biochemical results in 19 patients with pseudohypoparathyroidism with 49 imaging assessments. No cases of nephrocalcinosis were identified. Routine screening for nephrocalcinosis in pseudohypoparathyroidism may not be necessary.

https://ift.tt/2How1fM

Survival of Patients With Multiple Intracranial Metastases Treated With Stereotactic Radiosurgery: Does the Number of Tumors Matter?

imageBackground: Defining prognostic factors is a crucial initial step for determining the management of patients with brain metastases. Randomized trials assessing radiosurgery have commonly limited inclusion criteria to 1 to 4 brain metastases, in part due to multiple retrospective studies reporting on the number of brain metastases as a prognostic indicator. The present study reports on the survival of patients with 1 to 4 versus ≥5 brain metastases treated with radiosurgery. Methods: We evaluated a retrospective multi-institutional database of 1523 brain metastases in 507 patients who were treated with radiosurgery (Gamma Knife or Cyberknife) between 2001 and 2014. A total of 243 patients were included in the analysis. Patients with 1 to 4 brain metastases were compared with patients with ≥5 brain metastases using a standard statistical analysis. Cox hazard regression was used to construct a multivariable model of overall survival (OS). To find covariates that best separate the data at each split, a machine learning technique Chi-squared Automated Interaction Detection tree was utilized. Results: On Pearson correlation, systemic disease status, number of intracranial metastases, and overall burden of disease (number of major involved organ systems) were found to be highly correlated (P

https://ift.tt/2HRV0sJ

Retrospective Analysis of Cisplatin Nephrotoxicity in Patients With Head and Neck Cancer Receiving Outpatient Treatment With Concurrent High-dose Cisplatin and Radiotherapy

imageObjectives: Cisplatin remains the pivotal chemotherapy in squamous cell carcinoma of the head and neck (SCCHN), with nephrotoxicity considered the dose-limiting toxicity. The purpose of our study was to propose an outpatient high-dose cisplatin protocol aimed at preventing nephrotoxicity and to analyze the results of its utilization in patients with SCCHN treated with concurrent radiotherapy. Materials and Methods: We retrospectively evaluated 82 SCCHN patients treated with outpatient high-dose cisplatin concurrent with radiotherapy at our institution. Acute kidney injury (AKI) and chronic kidney disease were defined by Kidney Disease Improving Global Outcomes criteria. Associated factors were identified using analysis of covariance models for categorical variables and adjusted Pearson correlations for continuous variables. Results: The incidence of AKI during treatment was 34.2%. With a median follow-up of 25.7 months, the average decrease in estimated glomerular filtration rate was 12.57 mL/min/1.73 m2 (SD=18.58). At 1 year and at last follow-up, 5.4% and 4.4% of patients had estimated glomerular filtration rate

https://ift.tt/2F8dW3D

Targeted Prostate Biopsy Gleason Score Heterogeneity and Implications for Risk Stratification

imageObjectives: To quantify Gleason score (GS) heterogeneity within multiparametric magnetic resonance imaging (MRI)-targeted prostate biopsies and to determine impact on National Comprehensive Cancer Network (NCCN) risk stratification. Methods: An Institutional Review Board-approved retrospective study was performed on men who underwent Artemis (MRI-transrectal–ultrasound fusion) targeted biopsy (TB) for suspected prostate cancer between 2012 and 2015. Intratarget heterogeneity was defined as a difference in GS between 2 cores within a single target in patients with ≥2 positive cores. Prostate specific antigen, maximum tumor diameter, apparent diffusion coefficient, MRI suspicion score, prostate volume, systematic biopsy (SB) GS, and T-stage were analyzed for correlation with heterogeneity. Changes in NCCN risk based on high versus low GS on TB, SB alone, and SB+TB were compared. Results: Fifty-three patients underwent TB of 73 suspected lesions. Seventy percent (51/73) had ≥2 positive cores, thus meeting inclusion criteria for heterogeneity analysis. Fifty-five percent (28/51) of qualifying targets showed GS heterogeneity. None of the evaluated factors showed a significant relationship with heterogeneity. NCCN low-risk, intermediate-risk, and high-risk groups were 30%, 49%, and 21%, respectively, with SB alone. Adding low GS TB to SB resulted in 17%, 55%, 28% in each risk group, while using high GS+SB resulted in 4%, 54%, and 42%. Overall, the addition of TB resulted in higher NCCN risk groups in 38% of cases. Conclusions: Over half of multiparametric MRI-defined targets demonstrated GS heterogeneity. The addition of high GS from TB leads to risk inflation compared with using SB alone. Further research is needed on how to integrate these findings into current risk stratification models and clinical practice.

https://ift.tt/2HUL0Pn

Phase I Trial Using Induction Ciplatin, Docetaxel, 5-FU and Erlotinib Followed by Cisplatin, Bevacizumab and Erlotinib With Concurrent Radiotherapy for Advanced Head and Neck Cancer

imageObjectives: Bevacizumab (avastin) and erlotinib (tarceva) had shown early clinical activity against head and neck cancer (HNC). We initiated a phase I trial of induction cisplatin, docetaxel, 5-fluorouracil and erlotinib (TPF-E) followed by cisplatin, bevacizumab and erlotinib (PA-E) with radiotherapy (XRT) for advanced HNC. The goal was to determine maximum tolerated erlotinib dose. Methods: Eligible patients had stage IVA or higher HNC with good performance status, hematologic, and renal reserve. Two cycles of induction TPF-E were administered. XRT was administered with concurrent weekly cisplatin and bevacizumab every 2 weeks. Initial erlotinib dose was 50 mg daily from start of induction chemotherapy until radiotherapy completion. Erlotinib dose escalations to 100 and 150 mg were planned. Results: Thirteen patients with previously untreated locoregional disease (11 patients) or oligometastatic (2 patients) HNC were enrolled. Totally, 11 of 13 patients completed XRT as planned. Four of 8 patients in cohort 1 (erlotinib 50 mg), 3 of 4 patients in cohort 2 (100 mg), and 0 of 1 patients in cohort 3 (150 mg) completed the regimen. Two patients had significant gastrointestinal complications (bleeding and perforation), and 1 had dose-limiting diarrhea. Maximum tolerated dose was reached at 50 mg erlotinib. At median 23.4 months follow-up, 5 patients (38%) have no evidence of disease, and 2 (15%) have stable but measurable disease. Conclusions: Erlotinib in combination with induction TPF followed by erlotinib, cisplatin, and bevacizumab with XRT is active but toxic. Gastrointestinal toxicities partly caused high rates of study withdrawal. All doses studied in this protocol caused unexpected toxicities and we do not recommend advancement to phase II.

https://ift.tt/2HmGXKF

Comparison of Demographics, Tumor Characteristics, and Survival Between Pancreatic Adenocarcinomas and Pancreatic Neuroendocrine Tumors: A Population-based Study

imageObjective: The objective of this study is to compare the incidence, demographics, tumor characteristics, and survival between patients with pancreatic neuroendocrine tumors (PNETs) and pancreatic adenocarcinomas. Materials and Methods: Between 2004 and 2012, all cases of pancreatic adenocarcinomas and PNETs were extracted from the population-based cancer registries of the Surveillance Epidemiology and End Results program. To identify the cases, a combination of topographical and histology codes based on ICD-O-3 were used. Incidence, demographics, tumor characteristics, and survival was then compared between these 2 histologic subtypes of pancreatic cancer. Results: A total of 57,688 patients with pancreatic cancer were identified, of which 53,753 (93%) had pancreatic adenocarcinoma and 3935 (7%) had PNET. The overall age-adjusted incidence of PNETs between 2004 and 2012 was 0.52 per 100,000 per year, whereas that for pancreatic adenocarcinomas during the same period was 7.34 per 100,000 per year. PNETs had a significantly younger median age at diagnosis (61 vs. 69 y). A significant proportion of PNETs were diagnosed at stage I (20.5% vs. 6.0%) and were well differentiated (32.8% vs. 4.5%) compared with adenocarcinomas. Five-year cause-specific survival was 51.3% and 5.0% for PNETs and pancreatic adenocarcinomas, respectively. In multivariate analysis, pancreatic adenocarcinomas had a hazard ratio for death of 4.02 (95% confidence interval, 3.79-4.28) when compared with PNETs. Conclusions: PNETs present with favorable features such as higher proportion of early-stage tumor, higher proportion of well differentiated tumors, and younger age at diagnosis. PNETs have a significantly better survival than pancreatic adenocarcinomas even after adjusting for age, sex, race, site, grade, and stage.

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Locally Advanced Cervical Cancer: Outcomes With Variable Adherence to Treatment

imageObjective: Adherence to treatment regimen and schedule is recommended to improve control of disease and overall survival (OS) in locally advanced cervical cancer. However, treatment-related toxicities and patient and physician factors all impact timely completion of treatment. We sought to correlate adherence to treatment plan with survival and toxicities of patients treated for locally advanced cervical cancer. Materials and Methods: A retrospective review of patients treated for advanced cervical cancer at our institution between 2003 and 2011 was performed. Demographics, clinicopathologic variables, treatment, and disease outcomes were collected. Endpoints of disease outcome were disease-free survival and OS. Statistical analyses were performed using the Kaplan-Meier method, log-rank test, and Cox regression analysis. Results: A total of 162 patients met the inclusion criteria and were included in study analysis. A total of 95% of patients were treated with both radiation and concurrent chemotherapy. Mean radiation dose to point A was 72 Gy. In total, 77% had complete response to primary therapy. Severe (grade 3/4) late radiation toxicities were seen in 10.5% of patients. Stage and total radiation dose to point A were significant predictors of survival for the entire cohort. Among patients receiving at least 72 Gy and brachytherapy, duration of treatment was significantly associated with both disease-free survival and OS. Conclusions: Adherence to both optimal treatment time and radiation dose is significantly associated with improved survival. Total radiation dose is an independent predictor of survival among patients with locally advanced cervical cancer.

https://ift.tt/2F8tQLb

Patient-reported Adherence to Adjuvant Aromatase Inhibitor Therapy Using the Morisky Medication Adherence Scale: An Evaluation of Predictors

imageObjectives: Endocrine therapy is part of standard adjuvant therapy for patients with hormone receptor-positive breast cancer and has been shown to improve recurrence-free and overall survival. However, adherence to endocrine therapy is suboptimal and is difficult to measure. In this study we evaluate the feasibility of using the Morisky Medication Adherence Scale (MMAS) to assess patient adherence to aromatase inhibitor (AI) therapy. Methods: Patients with stage 1 to 3, hormone receptor-positive breast cancer receiving adjuvant AI therapy were prospectively enrolled on an Institutional Review Board approved protocol. The MMAS questionnaire was administered to each patient and adherence was measured. Information on duration of AI therapy, patient and tumor characteristics, and treatment was collected. A multivariable logit model approach was utilized to evaluate potential barriers to adherence. Results: Between 2011 and 2014, 100 patients were enrolled. The distribution of adherence levels was 13% low, 37% medium, and 50% high. High adherence was reported more frequently in white women (58%), patients with stage 2 and 3 disease (54%), and patients who did not receive chemotherapy (62%). Multivariable analysis demonstrated that higher adherence was more likely in white women compared with African American women (estimated odds ratio=2.8). Conclusions: Using the MMAS, only 50% of women with stage 1 to 3 breast cancer reported high adherence to AI therapy, consistent with other reports showing suboptimal adherence to adjuvant endocrine therapy. The MMAS allows for the rapid assessment of adherence to oral adjuvant endocrine therapy and is valuable in a busy clinical setting.

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Utilization of Postoperative Chemoradiotherapy Among Women in the United States With High-risk Cervical Cancer

imageObjective: Prospective randomized data demonstrates that chemoradiotherapy (CRT) improves overall survival in women with high-risk pathologic features following radical hysterectomy. Despite this, not all high-risk patients receive adjuvant CRT and the patterns of care in this patient population are unknown. We sought to investigate the rates of adjuvant therapy utilization through analysis of the National Cancer Database. Materials and Methods: The National Cancer Database was queried for women with cervical cancer treated initially with hysterectomy from 2002 to 2012. Patients without high-risk pathologic features were excluded: pN+, positive surgical margins, and parametrial invasion (Peters' criteria). Among the 5947 evaluable patients, univariable analysis and multivariable analysis were performed to investigate potential factors associated with CRT utilization and overall survival following diagnosis. Results: Adjuvant CRT was performed in 41.8% of women and adjuvant radiotherapy, chemotherapy, and no adjuvant therapy was utilized in 9.8%, 23.6%, and 24.8% of women, respectively. On multivariable analysis, CRT utilization was associated with younger age, race, lower facility volume, pN+, parametrial invasion, and a negative surgical margin. Residence distance to treating facility, year of diagnosis, household income, insurance status, and facility type did not predict for CRT utilization. Conclusions: Despite level I evidence supporting its use, less than half of women in this large US cohort with high-risk cervical cancer received adjuvant CRT. Use of adjuvant CRT for women did not significantly increase between 2002 and 2012. Patient age, race, and pathologic risk factors were associated with use of adjuvant CRT.

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Perioperative Mortality in Nonelderly Adult Patients With Cancer: A Population-based Study Evaluating Health Care Disparities in the United States According to Insurance Status

imageObjectives: The purpose of this study was to evaluate whether insurance status predicts for perioperative mortality (death within 30 d of cancer-directed surgery) for the 20 most common surgically treated cancers. Methods: The SEER database was examined for the 20 most common surgically resected cancers and included nonelderly adults, aged 18 to 64 years. The database was queried from 2007 to 2011, with a total of 506,722 patients included in the analysis. Results: Insurance status for all patients were the following: non-Medicaid insurance (83%), any Medicaid (10%), uninsured (4%), and unknown (3%). In univariate analyses, predictors for perioperative mortality included insurance status (P

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Secondary Surgery Versus Chemotherapy for Recurrent Ovarian Cancer

imageObjective: The best course of treatment for recurrent ovarian cancer is uncertain. We sought to determine whether secondary cytoreductive surgery for first recurrence of ovarian cancer improves overall survival compared with other treatments. Materials and Methods: We assessed survival using Surveillance, Epidemiology and End Results-Medicare data for advanced stage ovarian cancer cases diagnosed from January 1, 1997 to December 31, 2007 with survival data through 2010 using multinomial propensity weighted finite mixture survival regression models to distinguish true from misclassified recurrences. Of 35,995 women ages 66 years and older with ovarian cancer, 3439 underwent optimal primary debulking surgery with 6 cycles of chemotherapy; 2038 experienced a remission. Results: One thousand six hundred thirty-five of 2038 (80%) women received treatment for recurrence of whom 72% were treated with chemotherapy only, 16% with surgery and chemotherapy and 12% received hospice care. Median survival of women treated with chemotherapy alone, surgery and chemotherapy, or hospice care was 4.1, 5.4, and 2.2 years, respectively (P

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Vulvar Recurrences After Intensity-modulated Radiation Therapy for Squamous Cell Carcinoma of the Anus

imageObjectives: The objective is to determine localregional control (LRC), distant metastasis free survival, disease-free survival, overall survival (OS), and toxicity for patients with squamous cell carcinoma of the anus treated with definitive chemotherapy and intensity-modulated radiation therapy (IMRT). Materials and Methods: We conducted a retrospective review of patients treated using IMRT for squamous cell carcinoma of the anus at our institution since 2005. Patients with local recurrences were identified and reviewed. The Kaplan-Meier curves were used for LRC and OS. Results: From 2005 to 2014, 52 patients were treated with IMRT-based chemoradiation for squamous cell carcinoma of the anus. Median dose to the primary tumor was 54 Gy. LRC, distant metastasis free survival, OS, and disease-free survival were 92.3%, 88.5%, 86.5%, and 84.6%, respectively, with a median follow-up of 20 months. Two local failures occurred at the anal primary site and 2 in the vulva. Despite subsequent palliative radiotherapy and chemotherapy, neither patient with a vulvar recurrence achieved disease control. Conclusions: In a cohort of patients treated with IMRT-based chemoradiation, 2 vulvar recurrences were identified within the avoided external genitalia despite limited recurrence rates within the cohort overall. This experience suggests that for patients with a locally advanced primary tumor and bulky bilateral inguinal or pelvic disease, the in-transit vulvar dermal lymphatics may be at risk for subclinical involvement and subsequent recurrence. If substantiated by a similar pattern of recurrence at other institutions, the external genitalia may need to be reclassified from an avoidance structure to a clinical treatment volume in patients with locally advanced anal cancer.

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Malignant Peripheral Nerve Sheath Tumors: A Single Institution’s Experience Using Combined Surgery and Radiation Therapy

imagePurpose: The purpose of this study is to investigate local control (LC), survival outcomes, and associated prognostic factors for patients with malignant peripheral nerve sheath tumors (MPNSTs) treated with combined surgery and radiation therapy (RT). Methods: We reviewed the medical records of 71 consecutive patients treated with surgery and RT for localized MPNST between 1965 and 2012. Preoperative RT was used to treat 23 patients (32%) to a median dose of 50 Gy (range, 50 to 60 Gy), whereas 48 (68%) received postoperative RT to a median dose of 64 Gy (range, 45 to 70 Gy). Results: Median follow-up for living patients was 118 months (range, 21 to 512 mo). The 5-year LC, distant metastatic free survival, and disease-specific survival rates were 84%, 62%, and 66%, respectively. To identify predictors of outcome, several multivariate models were constructed: (1) positive/uncertain surgical margin status was the only factor adversely associated local relapse at 5 years (28% vs. 5% for negative margins; P=0.02; hazard ratios 5.92; 95% confidence interval, 1.3-27.4). (2) No factors were significantly associated with distant metastatic free survival. Of the 35 patients (49%) who sustained disease relapse, only 3 were ultimately salvaged. Only 2 patients had grade 2 late toxicities (necrosis, fibrosis) based on Common Terminology Criteria for Adverse Events version 4.03 criteria, and 1 patient had grade 1 edema. Conclusions: Combination therapy with surgery and RT provides favorable LC. Distant recurrences, however, continue to be challenging with limited salvage success at the time of relapse.

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A Pooled Analysis of Biochemical Failure in Intermediate-risk Prostate Cancer Following Definitive Stereotactic Body Radiotherapy (SBRT) or High-Dose-Rate Brachytherapy (HDR-B) Monotherapy

imageObjectives: To investigate biochemical relapse-free survival (BRFS) in men with National Comprehensive Cancer Network-defined intermediate-risk prostate cancer (PC) treated with either stereotactic body radiotherapy (SBRT) or high-dose-rate brachytherapy (HDR-B) monotherapy. Materials and Methods: A retrospective, multi-institutional analysis of 437 patients with intermediate-risk PC treated with SBRT (N=300) or HDR-B (N=137) was performed. Men who underwent SBRT were treated to 35 to 40 Gy in 4 to 5 fractions. A total of 95.6% who underwent HDR-B were treated to 42 Gy in 6 fractions. Baseline patient characteristics were compared using a T test for continuous variables and the Mantel-Haenszel χ2 metric or Fisher exact test for categorical variables. Kaplan-Meier curves were generated to estimate 5-year actuarial BRFS. Multivariate analysis using a Cox proportional-hazards model was used to evaluate factors associated with biochemical failure. Results: The mean age at diagnosis was 68.4 (SD±7.8) years. T-category was T1 in 63.6% and T2 in 36.4%. Mean initial prostate-specific antigen was 7.4 (SD±3.4) ng/mL. Biopsy Gleason score was ≤3+4 in 82.8% and 4+3 in 17.2%. At a median of 4.1 years of follow-up, the BRFS rate (Phoenix definition) was 96.3%, with no difference when stratifying by treatment modality or biologically equivalent dose (BED1.5). On multivariate analysis, age (hazard ratio 1.08, P=0.04) and biopsy Gleason score (hazard ratio 2.48, P=0.03) were significant predictors of BRFS. Conclusions: With a median follow-up period of 4 years, SBRT and HDR-B monotherapy provide excellent BRFS in intermediate-risk PC. Longer-term follow-up is necessary to determine the ultimate efficacy of these hypofractionated approaches, but they appear promising relative to standard fractionation outcomes.

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Disparity in Outcomes for Adolescent and Young Adult Patients Diagnosed With Pediatric Solid Tumors Across 4 Decades

imageObjective: Cancer mortality is a leading cause of disease-related death in the adolescent and young adult (AYA) population. Compared with older and younger patients, AYA patients often experience worse cancer-specific outcomes. Here, we compare AYA and pediatric overall survival (OS) in the most common pediatric extracranial solid tumors. Materials and Methods: Using the US Surveillance, Epidemiology, and End Results database, we studied patients (age, 0 to 39 y) diagnosed with Ewing sarcoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, and Wilms tumor. Results: A total of 12,375 patients (age, 0 to 39 y) were diagnosed between 1973 and 2010 (8247 pediatric and 4128 AYA patients). AYA patients with rhabdomyosarcoma and Ewing sarcoma were more likely to present with metastatic disease. OS was significantly worse in the AYA cohort for all tumor types (P

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Impact of Staging With Positron-emission Tomography (PET) and Comorbidities on Management and Survival of American Veterans With Stage I-III Non–Small Cell Lung Cancer

imageObjectives: The extent of whether staging by fluorodeoxyglucose positron-emission tomography (PET) impacts outcomes in American Veterans with stage I-III non–small-cell lung cancer (NSCLC) is unknown. We investigated impact of fluorodeoxyglucose PET staging and age-adjusted comorbidities (AACs) on management and survival of NSCLC in this group. Materials and Methods: We performed a retrospective review to identify with NSCLC who underwent initial PET scan and received care at the Ann Arbor Veterans Hospital between 2005 and 2010. Survival outcomes were estimated by Kaplan-Meier methods, quantile regressions, and Cox proportional hazards models, after accounting for age at diagnosis, sex, AAC, and initial treatment. Results: The number of PET scans increased from 0 in 2005 to 66 in 2010. There were 170 men, 4 women, median age 64 years. Median AAC score was 4. In CS I (n=54), initial PET upstaged 5 patients. Median survival for no change in PET stage was 27.43 versus 67 months for upstaged patients (P=0.034). For CS II (n=15), initial PET scan upstaged 1 patient. Median survival for no change in PET stage was 16.53 versus 2.8 months for upstaged patient (P=0.335). For CS III (n=104), PET scan upstaged 20 patients. Median survival for no change in PET stage was 13.3 versus 3.8 months for upstaged patients (P=0.016). Conclusions: PET scans resulted in upstaging in 15% in CS I-III NSCLC. AAC scores dictated therapy decisions and outcomes more than PET staging. Veterans had lower 5-year survival rates (26.3%, 15.8%/13.4%) compared with 53% and 27% in age/sex/time-period matched SEER data for stage I-II/III NSCLC.

https://ift.tt/2HVbUa4

Experimental Investigation of the Flow Structure over a Delta Wing Via Flow Visualization Methods

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Here, we present a protocol to observe unsteady vortical flows over a delta wing using a modified smoke flow visualization technique and investigate the mechanism responsible for the oscillations of the leading-edge vortex breakdown locations.

https://ift.tt/2HOLokS

Grip Strength Indicative of Cognition in Major Depression

MONDAY, April 23, 2018 -- For individuals with major depression and bipolar disorder, grip strength is positively associated with cognition, according to a study published online April 18 in JAMA Psychiatry. Joseph Firth, Ph.D., from the University...

https://ift.tt/2qSSdaM

Birch Pollen-Related Foods Can Trigger Dermatitis Reactions

MONDAY, April 23, 2018 -- In patients with atopic dermatitis (AD) and birch pollen allergy, consumption of birch pollen-related foods is associated with allergic reactions and deterioration of AD, according to a study published online April 13 in...

https://ift.tt/2HpmHMz

Pediatric Exposures to Liquid Nicotine Down From 2015 to 2016

MONDAY, April 23, 2018 -- Pediatric exposures to liquid nicotine decreased from 2015 to 2016, but exposure still poses serious risks to children, according to a study published online April 23 in Pediatrics. Preethi Govindarajan, from the Research...

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Too Few Adults Taking Epilepsy Meds Have Seizure Control

MONDAY, April 23, 2018 -- Although most adults with epilepsy report taking epilepsy medication, less than half of those report having their seizures controlled, according to research published in the April 20 issue of the U.S. Centers for Disease...

https://ift.tt/2HmlMfN

Choroidal Thickness Changes in Patients With Untreated DM

MONDAY, April 23, 2018 -- The choroidal thickness changes in patients with untreated diabetes mellitus over time, according to a study published online April 14 in Clinical & Experimental Ophthalmology. Hiroaki Endo, from Teine Keijinkai...

https://ift.tt/2qSS8E0

Belimumab Aids Anti-dsDNA+, Hypocomplementemic Lupus

MONDAY, April 23, 2018 -- Weekly belimumab is associated with greater benefit than placebo for patients with hypocomplementemic/anti-double stranded (ds)DNA-positive systemic lupus erythematosus (SLE), according to a study published online April 18...

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Cancer Screening More Likely After a Previous False Positive

MONDAY, April 23, 2018 -- Patients who previously had a false-positive breast or prostate cancer screening test result are more likely to have future screenings, according to a study published online April 23 in Cancer. Glen B. Taksler, Ph.D., from...

https://ift.tt/2qSS7zW

Age- and Weight-Based Screening Identifies Half With Prediabetes

MONDAY, April 23, 2018 -- Targeted diabetes screening based only on age and weight criteria will identify approximately half of U.S. adults with dysglycemia, according to a study published online April 12 in the Journal of General Internal...

https://ift.tt/2Hn25oc

Phone App Linked to Improved Psoriasis Treatment Adherence

MONDAY, April 23, 2018 -- A smartphone app is associated with improved short-term adherence to a cutaneous foam treatment for psoriasis, according to a study published online April 14 in the British Journal of Dermatology. Mathias Tiedemann...

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Celecoxib Lowers Opioid Use Post Head & Neck Cancer Surgery

MONDAY, April 23, 2018 -- For patients undergoing head and neck cancer (HNC) surgery, perioperative use of celecoxib is associated with reduced use of opioids after surgery, according to a study published online April 18 in JAMA Otolaryngology-Head...

https://ift.tt/2Hn23N6

An In Ovo Model for Testing Insulin-mimetic Compounds

In this study, we describe an in-ovo system as a promising tool to test insulin-mimetic compounds in a living organism. The main advantages include adequate throughput rates and acceptable costs, which enable the identification of phytochemicals with insulin-mimetic properties.

https://ift.tt/2qUHOeK

Dynamic characteristics of oxygen consumption



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Folate promotes S-adenosyl methionine reactions and the microbial methylation cycle and boosts ruminants production and reproduction

Folate has gained significant attention due to its vital role in biological methylation and epigenetic machinery. Folate, or vitamin (B9), is only produced through a de novo mechanism by plants and micro-organism...

https://ift.tt/2KaYFTu

Long-term music training modulates the recalibration of audiovisual simultaneity

Abstract

To overcome differences in physical transmission time and neural processing, the brain adaptively recalibrates the point of simultaneity between auditory and visual signals by adapting to audiovisual asynchronies. Here, we examine whether the prolonged recalibration process of passively sensed visual and auditory signals is affected by naturally occurring multisensory training known to enhance audiovisual perceptual accuracy. Hence, we asked a group of drummers, of non-drummer musicians and of non-musicians to judge the audiovisual simultaneity of musical and non-musical audiovisual events, before and after adaptation with two fixed audiovisual asynchronies. We found that the recalibration for the musicians and drummers was in the opposite direction (sound leading vision) to that of non-musicians (vision leading sound), and change together with both increased music training and increased perceptual accuracy (i.e. ability to detect asynchrony). Our findings demonstrate that long-term musical training reshapes the way humans adaptively recalibrate simultaneity between auditory and visual signals.



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The Purge

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by Howard Greller       An absurdists' take on whole bowel irrigation Throw out your conceited opinions, for it is impossible for a person to begin to learn what he thinks he already knows. – Epictetus, Discourses, 2.17.1 A consensus means that everyone agrees to say collectively what no one believes individually. – Abba […]

EMCrit Project by Tox & Hound.



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An In Vivo Murine Sciatic Nerve Model of Perineural Invasion

We describe an in vivo murine model of perineural invasion by injecting syngeneic pancreatic cancer cells into the sciatic nerve. The model allows for quantification of the extent of nerve invasion, and supports investigation of the cellular and molecular mechanisms of perineural invasion.

https://ift.tt/2qSzCwo

Mom wins AED for school after son’s death at hockey practice

In addition to creating the 4AlecFoundation to raise awareness for undetected heart disease, Stephanie Kornet also won a national contest by sharing her son's story

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Webinar to be hosted on improving patient care with data

NHTSA's Office of EMS will discuss how two EMS agencies are using data to not only improve performance, but demonstrate value

https://ift.tt/2F9R7N7

The 2017 WHO classification of pituitary adenoma: overview and comments

Abstract

The fourth edition of the World Health Organization classification of endocrine tumors has been recently published. There are two critical changes to the classification for pituitary adenomas in this edition. One is that the term "atypical adenoma," which was characterized based on highly proliferative properties to predict adenomas that carry a poor prognosis, was completely eliminated due to the lack of definitive evidence. The other change is the introduction of more precise cell lineage-based classification of pituitary adenoma that is defined based on lineage-specific transcription factors and hormones produced. Accordingly, null cell adenomas have been re-defined as those that show completely negative immunostaining either for hormones or for adenohypophyseal transcription factors. In this review, we summarized these changes in the WHO classification and discussed topics that are relevant to the diagnosis of actual cases: immunohistochemical study for pituitary endocrine tumors, predictive markers for malignant potential, the relationship between somatotroph adenomas and somatostatin analogs, and characteristics of plurihormonal adenomas.



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Pulmonary mass: never judge a book by its cover

Summary

Background

This case shows that a tumor can present in an uncommon way. When dealing with pulmonary masses, tissue remains the most important issue.

Clinical presentation

We present the case of a 71-year-old woman with a mass of more than 10 cm in the left lung. Pulmonary CT scan and PET scan confirmed this with also revealing mediastinal, thoracic and paravertebral invasion, without extrathoracic metastatic lesions. Bronchoscopic evaluation and ultrasound guided transbronchial needle aspiration could not yield a diagnosis. Because of rapid clinical deterioration, new imaging was performed, showing a cavitary lesion with air-fluid level in the tumor. Extensive microbiological work-up remained negative.

Intervention

To yield a pathological diagnosis, we performed a thoracotomy, revealing a polymorphic lymphoid infiltrate with scattered large atypical B-cells infected with Epstein-Barr virus, vasculitis and granulomatosis leading to a diagnosis of Lymphomatoid Granulomatosis. The patient received 6 cycles of R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Methylprednisolone), 2 doses of Rituximab monotherapy, 4 doses of intrathecal Methotrexate and consolidation radiotherapy with a complete response.

Conclusion

Lymphomatoid granulomatosis (LYG) is a rare pulmonary disease, which should be included in the differential diagnosis of 'a pulmonary mass'. This case emphasizes the need for tissue acquisition.



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Severe hypoglycaemia in diabetic patients in Pre-hospital and Emergency Department care: a cross-sectional survey

We aimed to characterize hypoglycaemia episodes and patients examined by a Pre-hospital Medical Emergency Unit (PH) and in the Emergency Department (ED) of our hospital.

https://ift.tt/2HlANdQ

Nasal carriage, risk factors and antimicrobial susceptibility pattern of methicillin resistant Staphylococcus aureus among healthcare workers in Adigrat and Wukro hospitals, Tigray, Northern Ethiopia

The aim of this study was to determine nasal carriage, risk factors and antimicrobial susceptibility pattern of methicillin resistant Staphylococcus aureus among health care-workers of Adigrat and Wukro hospitals...

https://ift.tt/2HGRJiq

Cavernous Nerve Stimulation and Recording of Intracavernous Pressure in a Rat

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This study describes a simplified surgical procedure and technique for performing cavernous nerve stimulation with the isolation of the nerve-electrode complex using silicone glue and intracavernous pressure measurement.

https://ift.tt/2qSC0D8

Novel sequencing technologies to support industrial biotechnology

Abstract
Industrial biotechnology develops and applies microorganisms for the production of bioproducts and enzymes with applications ranging from food and feed ingredients and processing to bio-based chemicals, biofuels and pharmaceutical products. Next generation DNA sequencing technologies play an increasingly important role in improving and accelerating microbial strain development for existing and novel bio-products via screening, gene and pathway discovery, metabolic engineering, and additional optimization and understanding of large-scale manufacturing. In this mini-review, we describe novel DNA sequencing and analysis technologies with a focus on applications to industrial strain development, enzyme discovery and microbial community analysis.

https://ift.tt/2qSQnGI

Microbial communities in bakken region produced water

Abstract
The Bakken Shale has become one of the United States' most important oil and gas producing regions. This study examined the microbiology and geochemical characteristics of Bakken region produced water from 17 well sites sampled from the three-phase separator and produced water holding tank over a six-month time frame. Produced water samples had high total dissolved solids (TDS) (220,000 mg/L – 350,000 mg/L) and low dissolved organic carbon (DOC) concentrations (41 mg/L – 132 mg/L). Microbial abundances varied between 101–104 16S rRNA gene copies/mL, approximately four orders of magnitude below those observed for produced waters from other hydraulic fracturing regions. The most abundant bacterial orders found in produced water samples were Bacillales, Halanaerobiales, and Pseudomonadales, consistent with observations from other unconventional resource plays. Our observations suggest temporal community structuring, as produced waters sampled early in our sampling period were dominated by Halanaerobiales, and produced waters sampled at the remaining winter sampling time points were characterized by high relative abundances of Bacillales and Pseudomonadales. Data from this study extends the current available knowledge of the microbiology and chemistry associated with produced water from the Bakken region and provides insights into microbial community dynamics in hypersaline subsurface fluids.

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Genotypic variation in Pinus radiata responses to nitrogen source are related to changes in the root microbiome

Abstract
Variation in traits within a plant species contributes to differences in soil physicochemistry and rhizosphere microbial communities. However, how intraspecific variation in plant responses to nitrogen (N) shapes these communities remains unclear. We studied whether plant responses to organic and inorganic N forms vary among genotypes, and if these responses were associated with variation in root-associated communities. We investigated how the root microbiomes of two Pinus radiata genotypes were altered by two years of N-fertilisation in field conditions. We characterised rhizosphere bacterial and fungal communities, as well as root-associated fungal communities, of trees receiving yearly additions of NH4NO3 or L-arginine, and control trees. We also measured plant traits and rhizosphere soil physicochemical properties. Two main findings emerged: (1) N form and tree genotype affected soil physicochemical properties as well as plant measures, and these responses were associated with variation in microbial communities, and (2) rhizosphere and root-associated communities differed in their responses to N form and host genotype. Our results suggest that N forms have different influences on N and carbon dynamics at the plant-soil interface by inducing root-mediated responses that are associated with shifts in the root microbiome such that communities more closely associated with roots are more sensitive to genotype-specific responses.

https://ift.tt/2qRzblJ

Lysosomal damage after spinal cord injury causes accumulation of RIPK1 and RIPK3 proteins and potentiation of necroptosis

Lysosomal damage after spinal cord injury causes accumulation of RIPK1 and RIPK3 proteins and potentiation of necroptosis

Lysosomal damage after spinal cord injury causes accumulation of RIPK1 and RIPK3 proteins and potentiation of necroptosis, Published online: 23 April 2018; doi:10.1038/s41419-018-0469-1

Lysosomal damage after spinal cord injury causes accumulation of RIPK1 and RIPK3 proteins and potentiation of necroptosis

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Cell-Free Circulating Methylated SEPT9 for Noninvasive Diagnosis and Monitoring of Colorectal Cancer

Identification of early-stage tumor and monitoring therapeutic efficacy and recurrence or metastasis of colorectal cancer (CRC) are urgently warranted for improving the outcome of CRC patients and reducing the disease-related mortality. In this study, we evaluated the diagnostic value of cell-free circulating methylated SEPT9 (mSEPT9) for CRC and beyond CRC and examined the potentiality of mSEPT9 in assessing therapeutic efficacy and monitoring recurrence of CRC. Our results confirmed the favorable diagnostic value of plasma mSEPT9 for CRC, with a sensitivity of 61.22% (95% confidence interval (CI): 51.33%–70.27%) and specificity of 93.7% (95% CI: 91.09%–95.57%) using 2/3 algorithm. The positive rate of mSEPT9 in CRC was correlated with tumor size, histological grade, and general histological type (). Beyond CRC, gastric cancer patients also presented a high positive rate of plasma mSEPT9 (70%). The conversions between preoperative and postoperative plasma mSEPT9 reflected the therapeutic efficacy of curatively intended surgery for CRC patients. The persistent positivity of plasma mSEPT9 after surgery (within 7–14 days) was highly associated with impending recurrences or metastases (within one year), with a sensitivity of 100%. Postoperative mSEPT9 status during follow-up also provided valuable indication for CRC recurrence or metastases, with a good consistency (kappa = 0.818, ). Our results verified the reliability of plasma mSEPT9 as a biomarker for noninvasive diagnosis of CRC. More significantly, we revealed its valuable role in appraising CRC therapeutic efficacy and monitoring CRC recurrences or metastases. Further studies with larger sample sizes are needed to verify and elucidate the clinical utility of the promising findings.

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